Biomedical subjects

H Konno

Publications and source records attributed to H Konno.

At least 19 recordsLinked to original sources

PubMed2003

Attenuated nuclear shrinkage in neurones with nuclear inclusions of SCA1 brains.

BACKGROUND: Spinocerebellar ataxia type 1 (SCA1) is one of the autosomal dominant neurodegenerative disorders commonly linked to pathological expansion of the CAG repeat of the relevant gene. Nuclear inclusions and neurodegeneration are both triggered by this pathological expansion of the CAG/polyglutamine repeat on ataxin-1, but it remains to be determined whether or not nuclear inclusion formation is associated with accelerated neurodegeneration. OBJECTIVE: To examine the influence of nuclear inclusions on nuclear size and deformity in human brains from patients suffering from SCA1. MATERIAL: Pontine sections of brains obtained at necropsy from seven patients with SCA1 and five controls. METHODS: The size and deformity of each neuronal nucleus was quantified. Nuclei with and without inclusions were examined separately to assess the possible influence of nuclear inclusions on neurodegeneration. RESULTS: Nuclear shrinkage and deformity were more marked in SCA1 brains than in controls. This shrinkage was attenuated in neurones containing nuclear inclusions. CONCLUSIONS: The existence of nuclear inclusions in SCA1 is presumably linked to a mechanism that attenuates rather than accelerates nuclear shrinkage. This in vivo finding may provide a clue to constructing a rational therapeutic strategy for combating neurodegeneration associated with nuclear inclusions.

Adult↗

PubMed2003

[Metastatic lung tumor: report of two cases].

We herein report 2 cases of metastatic lung tumor. The first case was a 59-year-old female, who had undergone a left radical mastectomy for the treatment of breast cancer 18 years before. She was found to have a pulmonary nodule in the left lower lobe on the routine chest radiograph. She underwent a video-assisted thoracic surgery (VATS) partial resection of the left lower lobe. Tumor was diagnosed as a lung metastasis of the breast cancer microscopically. The second case was a 77-year-old man, who had undergone a right nephrectomy for the treatment of renal cell carcinoma. He was found to have 2 nodules in the right lung (1 in the middle lobe and the other in the lower lobe) on the follow-up computed tomography (CT) scan of the chest. He underwent VATS partial resections of the right middle and lower lobes. While the tumor in the lower lobe was diagnosed as a lung metastasis of the renal cell carcinoma, the tumor in the middle lobe turned out a primary lung cancer.

Adenocarcinoma, Papillary↗

PubMed2002

Comprehensive sequence analysis of translation termination sites in various eukaryotes.

Recent investigations into the translation termination sites of various organisms have revealed that not only stop codons but also sequences around stop codons have an effect on translation termination. To investigate the relationship between these sequence patterns and translation as well as its termination efficiency, we analysed the correlation between strength of consensus and translation efficiency, as predicted according to Codon Adaptation Index (CAI) value. We used RIKEN full-length mouse cDNA sequences and ten other eukaryotic UniGene datasets from NCBI for the analyses. First, we conducted sequence profile analyses following translation termination sites. We found base G and A at position +1 as a strong consensus for mouse cDNA. A similar consensus was found for other mammals, such as Homo sapiens, Rattus norvegicus and Bos taurus. However, some plants had different consensus sequences. We then analysed the correlation between the strength of consensus at each position and the codon biases of whole coding regions, using information content and CAI value. The results showed that in mouse cDNA, CAI value had a positive correlation with information content at positions +1. We also found that, for positions with strong consensus, the strength of the consensus is likely to have a positive correlation with CAI value in some other eukaryotes. Along with these observations, biological insights into the relationship between gene expression level, codon biases and consensus sequence around stop codons will be discussed.

3' Untranslated Regions↗

PubMed2001

Correlation between sequence conservation of the 5' untranslated region and codon usage bias in Mus musculus genes.

