Neural cell adhesion molecule is a cardioprotective factor up-regulated by metabolic stress

Screening for cell surface proteins up-regulated under stress conditions may lead to the identification of new therapeutic targets. To search for genes whose expression was enhanced by treatment with oligomycin, a mitochondrial-F₀F₁ ATP synthase inhibitor, signal sequence trapping was performed in H9C2 rat cardiac myoblasts. One of the genes identified was that for neural cell adhesion molecule (NCAM, CD56), a major regulator of development, cell survival, migration, and neurite outgrowth in the nervous system. Immunohistochemical analyses in a mouse myocardial infarction model revealed that NCAM was strongly expressed in residual cardiac myocytes in the infarcted region. Increased expression of NCAM was also found during the remodeling period in a rat model of hypertension-induced heart failure. Lentivirus-mediated knockdown of NCAM decreased the cell growth and survival following oligomycin treatment in H9C2 cells. In primary rat neonatal cardiac myocytes, NCAM was also found to be up-regulated and played a protective role following oligomycin treatment. Analyses of downstream signaling revealed that knockdown of NCAM significantly decreased the basal AKT phosphorylation level. In contrast, NCAM mimetic peptide P2d activated AKT and significantly reduced oligomycin-induced cardiomyocyte death, which was abolished by treatment with the PI3K inhibitor LY-294002 as well as overexpression of the dominant-negative AKT mutant. These findings demonstrate that NCAM is a cardioprotective factor up-regulated under metabolic stress in cardiomyocytes and augmentation of this signal improved survival.     

Feasibility of tailored, selective and effective anticancer chemotherapy by direct injection of docetaxel-loaded immunoliposomes into Her2/neu positive gastric tumor xenografts

We assessed the effects of direct injection of docetaxel-loaded immuno-(trastuzumab)-liposomes (IDL) on a xenograft mouse tumor model to determine potential clinical applications of intratumoral tailored chemotherapy against Her2/neu-overexpressing gastric cancer. The NCI-N87 Her2/neu overexpressing gastric cancer cell line xenograft mouse model was treated with IDL or docetaxel-loaded liposomes (DL). The ratio of the tumor volume of the treatment:control was determined. In addition, docetaxel pharmacokinetics in tumors were measured using high-performance liquid chromatography, and the cell viability and cell cycle distribution of Her2/neu positive cells were determined by flow cytometric analysis. The IDL group showed a significantly higher distribution of docetaxel in the N87 xenograft tumor tissues and superior antitumor efficacy compared to crude administration of docetaxel and/or trastuzumab and DL. The number of viable Her2/neu positive cells decreased following treatment with either free trastuzumab or IDL. On day 7 after treatment, a decrease in the G0/G1 phase of the cell cycle was observed in the DL and IDL groups compared to the control group. No local adverse effects were observed. These results suggest that intratumoral administration of IDL maintains a high concentration of docetaxel within the tumor leading to a safe and effective regional cancer therapeutic strategy. In addition to the inherent cytotoxic effect of trastuzumab, conjugation of trastuzumab to a liposome further enhanced the retention of docetaxel within the tumors. These data suggest that immuno-liposome mediated delivery of drugs is a promising new therapeutic option for patients with advanced gastric cancer that overexpress Her2/neu.     

Genetic pathways of multiple esophageal squamous cell carcinomas

Whether multiple esophageal squamous cell carcinomas (SCCs) in a patient develop through an identical genetic pathway is still unclear. We examined multiple esophageal SCCs for alterations of p53, p16, IRF and mitochondrial DNA (mtDNA) and microsatellite instability (MSI). Thirty patients with multiple superficial esophageal SCCs, 23 with double lesions and 7 with triple lesions, were enrolled. Loss of heterozygosity (LOH) of p53 (TP53), p16 (D9S171), IRF (IRF) and other microsatellite loci including D1S191, D17S858, D18S58 and D18S61 of the tumors was examined by microsatellite assay. Mutations of p16 and mtDNA were examined with PCR single-strand conformation polymorphism (SSCP) analysis. LOH of p53, p16 and IRF were detected in 16 of 50 (32%), 5 of 38 (13%) and 5 of 48 (10%) tumors, respectively. Mutations of p16 were detected in 4 of 67 (6%) tumors. Six of 67 (9%) tumors had mtDNA alterations and none of the tumors showed high-frequency MSI. All 30 patients showed one or more gene alterations in one or more genetic loci. Discordant genetic patterns among individual lesions within a patient were observed in 28 of the 30 (93%) patients. The most discordant locus was TP53, present in 11 of 29 (38%) informative cases, followed by D18S61, present in 11 of 30 (37%) informative cases. These results suggest that the genetic pathways of multiple esophageal SCCs may differ even within the same patient.     

