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Biomedical subjects

Koji Yamaguchi

Publications and source records attributed to Koji Yamaguchi.

At least 19 recordsLinked to original sources

The polyamine spermine protects against high salt stress in Arabidopsis thaliana.

It is well known that changes in abiotic conditions such as the concentration of ions, temperature and humidity lead to modulation of polyamine contents in plants. However, little is known about the relevant parts these polyamines play in abiotic stress responses. Here we addressed a specific role of spermine during high salt stress using an Arabidopsis double knockout-mutant plant (acl5/spms) which cannot produce spermine. The mutant showed higher sensitivity to high salt than wild type plants. This phenotype was cured by exogenous spermine but not by the other polyamines putrescine and spermidine, suggesting a strong link between spermine-deficiency and NaCl-hypersensitivity. The mutant was also hypersensitive to high levels of KCl but not to MgCl(2) or to high osmoticum. NaCl-hypersensitivity of the mutant was compromised by treatment with Ca(2+) channel blockers. Moreover, the mutant showed poor growth on Ca(2+)-depleted Murashige-Skoog agar media. The data suggest that the absence of spermine causes an imbalance in Ca(2+) homeostasis in the mutant plant. Based on the data obtained, we propose a model for a role of spermine in high salt stress responses.

Arabidopsis↗

A protective role for the polyamine spermine against drought stress in Arabidopsis.

Cellular polyamine content often changes in response to abiotic stresses. However, its physiological relevance is unknown. We found that an Arabidopsis mutant plant (acl5/spms), which cannot produce spermine, is hypersensitive to high salt. Examination of drought sensitivity of the mutant and comparison with wild type plants indicated hypersensitivity to drought. This phenotype was cured by spermine pretreatment but not by the other polyamines putrescine and spermidine, suggesting that drought-hypersensitivity exhibited by the mutant is due to spermine deficiency. The water loss rate of wild type and mutant plants were similar until 20 min after onset of dehydration stress, but after a longer exposure the rate in mutant plants was higher than in wild type plants. Consistent with this result, the stomata of the mutant leaves remained open while in wild type leaves they closed. Based on the collected data, we discuss a role for spermine in response to drought stress.

Arabidopsis↗

Significance of mesenteric lymphadenopathy after pancreaticoduodenectomy for periampullary carcinomas: evaluation with serial MDCT studies.

OBJECTIVE: To evaluate the significance of mesenteric lymphadenopathy arising after pancreaticoduodenectomy (PD) for periampullary carcinomas. MATERIALS AND METHODS: Serial multidetector CT (MDCT) studies in 44 patients after PD for periampullary carcinomas (Group A) were retrospectively reviewed, the incidence and interval changes of mesenteric lymphadenopathy were evaluated, and comparisons were made with 21 patients who underwent PD for benign diseases (Group B). RESULTS: In Group A, mesenteric lymphadenopathy was seen in 31 of 44 (70.5%) patients. The short axis diameter of the largest lymph node ranged from 6.2 to 11.5mm (mean+/-S.D.: 8.6+/-1.4mm), and the short-axis-to-long-axis (S/L) ratio ranged from 0.46 to 0.99 (mean+/-S.D.: 0.69+/-0.12). Six of the 31 (19.4%) mesenteric lymphadenopathy cases showed interval increases in size on follow-up studies, and three cases showed new development of mesenteric lymphadenopathy: all of these nine cases had concurrent recurrence in the mesenteric root. In Group B, 11 (52.4%) had mesenteric lymphadenopathy. The short axis diameter of the largest lymph node ranged from 5.6 to 10.9mm (mean+/-S.D.: 8.0+/-1.9mm) and the S/L ratio ranged from 0.48 to 0.93 (mean+/-S.D.: 0.67+/-0.12). Differences in the incidence, short axis diameter and S/L ratio were not significant between Groups A and B (p=0.154, 0.271 and 0.654, respectively). CONCLUSION: Mesenetric lymphadenopathy after PD less likely reflects recurrence. Lymph node metastasis may be suggested only when coexisting recurrent mass is found in the proximal mesenteric root.

Adult↗

S100A11, a putative tumor suppressor gene, is overexpressed in pancreatic carcinogenesis.

