Antiproliferative protein Tob directly regulates c-myc proto-oncogene expression through cytoplasmic polyadenylation element-binding protein CPEB.

The regulation of mRNA deadenylation constitutes a pivotal mechanism of the post-transcriptional control of gene expression. Here we show that the antiproliferative protein Tob, a component of the Caf1-Ccr4 deadenylase complex, is involved in regulating the expression of the proto-oncogene c-myc. The c-myc mRNA contains cis elements (CPEs) in its 3'-untranslated region (3'-UTR), which are recognized by the cytoplasmic polyadenylation element-binding protein (CPEB). CPEB recruits Caf1 deadenylase through interaction with Tob to form a ternary complex, CPEB-Tob-Caf1, and negatively regulates the expression of c-myc by accelerating the deadenylation and decay of its mRNA. In quiescent cells, c-myc mRNA is destabilized by the trans-acting complex (CPEB-Tob-Caf1), while in cells stimulated by the serum, both Tob and Caf1 are released from CPEB, and c-Myc expression is induced early after stimulation by the stabilization of its mRNA as an 'immediate-early gene'. Collectively, these results indicate that Tob is a key factor in the regulation of c-myc gene expression, which is essential for cell growth. Thus, Tob appears to function in the control of cell growth at least, in part, by regulating the expression of c-myc.

MicroRNA-18a modulates STAT3 activity through negative regulation of PIAS3 during gastric adenocarcinogenesis.

BACKGROUND: MicroRNA (miRNA, miR)-18a is a member of the miR-17-92 cluster, an important locus that is markedly overexpressed in several cancers and associated with cancer development and progression. However, the mechanism of action of the miR-17-92 cluster and its individual miRNAs are largely unknown. METHODS AND RESULTS: In this study, we investigated the expression of the miR-17-92 cluster by in situ hybridisation (ISH) assay and copy-number analysis in gastric tissue microarray (TMA) specimens. We determined that miR-18a was present at higher levels than the other five miRNAs in the cluster. In addition, we identified Protein Inhibitor of Activated Signal Transducer and Activator of Transcription 3 (PIAS3) as a direct target of miR-18a in gastric cancer. miR-18a level was positively correlated with levels of Survivin, Bcl-xL, and c-Myc, which are downstream transcriptional targets of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3-induced transcription can be negatively regulated by PIAS3; consistent with this, PIAS3 level was negatively correlated with levels of Survivin, Bcl-xL, and c-Myc. CONCLUSION: Our findings indicate that miR-18a acts as an oncogene and plays a role in gastric adenocarcinogenesis, at least in part by negatively regulating PIAS3 and thereby modulating expression of STAT3 target genes.

[Huge right atrial myxoma].

Myxomas are account for approximately half of primary cardiac tumors, and 75% cases originate in left atrium. We report our experience of a right atrial myxoma. A 68-year-old woman was referred to us due to anorexia, general fatigue and facial edema. Echocardiogram, computed tomography (CT), magnetic resonance imaging (MRI), and catheter angiocardiogram revealed a huge tumor in right atrium. The tumor was resected completely with the attached right atrial free wall under cardiopulmonary bypass. Pathological examination showed myxomatous tissue. Postoperative course was uneventful. She discharged the hospital on the 37th day after the operation, and is now doing well without any symptoms.

Diurnal change of thyroid-stimulating hormone mRNA expression in the rat pars tuberalis.