The codon adaptation index (CAI) values of all protein-coding sequences of the full-length cDNA libraries of Mus musculus were computed based on the RIKEN mouse full-length cDNA library. We have also computed the extent of consensus in flanking sequences of the initiator ATG codon based on the 'relative entropy' values of respective nucleotide positions (from -20 to +12 bp relative to the initiator ATG codon) for each group of genes classified by CAI values. With regard to the two nucleotides positions (-3 and +4) known to be highly conserved in Kozak's consensus sequence, a clear correlation between CAI values and relative entropy values was observed at position -3 but this was not significant at position +4, although a significant correlation was found at position -1 of the consensus sequence. Further, although no correlation was observed at any additional positions, relative entropy values were very high at positions -4, -6, and -8 in genes with high CAI values. These findings suggest that the extent of conservation in the flanking sequence of the initiator ATG codon including Kozak's consensus sequence was an important factor in modulation of the translation efficiency as well as synonymous codon usage bias particularly in highly expressed genes.

5' Untranslated Regions↗

PubMed2001

Decrease of substance P in the parabrachial nucleus of multiple system atrophy.

In the parabrachial nucleus (PBN), which has been known to play an important regulating role for various autonomic functions, many projecting nerve fiber terminals containing substance P (SP) from the nucleus of the solitary tract (NTS) and other areas are found and effect a modulatory influence on the transmission in the PBN. Postmortem brains were obtained from four multiple system atrophy (MSA) patients with autonomic failure and four control patients without any nervous disease, and an immunohistochemical staining for SP was performed on serial 10-microm-thick sections from paraffin-embedded pons including the PBN after immersion fixation in 10% formalin. In the PBN of all MSA patients, a marked decrease in SP-like immunoreactive (SPLI) nerve fiber terminals was revealed compared with the controls. In addition, an obvious astrocytosis was found in the PBN by simultaneous histopathological evaluation, for the preservation of neurons themselves. Therefore, the projecting SP pathway to the PBN may also be primarily involved in the pathophysiological mechanism of the autonomic failure of MSA patients.

Autonomic Nervous System Diseases↗

PubMed2001

Delineating developmental and metabolic pathways in vivo by expression profiling using the RIKEN set of 18,816 full-length enriched mouse cDNA arrays.

We have systematically characterized gene expression patterns in 49 adult and embryonic mouse tissues by using cDNA microarrays with 18,816 mouse cDNAs. Cluster analysis defined sets of genes that were expressed ubiquitously or in similar groups of tissues such as digestive organs and muscle. Clustering of expression profiles was observed in embryonic brain, postnatal cerebellum, and adult olfactory bulb, reflecting similarities in neurogenesis and remodeling. Finally, clustering genes coding for known enzymes into 78 metabolic pathways revealed a surprising coordination of expression within each pathway among different tissues. On the other hand, a more detailed examination of glycolysis revealed tissue-specific differences in profiles of key regulatory enzymes. Thus, by surveying global gene expression by using microarrays with a large number of elements, we provide insights into the commonality and diversity of pathways responsible for the development and maintenance of the mammalian body plan.

Animals↗

PubMed2001

Functional annotation of a full-length mouse cDNA collection.

The RIKEN Mouse Gene Encyclopaedia Project, a systematic approach to determining the full coding potential of the mouse genome, involves collection and sequencing of full-length complementary DNAs and physical mapping of the corresponding genes to the mouse genome. We organized an international functional annotation meeting (FANTOM) to annotate the first 21,076 cDNAs to be analysed in this project. Here we describe the first RIKEN clone collection, which is one of the largest described for any organism. Analysis of these cDNAs extends known gene families and identifies new ones.

Animals↗

PubMed2001

Comparative evaluation of 5'-end-sequence quality of clones in CAP trapper and other full-length-cDNA libraries.