PURPOSE: Recent microarray analyses revealed that expression of S100A11 is up-regulated in pancreatic cancer. The aim of the present study was to evaluate the association of S100A11 with pancreatic carcinogenesis. EXPERIMENTAL DESIGN: We measured S100A11 mRNA expression in various clinical samples related to pancreatic cancer and its precursor lesions, intraductal papillary mucinous neoplasm (IPMN) and pancreatic intraepithelial neoplasia, by quantitative reverse transcription-PCR. RESULTS: Levels of S100A11 were significantly higher in pancreatic cancer (n=22) and IPMN (n=18) bulk tissues than in nonneoplastic bulk tissues (n=22; P<0.0001 for both). Levels of S100A11 did not differ between pancreatic cancer and IPMN bulk tissues. In microdissection analyses, however, IPMN cells (n=21) expressed significantly higher levels of S100A11 than did cancer cells (n=23; P=0.003). The median level of S100A11 expression was higher in pancreatic intraepithelial neoplasia cells (n=6) than in cancer cells. In pancreatic juice analyses, cancer-related (n=24; P=0.004) and IPMN-related (n=18; P=0.001) juice expressed significantly higher levels of S100A11 than did chronic pancreatitis-related juice (n=23). CONCLUSIONS: The present data suggest that expression of S100A11, a putative tumor suppressor gene, is increased in the early stage of pancreatic carcinogenesis and decreased during subsequent progression to cancer. Analysis of the S100A11 level in pancreatic juice may be an effective tool for screening of patients with high-risk lesions that could progress to pancreatic cancer or detecting early-stage pancreatic cancer.

Carcinoma↗

S100P is an early developmental marker of pancreatic carcinogenesis.

PURPOSE: Our goal was to clarify the involvement and clinical significance of S100P in pancreatic carcinogenesis. EXPERIMENTAL DESIGN: We examined S100P expression in 45 bulk pancreatic tissues; in microdissected cells, including invasive ductal carcinoma (IDC) cells (20 sections), pancreatic intraepithelial neoplasia (PanIN) cells (12 sections), intraductal papillary mucinous neoplasm (IPMN) cells (19 sections), and normal epithelial cells (11 sections); and in pancreatic juice samples from 99 patients with pancreatic diseases (32 cancer, 35 IPMN, and 32 chronic pancreatitis samples). We used quantitative real-time reverse transcription-PCR with gene-specific priming to measure S100P in these various types of samples. RESULTS: In bulk tissue analyses, pancreatic cancer and IPMN expressed significantly higher levels of S100P than did nonneoplastic pancreas (P<0.017 and P=0.0013, respectively). Microdissection analyses revealed that IPMN expressed significantly higher levels of S100P than did IDC (P<0.0001) and PanIN (P=0.0031), although S100P expression did not differ between IDC and PanIN (P=0.077). In pancreatic juice analyses, cancer and IPMN juice expressed significantly higher levels of S100P than did pancreatitis juice (both P<0.0001). Receiver operating characteristic curve analyses revealed that measurement of S100P in pancreatic juice was useful for discriminating neoplastic disease from chronic pancreatitis (area under the curve=0.837; 95% confidence interval, 0.749-0.903). CONCLUSION: S100P may be an early developmental marker of pancreatic carcinogenesis, and measurement of S100P in pancreatic juice may be useful for early detection of pancreatic cancer or screening of early pancreatic carcinogenesis.

Adenocarcinoma, Mucinous↗

Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer.

The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-kappaB (NF-kappaB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-kappaB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-kappaB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-kappaB by inflammatory stimuli, including interleukin-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-kappaB. NF-kappaB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-kappaB suppressed the enhanced cell proliferation. Our data suggest that NF-kappaB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-kappaB activation in part through Shh overexpression.

Animals↗

Quantitative analysis of human telomerase reverse transcriptase in pancreatic cancer.

Although telomerase activity is a promising diagnostic marker, clinical introduction of this marker for cancer diagnosis is still problematic due to the lack of means of evaluating sample quality. Human telomerase reverse transcriptase (hTERT), one of the subunits of telomerase, is also a promising diagnostic marker. In the present study, we did large-scale analysis of 88 pancreatic juice samples to determine the feasibility of quantitative analysis of hTERT mRNA for diagnosis of pancreatic cancer. We found significant differences in hTERT expression among carcinoma-derived, intraductal papillary mucinous neoplasm (IPMN)-derived, and chronic pancreatitis-derived juice samples. Results showed that quantitative analyses of hTERT mRNAs are more useful in discriminating carcinoma from IPMN than from chronic pancreatitis. When the specificity was set at 100%, the sensitivity for differentiation between carcinoma and IPMN was 43.5%, whereas the sensitivity of cytologic examination was 22.0%. There were significant differences in hTERT expression among carcinoma cells, IPMN cells, and normal ductal cells isolated from pancreatic tissues by microdissection. Lymphocytes and hyperplastic epithelial cells isolated from tissues with the histologic appearance of pancreatitis showed various expression levels of hTERT. Our results suggest that quantitative analysis of hTERT mRNA in pancreatic juice is advantageous over cytologic analysis for differentiation between carcinoma and IPMN but probably not for differentiation between carcinoma and chronic pancreatitis.

DNA-Binding Proteins↗

Analysis of in vitro skin permeation of 22-oxacalcitriol having a complicated metabolic pathway.