Thyroid-stimulating hormone (TSH)-producing cells (TSH cells), which account for a large fraction of the cells in the rat pars tuberalis (PT), have been found to express MT1 melatonin receptor and mammalian clock genes at high densities. Although these findings suggest that TSH production in the rat PT is regulated by melatonin and/or the biological clock, there have been no studies focusing on the diurnal change and regulation mechanism of TSH production in the rat PT. Therefore, in the present study, we examined diurnal changes of in TSH beta and alpha-glycoprotein subunit (alpha GSU) mRNA expression and TSH immunoreactivity (-ir) in the rat PT, and also examined the relationship between melatonin and TSH production in vivo. Both TSH beta mRNA expression and alpha GSU mRNA expression in the PT showed diurnal variations: the expression levels were lowest at the light phase [Zeitgeber time (ZT)4] and high at the dark phase (ZT12 and ZT20). TSH-ir in the PT showed the lowest level at ZT4, as was found for mRNA expression. Interestingly, TSH-ir, which was confined to the Golgi apparatus at ZT4, spread to the cytoplasm, and most of the TSH cells in the PT were uniformly immunostained in the cytoplasm at ZT20. Despite the fact that chronic administration of melatonin suppressed TSH beta and alpha GSU mRNA expression, TSH-ir in the PT was significantly enhanced. These findings results clearly show that there are diurnal changes in TSH expression and accumulation in rat PT-TSH cells and suggest that these fluctuations are regulated by melatonin.

HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination.

An ATM-dependent cellular signal, a DNA-damage response, has been shown to be involved during infection of human immunodeficiency virus type-1 (HIV-1), and a high incidence of malignant tumor development has been observed in HIV-1-positive patients. Vpr, an accessory gene product of HIV-1, delays the progression of the cell cycle at the G2/M phase, and ATR-Chk1-Wee-1, another DNA-damage signal, is a proposed cellular pathway responsible for the Vpr-induced cell cycle arrest. In this study, we present evidence that Vpr also activates ATM, and induces expression of gamma-H2AX and phosphorylation of Chk2. Strikingly, Vpr was found to stimulate the focus formation of Rad51 and BRCA1, which are involved in repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), and biochemical analysis revealed that Vpr dissociates the interaction of p53 and Rad51 in the chromatin fraction, as observed under irradiation-induced DSBs. Vpr was consistently found to increase the rate of HR in the locus of I-SceI, a rare cutting-enzyme site that had been introduced into the genome. An increase of the HR rate enhanced by Vpr was attenuated by an ATM inhibitor, KU55933, suggesting that Vpr-induced DSBs activate ATM-dependent cellular signal that enhances the intracellular recombination potential. In context with a recent report that KU55933 attenuated the integration of HIV-1 into host genomes, we discuss the possible role of Vpr-induced DSBs in viral integration and also in HIV-1 associated malignancy.

Combination chemotherapy with docetaxel and nedaplatin for recurrent esophageal cancer in an outpatient setting.

The purpose of this study was to address the feasibility of combination chemotherapy of docetaxel and nedaplatin for recurrent esophageal cancer patients in an outpatient setting. Patients received docetaxel (30 mg/m(2) intravenously) on day 1 and nedaplatin (40 mg/m(2) intravenously) on day 1 every 2 weeks. In total, 28 patients with recurrent esophageal cancer after the initial treatment (esophagectomy, chemotherapy and/or chemoradiotherapy) were enrolled. Each patient received six cycles of treatment and was evaluated with a computed tomography scan. The percentage of patients who completed this therapy was 60.7%. Complete response and partial response were achieved by 3.6% and 35.7% of patients, respectively. The most frequent toxicities were leukopenia and anemia; non-hematological toxicities were generally mild. There was no treatment-related death. The median survival time and 1-year survival rate were 8.5 months and 15.9%, respectively. This outpatient combination chemotherapy was useful as second-line chemotherapy for recurrent esophageal cancer.

[Open stent-grafting applied with the Matsui-Kitamura stent to a distal arch aneurysm].

An open stent-grafting applied with the Matsui-Kitamura (MK) stent to a distal arch aneurysm is presented herein. The graft using the MK stent at its distal end was successfully inserted into the descending thoracic aorta through a J-shaped sheath-introducer. The major advantages of this stent-graft include its flexibility, shape memory, and small profile when compressed, compared with other devices. This technique may be feasible and clinically effective in the treatment of distal arch aneurysm.