To enhance the usefulness of the laboratory mouse and to facilitate the rapid assay of gene functions we have been collecting the entire set of mouse full-length cDNA by one-pass sequencing. To collect full-length cDNA clones efficiently, it is critical to construct high-quality cDNA libraries. In recent years, we have been developing a way to construct full-length cDNA libraries by using biotinylation of the cap structure (the 'CAP-trapper' method) coupled with treatment to increase reverse transcriptase efficiency at high temperature by the addition of trehalose. In this paper we report our evaluation of the quality of CAP trapper and a number of other full-length cDNA libraries, including the results of 5' end analysis of clones in CAP trapper and the other libraries. We used a procedure that compared the 5'-ends of cDNA clones with those of genes in the public databases. Our analysis showed that 63% of cDNA clones in CAP trapper libraries had sequences that were either the same length as those of equivalent genes in the public database or 5'-extended, and that 90% of these clones maintained their coding sequences. These results indicate that the CAP trapper library is a promising tool for collecting full-length cDNA in large-scale projects. Comparison of the quality of CAP trapper with that of other full-length-cDNA libraries confirmed the value of these libraries.

Algorithms↗

PubMed2001

Balanced-size and long-size cloning of full-length, cap-trapped cDNAs into vectors of the novel lambda-FLC family allows enhanced gene discovery rate and functional analysis.

We have developed a new class of cloning vectors: lambda-full-length cDNA (lambda-FLC) cloning vectors. These vectors can be bulk-excised for preparing full-length cDNA libraries in which a high proportion of the plasmids carry large inserts that can be transferred into other (for example, functional) vectors. Unlike other cloning vectors, lambda-FLC vectors accommodate a broad range of sizes of eukaryotic cDNA inserts because they contain "size balancers." Further, the main protocol we use for direct bulk excision of plasmids is mediated by a Cre-lox system and is apparently free of size bias. The average size of the inserts from excised plasmid cDNA libraries was 2.9 kb for standard and 6.9 kb for size-selected cDNA. The average insert size of the full-length cDNA libraries was correlated to the rate of new gene discovery, suggesting that effectively cloning rarely expressed mRNAs requires vectors that can accommodate large inserts from a variety of sources. Part of the vectors are also suitable for bulk transfer of inserts into various functional vectors.

Animals↗

PubMed2001

Combination of early and delayed SPET imaging using technetium-99m ethyl cysteinate dimer immediately after local intra-arterial thrombolysis.

The aim of this study was to investigate the prognostic utility of post-treatment technetium-99m ethyl cysteinate dimer (99mTc-ECD) single-photon emission tomography (SPET) for predicting ischemic tissue outcome in cases involving embolic middle cerebral artery occlusion treated with local intra-arterial thrombolysis. We examined twenty-five patients with a moderately ischemic area determined using pretreatment technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) SPET, and with complete recanalization within 6 h. Post-treatment 99mTc-ECD SPET studies, consisting of scanning for 0.5-6.5 min (early scan) and 15-21 min (delayed scan) after tracer injection, were performed immediately after thrombolysis. The extent of the affected area outlined on pretreatment 99mTc-HMPAO SPET was used for the post-treatment early and delayed 99mTc-ECD SPET images, and the AR/CE ratio (ratio of affected regional activity to cerebellar activity) was calculated. The washout index of 99mTc-ECD in the affected area was also calculated by dividing the difference between the AR/CE ratio in the early and delayed images by the AR/CE ratio in the early image. Twelve patients without infarction or with small subcortical/basal ganglial infarction, ten with medium or large cortical infarction, and three with hemorrhage were identified by follow-up computed tomography. Although the AR/CE ratio in post-treatment early 99mTc-ECD SPET images was significantly higher in the hemorrhagic group than in the cortical infarction group, this value did not differentiate the reversible ischemia group from either the cortical infarction or the hemorrhagic group. The AR/CE ratio in post-treatment delayed 99mTc-ECD SPET images statistically differentiated the reversible ischemia group from both the cortical infarction and the hemorrhagic group. However, the difference between the cortical infarction and hemorrhagic groups was not statistically significant. The washout index of 99mTc-ECD statistically differentiated all three groups. This study demonstrated that a combination of early and delayed 99mTc-ECD SPET imaging performed immediately after thrombolysis predicts ischemic tissue outcome.