PURPOSE: The purpose of this study is to analyze simultaneous skin permeation and metabolism of 22-oxacalcitriol (OCT) having several metabolites in skin by observing skin permeation of only unchanged OCT through excised rat skin. METHODS: A diffusion model including metabolic processes was employed to express simultaneous skin permeation and metabolism of OCT. In vitro permeation experiments of OCT from Oxarol ointment through full-thickness and stripped rat skin were carried out using Franz-type diffusion cells. Time courses of unchanged OCT amounts in ointment, skin, and receptor fluid were determined and fitted to diffusion equations to obtain permeation parameters and a metabolic rate. RESULTS: Fitting curves of the skin permeation profile obtained by the model were sufficiently close to observed data of unchanged OCT amounts in ointment, skin, and receptor fluid. The following parameters were obtained: metabolic rate of 1.37 x 10(-1) h(-1), and diffusion constants of OCT in stratum corneum (SC) (D(SC)) and viable epidermis and dermis (VED) (D(VED)) of 1.50 x 10(-7) and 2.96 x 10(-4) cm2/h, respectively. The partition coefficient of OCT for SC/ointment (K(SC/D)) was 7 times greater than that of VED/ointment (K(VED/D)). CONCLUSIONS: The present analysis made it possible to calculate skin permeation parameters (partitioning, diffusivity, and metabolic rate) of OCT without requiring metabolic information, e.g., quantification of metabolites or identification of metabolic pathways. This would be widely applicable for drugs that are not suitable for conventional methods due to complicated metabolic pathways.

Algorithms↗

Quantitative analysis of MUC1 and MUC5AC mRNA in pancreatic juice for preoperative diagnosis of pancreatic cancer.

Pancreatic juice is a promising type of diagnostic sample for pancreatic cancer, and members of the mucin (MUC) family are diagnostic candidates. To evaluate the utility of MUC family members as diagnostic markers, we measured MUC mRNA expression in pancreatic tissues and pancreatic juice obtained from patients with different pancreatic diseases as well as in pancreatic cancer cell lines by real-time PCR. Furthermore, to support the possibility of early diagnosis by quantification of MUC1 and MUC5AC, immunohistochemistry and microdissection-based quantitative analysis of mRNA were carried out. There was no significant correlation between MUC1 and MUC5AC expression in cell lines. When beta-actin was used as a reference gene, median MUC1 and MUC5AC mRNA expression levels were remarkably greater in tumoral tissues than in non-tumoral tissues, but median MUC4 and MUC6 mRNA expression levels were not. Receiver operating characteristic curve analysis showed that quantitative analysis of MUC1 and MUC5AC mRNA in pancreatic juice is better diagnostic modality than that of MUC4 and MUC6 mRNA. Immunohistochemistry showed that MUC1 and MUC5AC were highly expressed in invasive ductal carcinomas (IDC) and moderately expressed in high-grade pancreatic intraepithelial neoplasia (PanIN); no staining was observed in normal ducts. Analysis of cells isolated by microdissection showed stepwise upregulation of MUC1 and MUC5AC in the development of high-grade PanIN to IDC. Our results suggest that MUC1 and MUC5AC are upregulated stepwise in pancreatic carcinogenesis and that quantitative assessment of MUC1 and MUC5AC mRNA in pancreatic juice has high potential for preoperative diagnosis of pancreatic cancer.

Biomarkers, Tumor↗

Type of gastrointestinal reconstruction affects postoperative recovery after pancreatic head resection.

BACKGROUND/PURPOSE: The postoperative recovery of gastric motility with various reconstructions after pancreatic head resection has been reported. However, little is known about this recovery after pancreatic head resection with segmental duodenectomy (PHRSD). Some have attributed gastric stasis after pylorus-preserving pancreatoduodenectomy (PPPD) to tube gastrostomy, but its effect on gastric motility has not been investigated. In this study, the postoperative recovery after PHRSD and PPPD, and gastric motility with and without gastrostomy after PPPD were investigated. METHODS: We analyzed the first appearance of gastric phase III motility, postoperative systemic status, and body weight (BW; n = 32). The Imanaga PPPD and PHRSD were compared because the procedures differ only in the length of the remaining duodenum. Traverso and Roux-en-Y PPPDs were compared because the two procedures are similar except for the creation of gastrostomy. RESULTS: (1) Times to first appearance of gastric phase III motility and BW recovery were significantly better after PHRSD than after the Imanaga PPPD (P < 0.05). (2) Times to first gastric phase III motility and resumption of a regular diet as well as periods of gastric sump tube use and postoperative hospital stay were significantly shorter after the Roux-en-Y than after the Traverso PPPD (P < 0.05). CONCLUSIONS: Preservation of as long a portion of the duodenum as possible, the choice of a Roux-en-Y duodenojejunostomy, and the avoidance of peritoneal fixation of the gastric wall may be factors that improve the recovery of gastric motility and BW after pancreatic head resection.