Clinical pharmacokinetics of anti-angiogenic photodynamic therapy with benzoporphyrin derivative monoacid ring-A in dogs having naturally occurring neoplasms.

The aim of this study was to examine the pharmacokinetics of clinically applied benzoporphyrin derivative monoacid ring-A (BPD-MA; Verteporfin), a second-generation photosensitizer, during a trial of photodynamic therapy (PDT) in nine dogs having naturally occurring neoplasms. After injecting BPD-MA at 0.5 mg/kg intravenously, its mean half-life (t1/2) was found to be 8.14 +/- 5.34 h, mean clearance (Cl) 35.13 +/- 9.62 ml/(h kg), the mean value of the volume of distribution (Vc) 0.08 +/- 0.01 l/kg and the mean steady state volume of distribution (Vss) 0.38 +/- 0.31 l/kg respectively. With the exception of a transitional increase in serum alkaline phosphatase activity, no other clinical abnormalities were observed. The t1/2 in dogs with naturally occurring tumours was longer than that in humans, but similar to that in rats. The values of Cl and Vss in dogs having naturally occurring neoplasms were lower than those in humans. It is suggested that the pharmacokinetics of BPD-MA in tumour-bearing dogs would be helpful in determining the protocol of a short drug-light interval PDT with BPD-MA that mainly targets the tumour vasculature.

[Double outlet right ventricle and pulmonary atresia with a birth weight of 1092 g].

A premature infant with double outlet right ventricle and pulmonary atresia with a birth weight of 1092 g is reported. He underwent right modified Blalock-Taussig (RMBT) shunt with an expand-polytetrafluoroethylene (ePTFE) tube of 3.0 mm in diameter between the right subclavian artery and the right pulmonary artery through right thoracotomy. Eleven days later, he had to undergo central shunt between the innominate artery and the main pulmonary trunk due to poor pulmonary blood flow. Soon after the central shunt, severe heart failure occurred due to excessive pulmonary blood flow. RMBT division was performed immediately. He finally attained definitive repair at 17 months of age. Postoperative course was uneventful and he was discharged on the 17th postoperative day.

[Severe tracheal compression resulting from atherosclerotic aortic arch aneurysm; report of a case].

A 70-year-old woman presented with severe respiratory insufficiency similar to an asthma attack. Computed tomography (CT) revealed an atherosclerotic aneurysm (maximum diameter 106 mm) on the aortic arch which resulted in a severe tracheal compression. We performed an aortic arch replacement. After the operation, we tried to manage breathing without a respirator twice without success. We then performed a tracheotomy on the 12th day after operation. The patient could breathe independently on the 19th day after the first operation. Peri-and postoperative respiratory management was difficult but the patient was discharged on the 86th day after operation without further complication.

[De Bakey type I aortic dissection complicating systemic lupus erythematosus; report of a case].

We report a 43-year-old patient of De Bakey type I aortic dissection [DA (I)] with a 2-year-history of systemic lupus erythematosus (SLE). He had had no treatment for SLE before the onset of dissection. Computed tomography (CT) on admission revealed DA (I), and he underwent emergency operation. Since the aortic valve and the left main coronary artery were severely damaged, aortic root replacement was performed. Coronary buttons were prepared in Carrel method and coronary reconstruction was performed in Piehler modification. After surgery, he suffered from repetitive hemolytic anemia. Corticosteroid therapy and rinsed blood transfusion were very effective for anemia. The combination with SLE and DA (I) was rare and this report of successful aortic root replacement is the second literature among English and Japanese papers.

Trigger digits-associated carpal tunnel syndrome: relationship between carpal tunnel release and trigger digits.