Follicular lymphoma with hepatic accumulation on FDG-PET/CT masquerading IgG4-related disease

Follicular lymphoma is clinically classified as a common type of indolent non-Hodgkin''s lymphoma, and its clinical diagnosis is difficult because B symptoms and elevated soluble interleukin-2 receptor (sIL-2R) levels are less frequent in follicular lymphoma than in other lymphomas. We report a case of follicular lymphoma masquerading immunoglobulin G4-related disease (IgG4-RD) with elevated IgG4 levels. A 67-year-old man presented to our hospital with a 1-year history of deep right supraclavicular and para-aortic lymph node lymphadenopathy on plain computed tomography (CT) findings along with elevated IgG4 levels, and the ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan showed heterogeneous diffuse FDG uptake in the liver, and FDG uptake was noted at multiple sites in the enlarged right supraclavicular and para-aortic lymph nodes. Excisional biopsy of the right supraclavicular lymph node, performed under general anesthesia, showed a tumor-like structure mimicking a normal germinal center in the lymphoid follicle; immunostaining was positive for B-cell lymphoma 2 and CD10 proteins with some plasma cells stained with IgG, only 30% of them were positive for IgG4, and no marked fibrosis characteristic of IgG4-RD was observed; therefore, follicular lymphoma was diagnosed, and all symptoms, including FDG uptake, improved with rituximab monotherapy. Differential diagnoses of slowly progressive generalized lymphadenopathy over the years with elevated serum IgG4 levels include IgG4-RD, Castleman''s disease, and indolent lymphoma. Multiple accumulation in the liver on FDG-PET/CT, if found, may suggest indolent lymphoma among them.     

Variations in the preoperative resources use and the practice pattern in Japanese cholecystectomy patients

Purpose  

There are several preoperative treatment options, such as the staged bile duct intervention (BDI), for the successful completion of a cholecystectomy, regardless of the use of an open cholecystectomy (OC) or a laparoscopic cholecystectomy (LC). However, few studies have investigated how the characteristics of the patient or the hospital affect the preoperative resource use. This study determined the factors, including the hospital characteristics, associated with the preoperative resource utilization or with the treatment process.     

First jejunal vein oriented mesenteric excision for pancreatoduodenectomy

Background

Dissection of the pancreatic head from the superior mesenteric vein (SMV) and artery (SMA) are major points of bleeding in pancreaticoduodenectomy (PD) because of congestion of the pancreatic head. The “SMA-first” approach, which involves ligating the artery from the SMA first, can be used to solve this problem. However, the SMA-first approach has problematic anatomical issues. We applied a new surgical approach, first jejunal vein oriented mesenteric excision (FME), for PD. This study aimed to clarify the effect of FME on reduction of bleeding during PD.

Methods

The jejunal vein, the most frequent source of bleeding during dissection of the mesoduodenum, was identified at the beginning of dissection of the pancreatic head from SMV and SMA. The mesoduodenum, including plural IPDAs, was completely divided before dissection of the pancreatic head from the SMV. The perioperative outcomes of two groups, patients who underwent FME-based PD and patients who underwent standard PD, were compared. Additionally, the spatial characteristics of the first jejunal vein (FJV) were analyzed using computed tomography.

Results

FME-based PD significantly reduced intraoperative blood loss compared with conventional PD (569 vs. 1094 ml, P = 0.0315). The median distance of the FJV was 0 mm from the middle colic artery and 0 mm from the third portion of the duodenum. The FJV was posterior to the SMA in the majority of the patients but was anterior to the SMA in 16.7 % of patients.

Conclusions

FME is useful for reducing intraoperative bleeding.