Adult↗

PubMed2001

Intrahepatic cholangiojejunostomy for unresectable malignant biliary tumors with obstructive jaundice.

We reviewed our experience with intrahepatic cholangiojejunostomy as a palliative therapy for patients with unresectable malignant diseases involving the ductal confluence or the common hepatic duct. Fifteen patients with malignant biliary obstruction were treated by cholangiojejunostomy at our hospital. Two patients had intrahepatic cholangiocarcinoma, 7 had gallbladder carcinoma, 5 had bile duct carcionoma, and 1 had pancreatic carcinoma. Segment III cholangiojejunostomies were performed in 14 patients and segment V cholangiojejunostomy in 1. Contraindications for surgical resection were locoregional invasion of tumors involving the proper and/or common hepatic artery and portal vein in 15 patients and the presence of hepatic metastases in 6 patients. Liver metastases were detected in 5 of the 7 patients with gallbladder carcinoma. Postoperative complications occurred in 2 patients (13%), but there was no leakage of the cholangioenteric anastomosis in our series. There was no operative mortality after cholangiojejunostomy. Of the 9 patients who survived for more than 6 months after surgery, 7 showed a significant improvement in performance status (PS) (82 +/- 10%) 3 months after the surgery compared with the preoperative PS (70 +/- 7%). Four of the 9 patients had recurrent cholangitis as a late complication, but 4 were completely free from jaundice. Median survival after cholangioenteric bypass was 9 months (range, 2-25 months). With respect to tumor location, the median survival time was 4 months (range, 2-25 months) in patients with gallbladder carcinoma and 15.5 months (range, 12-22 months) in those with bile duct carcinoma. While the median survival period after surgery was only 3 months (range, 2 to 8 months) in the 5 patients with hepatic metastases from gallbladder carcinoma, 2 patients without liver metastasis survived for 9 and 25 months after segment III cholangioenteric bypass. In conclusion, cholangiojejunostomy can provide useful palliation for malignant biliary obstruction when combined with careful patient selection.

Bile Duct Neoplasms↗

PubMed2001

Huge cystic lymphangioma of the pancreas: report of a case.

We report herein the case of a 33-year-old woman who presented with palpable abdominal swelling found to be caused by a huge lymphangioma of the pancreas. An abdominal computed tomographic (CT) scan showed a large multilocular cystic mass with water-dense contents, which was derived from the pancreatic head. A pancreaticoduodenectomy (PD) was performed because the tumor had invaded the duodenum. The resected tumor, which was 23 x 12 x 23 cm in size with 21 of serous fluid, was pathologically diagnosed as a cystic lymphangioma. The endothelial cells lining the internal surface of the cystic spaces were immunohistochemically positive for factor VIII-R antigen and CD31. Our review of the literature revealed 45 reports of lymphangioma of the pancreas, including this one, but to the best of our knowledge this is only the fifth case that required a PD. Nevertheless, we recommend that a complete resection be performed to reduce the risk of recurrence.

Adult↗

PubMed2001

Antimetastatic effect of hepatotropic liposomal adriamycin on human metastatic liver tumors.