Of 875 idiopathic carpal tunnel syndrome (CTS) cases, 101 (11.5%) required trigger digit release operations within three years before and/or after carpal tunnel release (CTR); these 101 cases were investigated, retrospectively. Trigger digit release (TDR) was performed most often after the CTR, especially within three months. Next most common was at the same time as the CTR. The TDR performance rate after CTR was 5.9%. The nerve conduction study (NCS) comparison between trigger digits-associated CTS and isolated CTS showed that pre-operative distal motor latency was significantly more delayed in trigger digits-associated CTS, while there was no evidence of any difference due to age or gender. The difference of operative method (open or endoscopic procedure) did not influence the incidence rate of trigger digits after the CTR. This study suggested that trigger digits-associated CTS has a previously developed wide-ranging narrowing of the flexor tendon sheath.

[Open stent-grafting for a distal aortic arch aneurysm with a endotracheal tube].

An open stent-grafting for a distal aortic arch aneurysm with a endotracheal tube is presented herein. The graft which has a Gianturco Z stent at its distal end was successfully inserted into the descending thoracic aorta through a endotracheal tube without fluoroscopy. This technique might easily deploy the stent-graft without damage of aortic wall compared with other deployment methods.

[Off-pump coronary artery bypass grafting for restenosis after coronary angioplasty in the patient with left main shock syndrome].

A case of left main shock syndrome due to total occlusion of left main trunk was reported. A 65-year-old man with acute myocardial infarction developed cardiogenic shock shortly after admission. An emergency coronary angiogram revealed total occlusion of the left main trunk without collaterals. Immediately, a stent was implanted in the left main trunk and the lesion was successfully improved. However, the left coronary angiogram revealed 90% restenosis of the left main trunk in a coronary angiogram examined 6 months after stent placement. Since the patient suffered from poor cardiac function, off-pump coronary artery bypass grafting (left internal thoracic artery to left descending coronary artery) was successfully performed using an intracoronary shunt. No complications were observed.

[Application of transluminally place endoluminal prosthetic grafts for the treatment of multiple aortic aneurysms].

We have 5 cases with multiple aortic aneurysms who have undergone conventional abdominal aortic replacement with transluminally placed endoluminal prosthetic grafts (TPEGs) into the descending thoracic aorta. Simultaneous operation was done in one patient. A 2-stage operation was done in 4 patients, and the abdominal aortic aneurysm was performed on the first. One patient required urgent surgical intervention to treat migration of a stent-graft. However, there was no hospital death. The mean follow-up interval was 34 months and there were no complications correlated with the procedures. Application of TPEGs for the treatment of multiple aortic aneurysms may be a valuable treatment option.

[Case report of CABG for progressive coronary artery stenosis after 22-year history of Kawasaki disease].

More than 30 years has passed since Kawasaki disease was recognized as an independent disease entity, but the cardiovascular complications of Kawasaki disease are still not well known. We report an 22-year-old woman who underwent triple coronary artery bypass grafting because of a coronary artery aneurysm and multiple coronary artery stenoses, 22 years after the diagnosis of Kawasaki disease. A 2 cm coronary artery aneurysm due to Kawasaki disease was diagnosed when she was 10 years old, when she first presented with the symptom of dyspnea on effort. Since then, she was followed at the outpatient clinic. When she was 19 years old, the first coronary catheterization was performed. Two years later, the second coronary catheterization revealed progression of coronary artery disease. Therefore, coronary artery bypass grafting was performed. This case is rare from the point of view of long-term progression of coronary artery disease.

The expression of dystrophin and alpha1-syntrophin during skeletal muscle regeneration.

