Sphingosylphosphorylcholine is a novel messenger for Rho-kinase-mediated Ca2+ sensitization in the bovine cerebral artery: unimportant role for protein kinase C

Although recent investigations have suggested that a Rho-kinase-mediated Ca2+ sensitization of vascular smooth muscle contraction plays a critical role in the pathogenesis of cerebral and coronary vasospasm, the upstream of this signal transduction has not been elucidated. In addition, the involvement of protein kinase C (PKC) may also be related to cerebral vasospasm. We recently reported that sphingosylphosphorylcholine (SPC), a sphingolipid, induces Rho-kinase-mediated Ca2+ sensitization in pig coronary arteries. The purpose of this present study was to examine the possible mediation of SPC in Ca2+ sensitization of the bovine middle cerebral artery (MCA) and the relation to signal transduction pathways mediated by Rho-kinase and PKC. In intact MCA, SPC induced a concentration-dependent (EC50=3.0 micromol/L) contraction, without [Ca2+]i elevation. In membrane-permeabilized MCA, SPC induced Ca2+ sensitization even in the absence of added GTP, which is required for activation of G-proteins coupled to membrane receptors. The SPC-induced Ca2+ sensitization was blocked by a Rho-kinase inhibitor (Y-27632) and a dominant-negative Rho-kinase, but not by a pseudosubstrate peptide for conventional PKC, which abolished the Ca2+-independent contraction induced by phorbol ester. In contrast, phorbol ester-induced Ca2+ sensitization was resistant to a Rho-kinase inhibitor and a dominant-negative Rho-kinase. In primary cultured vascular smooth muscle cells, SPC induced the translocation of cytosolic Rho-kinase to the cell membrane. We propose that SPC is a novel messenger for Rho-kinase-mediated Ca2+ sensitization of cerebral arterial smooth muscle and, therefore, may play a pivotal role in the pathogenesis of abnormal contraction of the cerebral artery such as vasospasm. The SPC/Rho-kinase pathway functions independently of the PKC pathway.     

Gene transfer of dominant-negative mutants of extracellular signal-regulated kinase and c-Jun NH2-terminal kinase prevents neointimal formation in balloon-injured rat artery

We previously reported that extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), belonging to mitogen-activated protein kinases, are rapidly activated in balloon-injured artery. Therefore, we examined the role of these kinase activations in neointimal formation by using an in vivo gene transfer technique. We made the dominant-negative mutants of ERK (DN-ERK) and JNK (DN-JNK) to specifically inhibit endogenous ERK and JNK activation, respectively. Before balloon injury, these mutants were transfected into rat carotid artery using the hemagglutinating virus of Japan liposome method. In vivo transfection of DN-ERK and DN-JNK significantly suppressed the activation of ERK and JNK, respectively, after balloon injury, confirming successful expression of the transfected genes. Neointimal formation at 14 and 28 days after injury was prevented by gene transfer of DN-ERK or DN-JNK. Furthermore, bromodeoxyuridine labeling index and total cell-counting analysis at 7 days showed that either DN-ERK or DN-JNK remarkably suppressed smooth muscle cell (SMC) proliferation in both the intima and the media after injury. Gene transfer of wild-type ERK (W-ERK) or JNK (W-JNK) significantly enhanced neointimal hyperplasia at 14 days after injury. Furthermore, DN-ERK and DN-JNK significantly suppressed serum-induced SMC proliferation in vitro. We obtained the first evidence that in vivo gene transfer of DN-ERK or DN-JNK prevented neointimal formation in balloon-injured artery by inhibiting SMC proliferation. Thus, ERK and JNK activation triggers SMC proliferation, leading to neointimal formation. These kinases may be the new therapeutic targets for prevention of vascular diseases.     