Adriamycin (ADM) was encapsulated in a galactose-conjugated hepatotropic liposome (hLip-ADM) and its ability to enhance the antitumor effect while reducing toxicity was compared with that of free ADM and a control Lip-ADM (cLip-ADM), in two in vitro animal models. Liver metastases were induced in rats by an intravenous injection of 8 x 10(6) AH-130 rat hepatoma tumor cells. All forms of the ADM completely inhibited liver metastasis when given at a dose of 5 mg/kg on day 14 after tumor implantation, whereas liver metastatic foci were observed in six of ten rats in the control group. The reduction in ADM toxicity by liposomalization was remarkable, as significant body weight loss was observed only in the free ADM group, in which four of ten rats died. Additional experiments utilized a human colon cancer xenograft (TK-4) to induce the growth of the liver metastases in mice by orthotopic implantation. The hLip-ADM completely inhibited liver metastasis in rats (0/11), whereas liver metastases developed in 10 of 12 mice in the control group and in 5 of 12 mice given cLip-ADM. Interestingly, liposomal ADM did not have a significant inhibitory effect on transplanted tumor growth assessed 6 weeks after transplantation. These findings indicate that hLip-ADM may be an effective strategy for inhibiting liver metastases from human colon cancer.

Animals↗

PubMed2001

Impact of repeat hepatectomy on recurrent colorectal liver metastases.

BACKGROUND: Hepatic recurrence is seen in approximately 40% of patients undergoing hepatectomy for colorectal metastases. This study was designed to assess the risks and clinical benefits of repeat hepatectomy for those patients. METHODS: Twenty-six patients underwent repeat hepatectomy for hepatic recurrence, and their clinical data were retrospectively reviewed for operative morbidity and mortality, performance level, and survival. RESULTS: There was no operative mortality after repeat hepatectomy. Operative bleeding was significantly increased in the second hepatectomy; but operating time, duration of hospital stay, and performance status after the second hepatectomy were comparable with those of the initial hepatectomy. The median survival time from the second hepatectomy was 31 months, and the 3- and 5-year survival rates were 62% and 32%, respectively. A short disease-free interval (6 months or less) between the initial hepatectomy and diagnosis of hepatic recurrence in the remnant liver was significantly associated with poor survival after the second hepatectomy. CONCLUSIONS: Repeat resection contributed to clinical benefits for selected patients with hepatic recurrence after the initial hepatectomy for colorectal liver metastases. However, appearance of hepatic recurrence within 6 months or less after the initial hepatectomy is a poor prognostic factor for repeat hepatectomy.

Adult↗

PubMed2001

Computer-based methods for the mouse full-length cDNA encyclopedia: real-time sequence clustering for construction of a nonredundant cDNA library.

We developed computer-based methods for constructing a nonredundant mouse full-length cDNA library. Our cDNA library construction process comprises assessment of library quality, sequencing the 3' ends of inserts and clustering, and completing a re-array to generate a nonredundant library from a redundant one. After the cDNA libraries are generated, we sequence the 5' ends of the inserts to check the quality of the library; then we determine the sequencing priority of each library. Selected libraries undergo large-scale sequencing of the 3' ends of the inserts and clustering of the tag sequences. After clustering, the nonredundant library is constructed from the original libraries, which have redundant clones. All libraries, plates, clones, sequences, and clusters are uniquely identified, and all information is saved in the database according to this identifier. At press time, our system has been in place for the past two years; we have clustered 939,725 3' end sequences into 127,385 groups from 227 cDNA libraries/sublibraries (see http://genome.gse.riken.go.jp/).

5' Untranslated Regions↗

PubMed2001

Prevention of hepatic and peritoneal metastases by the angiogenesis inhibitor fr-118487 after removal of growing tumor in mice.