The expression of dystrophin and alpha1-syntrophin in rat tibialis anterior muscles were evaluated during a cycle of regeneration after myonecrosis induced by the injection of cardiotoxin. Immunohistochemical studies were performed in cryosections of muscles on days 1, 3, 5, 7, 10, 14, 21 and 28 after injection of cardiotoxin. Western blot analysis was also examined in muscle on days 1, 3, 5, 7, 10, 14, 21 and 28. In immunohistochemical studies, dystrophin was stained weakly at the sarcolemma of some regenerating muscle fibers on day 3, and by day 10 it was stained strongly on almost all regenerating muscle fibers. Alpha1-syntrophin was stained weakly at the sarcolemma of some regenerating fibers on day 5, and by day 14 it was detected on all regenerating muscle fibers. In Western blot analysis, dystrophin (DYS1) and alpha1-syntrophin (alpha1S) were completely absent on day 1. Re-expression of DYS1 and alpha1S was visible by day 5 and accelerated thereafter. The Western blots of DYS1 and alpha1S were densitometrically analyzed on each day. The protein levels on each day were converted to the percentage of the protein level on day 28, which was taken as 100%. From the sequential line based on these data, the following results were obtained on the chronological course of DYS1 and alpha1S. DYS1: 25% of the protein level on day 28 was reached by 3.5 days, 50% was reached by 5.3 days, and 90% was reached by 6.9 days. Alpha1S: 25% of the protein level on day 28 was reached by 4.6 days, 50% was reached by 6.0 days, and 90% was reached by 12.5 days. In this study, DYS1 regenerated earlier than alpha1S at the sarcolemma of regenerating muscle fibers.

Predicting blood transfusion factors in coronary artery bypass surgery.

OBJECTIVE: Blood conservation has become one of the most important issues in cardiac surgery. We clarified preoperative predictors of the need for blood transfusions during coronary artery bypass graft surgery. METHODS: Subjects were 89 patients--66 men (74%) and 23 women (26%) 40 to 84 years old (mean: 66.2 +/- 8.3 years)--undergoing isolated coronary artery bypass surgery from September 1997 to December 1999. Of these, 66 patients (74%) received transfusion during hospitalization and 23 (26%) did not. Nine risk factors detected by univariate study were entered in a multivariate logistic regression model of the relationship between preoperative variables and blood transfusion. RESULTS: Independent predictors were emergency surgery (P = .0023), lower hematocrit (P = .0027), older age (P = .0043), and the presence of peripheral vascular disease (P = .0070). Optimal cutoff of hematocrit for blood transfusion was 39% and age 64 years via receiver-operating characteristics curves based on the relation between sensitivity and specificity. CONCLUSION: Patients older than 64 years with hematocrit less than 39% and/or peripheral vascular disease should be treated routinely using preoperative storage of autologous blood whenever the patient's condition permits. For patients undergoing emergency surgery, further studies are required, including lowering transfusion threshold and using determinants other than hematocrit.

Results of 256 consecutive abdominal aortic aneurysm repairs using extraperitoneal approach.

Two hundred and fifty-six consecutive abdominal aortic aneurysms were repaired using three approaches for extraperitoneal exposure of the aorta and iliac vessels from February 1990 through September 1998. The perioperative mortality rate was 3.1% in 228 elective repairs and 14.3% in 28 ruptured cases. The initial 23 cases were repaired using Sicard's method. The duration of endotracheal intubation was 1.0+/-2.8 h, alimentation initiation was 2.7+/-1.6 days, and narcotic requirements were 1.2+/-1.1 times. Following these initial cases, we employed Williams' method for 192 abdominal aneurysms, however; repeated incisional pain and three cases of deforming bulge led us to avoid dividing muscles. In the last 13 cases, our approach was performed without muscle dividing. The narcotic requirements decreased to 0.3+/-0.7 times. As for postoperative complications, the larger skin incision approach had no shower embolism. However, the shorter skin incision had four cases of shower embolisms, one lymphorrhea and one vascular trauma by the aortic clamp. The extraperitoneal approach offers certain physiologic advantages with minimal disturbance of gastrointestinal and respiratory function. We believe that this method is useful for rapid approach to the proximal aorta in case of emergency. Postoperative wound complications could be prevented via an oblique incision without muscle dividing.