Adult↗

Inhibition of inducible nitric oxide synthase prevents hepatic, but not pulmonary, injury following ischemia-reperfusion of rat liver.

The aim of this study was to investigate the contribution of inducible nitric oxide synthase (iNOS)-derived nitric oxide on the liver and lung injury following hepatic ischemia-reperfusion (I/R) using a novel and potent iNOS inhibitor, ONO-1714. Rats were subjected to 90 min of partial hepatic ischemia followed by 3, 6, 12, and 24 hr of reperfusion. Expression of iNOS mRNA peaked at 3 hr of reperfusion in the liver and lung. Plasma nitric oxide levels were increased fourfold at 24 hr of reperfusion and plasma ALT was increased, reaching a peak at 12 hr of reperfusion; both were significantly inhibited by ONO-1714. Histological examination revealed extensive liver damage, whereas this was not seen in the ONO-1714 group. Lung injury was not significantly changed in groups with versus without ONO-1714. Nitrotyrosine expression was seen in regions similar to those of the histological injuries of the liver, while this staining was absent in the ONO-1714 group. These data show that generation of peroxynitrite could be involved in the pathogenesis of liver injury but not lung injury after hepatic I/R. Inhibition of iNOS could be applied for attenuation of liver injury following hepatic I/R.

Amidines↗

Hepatocellular carcinoma with a prominent vascular scar in the center: MR imaging findings.

We report herein a case of hepatocellular carcinoma (HCC) with a prominent central scar. Dynamic CT and MRI studies revealed a hypervascular liver mass and a washout of contrast material in the delayed phase. The tumor center showed particular hyperintensity on T2-weighted images and delayed or prolonged enhancement. The surgical specimen revealed moderately differentiated HCC with a central scar. The central scar consisted of prominent vascular channels and loose fibrous tissue, indicative of a vascular scar. We should understand MR imaging findings of this type of central scar in the HCC.

Aged↗

Hepatic ischemia/reperfusion injury is prevented by a novel matrix metalloproteinase inhibitor, ONO-4817.

BACKGROUND: Matrix metalloproteinases (MMPs) play an important role in inflammation and neoplastic invasion and metastasis. Little is known about the effects of MMP inhibitors on hepatic ischemia/reperfusion injury. The aim of this study is to examine the inhibitory effects of ONO-4817 (oral inhibitor of MMPs) in rats. METHODS: Hepatic ischemia/reperfusion was induced in male Wister rats by clamping the portal vein and hepatic artery. The animals were randomized into an ONO-4817 group (300 mg/kg body weight per/day) and a vehicle group by oral gavage of a test substance. Serum alanine aminotransferase, histologic changes, gelatinolytic activity, MMP-2 and MMP-9 activities, tissue inhibitor of metalloproteinase 2 (TIMP-2) messenger RNA (mRNA) levels, and mRNA and serum levels of tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) were measured in both groups. RESULTS: ONO-4817 prevented ischemia/reperfusion injury to the hepatocytes as shown by significant reductions of serum alanine aminotransferase and less severe histologic changes. Gelatinolytic activity was inhibited markedly in the liver of the ONO-4817 group as demonstrated by film in situ zymography. MMP-9 and MMP-2 activities also were inhibited in the ONO-4817 group as shown by gelatin zymography. TIMP-2 mRNA levels showed no significant differences between the 2 groups. TNFalpha mRNA showed no downregulation, but IL-1beta mRNA was downregulated in the liver of the ONO-4817 group 1 to 3 hours after reperfusion. Serum levels of TNFalpha and IL-1beta showed a significant decrease in the ONO-4817 group, compared with the vehicle group after reperfusion. CONCLUSIONS: Hepatic ischemia/reperfusion injury was improved by a novel MMP inhibitor, ONO-4817, not only by inhibition of gelatinolytic activity but also by a decrease in release of inflammatory cytokines.

Animals↗

International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.

Non-inflammatory cystic lesions of the pancreas are increasingly recognized. Two distinct entities have been defined, i.e., intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). Ovarian-type stroma has been proposed as a requisite to distinguish MCN from IPMN. Some other distinct features to characterize IPMN and MCN have been identified, but there remain ambiguities between the two diseases. In view of the increasing frequency with which these neoplasms are being diagnosed worldwide, it would be helpful for physicians managing patients with cystic neoplasms of the pancreas to have guidelines for the diagnosis and treatment of IPMN and MCN. The proposed guidelines represent a consensus of the working group of the International Association of Pancreatology.

Endocrine Surgical Procedures↗