We established a mouse rising dbl quote, left (low)primary tumor resection model" in which a transplanted tumor was resected after an orthotopic transplantation of colorectal cancer tissue to estimate the therapeutic effect of an angiogenesis inhibitor on metastasis. The angiogenesis inhibitor FR-118487 is a member of the fumagillin family. Here, 1 mg / kg / day of FR-118487 was subcutaneously administered to nude mice for 1 week, 2 weeks, or 4 weeks through an osmotic pump. Liver metastasis developed in 7 of 9 control mice, 2 of 6 mice that underwent the tumor resection 2 weeks after transplantation (early resection), and in all 7 of the mice that underwent the tumor resection 4 weeks after transplantation (late resection). In the short treatment trial, the FR-118487 administration immediately after the early resection completely inhibited both hepatic and peritoneal metastases, whereas its administration after the late resection had no effect on liver metastasis. In the prolonged treatment trial, inhibitory effects of prolonged treatment with FR-118487 on both hepatic and peritoneal metastases after the late resection were clearly demonstrated. The mice of the resection-alone group all died within 106 days after tumor inoculation, due to metastases of colon carcinoma. In contrast, half of the mice that underwent resection and then received antiangiogenic therapy were alive at the end of the observation period (160 days after transplantation). In conclusion, the combination of surgery and subsequent antiangiogenic therapy may be useful to prevent the distant metastasis of colorectal cancer and to improve the prognosis of patients with colorectal cancer.

Angiogenesis Inhibitors↗

PubMed2001

Urokinase receptor and vascular endothelial growth factor are synergistically associated with the liver metastasis of colorectal cancer.

Considering recent findings that the urokinase plasminogen activation (PA) system is involved in invasion and vascular endothelial growth factor (VEGF) is involved in angiogenesis of colorectal cancer, we evaluated these factors in the liver metastasis of primary colorectal cancer. Cancer tissues from 71 colorectal cancer patients were assayed quantitatively for antigen levels of urokinase type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 and -2 (PAI-1, PAI-2), and were also assayed immunohistochemically for expression of VEGF protein. Among the PA system factors, both the levels of uPAR and PAI-1 were significantly higher in larger tumors than in smaller ones, and were also significantly higher in tumors that invaded subserosa, serosa or adjacent organs than in mucosal, submucosal tumors or in tumors that invaded the muscle layer. The uPAR levels were significantly higher in tumors with liver metastasis than in those without. VEGF overexpression was significantly more frequent in tumors with lymph node involvement or liver metastasis than in those without. Among the PA system factors, the uPAR levels were significantly higher in tumors with VEGF overexpression and a multivariate analysis revealed that high uPA level and VEGF overexpression were independent risk factors for liver metastasis. The combination of high uPAR level and overexpression of VEGF was associated with the worst prognosis in patients with colorectal cancer. These results suggest that uPAR and VEGF might contribute synergistically to the liver metastasis of colorectal cancer.

Colorectal Neoplasms↗

PubMed2001

Effect of combination therapy with matrix metalloproteinase inhibitor MMI-166 and mitomycin C on the growth and liver metastasis of human colon cancer.

Several synthetic inhibitors of matrix metalloproteinases (MMPs) show antitumor, antimetastasis and antiangiogenesis effects in various models. Synergistic effects of combinations with conventional cytotoxic agents were reported previously. In this study, we examined the effects of a new selective MMP inhibitor, MMI-166, on tumor growth, angiogenesis and metastasis in a liver metastatic model of human xenotransplanted colon cancer (TK-4). We also investigated the synergistic effects of MMI-166 and a conventional cytotoxic agent, mitomycin C (MMC), in this model. Mice transplanted orthotopically with TK-4 were divided into 4 groups; a control group (treated with vehicle solution), an MMI-166 group in which MMI-166 was orally administered (p.o.) at a dose of 200 mg / kg, 6 days / week for 5 weeks, an MMC group in which MMC was administered intraperitoneally (i.p.) at a dose of 2 mg / kg / week for 5 weeks, and a combination group (treated with MMI-166 and MMC). MMI-166 did not inhibit transplanted tumor growth, but significantly inhibited liver metastasis compared with the control group and MMC group (P < 0.01). Significant antitumor and antimetastatic effects of the combination therapy were demonstrated. The microvessel density (MVD) detected by immunohistochemical staining with ER-MP12 antibody tended to be lower in the MMI-166 and the combination groups. These results suggest that MMI-166 has potential antimetastatic ability and a synergistic effect with MMC.

Animals↗