Layer-specific dilation of penetrating arteries induced by stimulation of the nucleus basalis of Meynert in the mouse frontal cortex

To clarify mechanisms through which activation of the nucleus basalis of Meynert (NBM) increases cerebral cortical blood flow, we examined whether cortical parenchymal arteries dilate during NBM stimulation in anesthetized mice. We used two-photon microscopy to measure the diameter of single penetrating arteries at different depths (∼800 μm, layers I to V) of the frontal cortex, and examined changes in the diameter during focal electrical stimulation of the NBM (0.5 ms at 30 to 50 μA and 50 Hz) and hypercapnia (3% CO₂ inhalation). Stimulation of the NBM caused diameter of penetrating arteries to increase by 9% to 13% of the prestimulus diameter throughout the different layers of the cortex, except at the cortical surface and upper part of layer V, where the diameter of penetrating arteries increased only slightly during NBM stimulation. Hypercapnia caused obvious dilation of the penetrating arteries in all cortical layers, including the surface arteries. The diameters began to increase within 1 second after the onset of NBM stimulation in the upper cortical layers, and later in lower layers. Our results indicate that activation of the NBM dilates cortical penetrating arteries in a layer-specific manner in magnitude and latency, presumably related to the density of cholinergic nerve terminals from the NBM.     

Inhibitor of apoptosis protein family as diagnostic markers and therapeutic targets of colorectal cancer

The apoptosis and antiapoptotic signaling pathways are important for regulating carcinogenesis and cancer progression, and for determining prognosis. Molecules involved in apoptosis represent potential cancer diagnostic markers and therapeutic targets. The inhibitor of apoptosis protein (IAP) family includes several important molecules involved in apoptosis that might represent such targets. Increasing evidence has demonstrated that the IAP family of proteins is integral for antiapoptotic and nuclear factor-κB signal transduction, and enhanced expression of IAPs contributes to colon carcinogenesis and its poor prognosis, as well as to drug resistance of tumors. X-linked IAP, cIAP1, cIAP2, and survivin are prognostic markers of colorectal cancer, and survivin and cIAP2 are also utilized to predict the effect of anticancer treatment in colorectal cancer patients. Novel therapies such as YM155 and LY2181308 targeting survivin, AEG35156 and phenoxodiol targeting X-linked IAP, AT-406 as a Smac mimetic, and survivin peptides are currently being evaluated in clinical trials. This report reviews the involvement of the IAP family in colorectal adenocarcinoma in order to summarize the role of the IAP family members as diagnostic and therapeutic targets, and to provide an overview of the future course of research in this area.     

Wide excision as a method of breast-conserving surgery for breast cancer

Breast-conserving treatment has become the standard treatment for early breast cancer, not only in Western countries but also in Japan. Wide excision is perferred to quadrantectomy because the former results in better cosmesis than the latter. However, the margin status may be positive more frequently in the former than in the latter. The results of our study indicated that positive margins and the absence of radiotherapy or endocrine therapy proved to be independent risk factors for local recurrence. Because margin status influences local control, tumor margins after wide excision should be accurately determined, and higher doses of radiotherapy and adjuvant therapy are indicated for patients with positive margins.     

Endoscopic Evaluation of Reflux Esophagitis After Proximal Gastrectomy: Comparison Between Esophagogastric Anastomosis and Jejunal Interposition

BACKGROUND: Although proximal gastrectomy has been performed more as a function-preserving surgery, reflux esophagitis can occur postoperatively, resulting in poor postoperative quality of life. To date, only a few reports have compared the methods of reconstruction performed after proximal gastrectomy, and the method most likely to prevent postoperative reflux esophagitis remains undetermined. METHODS: A retrospective review of 76 patients who underwent proximal gastrectomy with jejunal interposition (JI) or esophagogastrostomy (EG) at the Cancer Institute Hospital between April 1996 and August 2005 was performed. Preoperative characteristics, operative findings, and postoperative gastrointestinal fiberoscopy findings were reviewed and compared between JI and EG patients. Furthermore, we investigated the relationship between the length of interposed segment and operative and postoperative findings. RESULTS: The frequency of grade C or D reflux esophagitis was lower in the JI group than in the EG group (p = 0.001), although the former required a longer operation time (256.5 +/- 10.2 min) than the latter (195.8 +/- 8.2 min; p < 0.001). Other characteristics and postoperative clinical course did not differ between the groups. In the JI group, interposed segments 10 cm or shorter were advantageous in evaluating the remnant stomach when compared with interposed segments longer than 10 cm. No relationship was observed between the length of the interposed segment and clinical findings, except operation time. CONCLUSION: Jejunal interposition helps prevent reflux esophagitis after proximal gastrectomy. The optimal length of the interposed segment is undetermined; however, a length of 10 cm or shorter is preferred for endoscopic evaluation of the remnant stomach.     

Pylorus-preserving pancreaticoduodenectomy with combined resection of the portal vein and gastrointestinal reconstruction by imanaga procedure for ductal cancer of the head of the pancreas

Twenty-six patients who underwent pyloruspreserving pancreaticoduodenectomy (PPPD) for ductal cancer of the head of the pancreas between 1983 and 1993 were reviewed. Gastrointestinal continuity was restored by the methods of Imanaga (n=21) and Traverso (n=5). Combined resection of the portal vein and/or superior mesenteric vein was performed in 13 patients. Surgical complications occurred in 5 patients, but there were no postoperative deaths. Delayed gastric emptying was observed in 42% of patients. The median survival time for all 26 patients was 13 months. Three patients survived for more than 3 years, and one of them is currently alive without recurrence at 10 years. Differences in survival rates were not apparent between patients who underwent PPPD with and without portal vein resection. Survival rate after PPPD was compared with that after pancreaticoduodenectomy (PD) performed between 1974 and 1992; the difference was not significant. Patients who underwent noncurative PPPD had a significantly better survival rate than those who underwent noncurative PD (P<0.05). PPPD has improved the quality of life of the resected patients, without reducing survival rate. At present, PPPD by the Imanaga procedure could be the best choice for management of cancer of the pancreatic head.     

Adenocarcinoma of the minor duodenal papilla: report of a case

We report a case of adenocarcinoma of the minor duodenal papilla, a rare type of duodenal neoplasm. A 76-year-old man with a history of surgery for rectal cancer and gastric cancer was referred to us after a follow-up upper gastrointestinal endoscopy revealed an abnormal elevation in the minor duodenal papilla. The pathological diagnosis of a biopsy specimen was adenocarcinoma. Preoperative examination of other organs revealed a tumor in the ascending colon, which was also identified as adenocarcinoma. We performed synchronous pancreatoduodenectomy and ileocecal resection with lymph node dissection. Histopathological examination of the resected specimen revealed that the papilla tumor arose from the duodenal mucosa and infiltrated the submucosa of the duodenal wall, but not the pancreatic parenchyma. Based on these findings, we diagnosed primary adenocarcinoma of the minor duodenal papilla. To our knowledge, this is only the sixth such case reported in the English-language literature, and we review all six cases after this case report.     

Surgical Resection of Hilar Cholangiocarcinoma: Analysis of Survival and Postoperative Complications

Background Surgery is the only potentially curative treatment for hilar bile duct cancer. This study sought to evaluate the efficacy and feasibility of surgical management of hilar bile duct carcinoma, including radical hepatectomy, at a single institution. Methods We performed a retrospective review of 49 consecutive patients who underwent surgery at our hospital between 1990 and 2003. Results Altogether, 44 of 49 patients underwent radical hepatectomy combined with caudate lobectomy and lymphadenectomy. One and four patients underwent partial hepatectomy or bile duct resection, respectively. No patients underwent preoperative portal vein embolization. The 5-year survival rate was 39.7%, with a median survival time of 3.75 years. The postoperative morbidity and mortality rates were 46.8% and 2.0%, respectively. Cox’s proportional hazard model revealed that lymph node status and the residual tumor factor were independent prognostic factors. Multivariate analysis revealed that preoperative hyperbilirubinemia, postoperative complications, and extended surgical procedures were independently associated with postoperative hyperbilirubinemia. After potentially curative resection, 39.4% of patients suffered from disease recurrence. In 60% of the total cases, the sites of recurrence were distant metastases. Conclusion Surgery, including radical hepatectomy combined with caudate lobectomy and lymph node dissection, is a feasible, effective treatment for hilar bile duct cancer.