Biomedical subjects
Publications and source records attributed to K Ohsumi.
A series of B-ring modified combretastatin analogues were synthesized and their inhibitory activity against microtubule assembly, cytotoxic activity against Colon 26 adenocarcinoma cancer cell line were evaluated. Among these, pyridone derivative (19) showed strong antimitotic activity and cytotoxicity, along with excellent water-solubility.
A series of cis-restricted combretastatin analogues with 5-membered heterocycles were synthesized and their inhibitory activity against microtubule assembly and cytotoxic activity against the colon 26 adenocarcinoma cancer cell line were evaluated. Some of the heterocyclic analogues showed potent antitubulin activity and cytotoxicity. Compounds 16 and 35 showed marked tumor growth suppression in the colon 26 murine tumor model.
A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure-activity relationships of this series of compounds are also discussed.
Stercoral perforation of the colon or rectum is a rare cause of acute abdomen, with fewer than 70 cases documented in the literature. We report herein the case of a 60-year-old man who presented with anuria and epigastric pain with physical signs of peritonitis. An abdominal X-ray showed bilateral subphrenic free air accumulation, and an emergency laparotomy subsequently revealed perforation of the rectum, suggestive of a stercoral cause, which was treated by simple closure after debridement. Following an uneventful postoperative course, he was discharged from the hospital 3 weeks after his operation and is now doing well without having suffered any further gastrointestinal problems. The clinical features, diagnosis, and treatment of the disease are reviewed following the presentation of this case. Surgeons should be aware of the possibility of this fatal disease, despite its rare incidence. Furthermore, it is important to recognize the condition at an early stage because it has a significantly high mortality if not treated early. Conversely, the surgical outcome is satisfactory provided surgery is performed in due time.
BACKGROUND: A lack of change in prevalence of severe ulcer complications requiring emergency operation has been reported, despite the common use of histamine-2 (H2)-receptor antagonists and proton pump inhibitors. This may be attributable to use of ulcerogenic drugs or Helicobacter pylori (HP) infection, or both. In this study, HP infection was evaluated semiquantitatively in patients with peptic ulcer who required surgery, and the severity of histologic change was investigated. METHODS: We reviewed a total of 113 consecutive patients (98 men and 15 women) operated on for perforation, hemorrhage, or stenosis of gastroduodenal ulcer between January 1986 and December 1995. Detection of HP was carried out by immunohistochemical staining. We graded the density of HP infection according to the number of individual HP bacteria counted in a highly magnified visual field (x 1,000 of light microscopy). The grade of HP infection was defined as follows: (0) = 0; (1+) = 1-9; (2+) = 10-29; (3+) = 30-99; (4+) > or = 100. The severity of gastritis was evaluated by histologic examination using the criteria of Rauws. RESULTS: Although the number of operations for gastroduodenal ulcer declined significantly, the rate of emergency operation for gastroduodenal ulcer increased from 60% to 90%, with the result that the frequency of operations for perforation or bleeding remained virtually constant and that for stenosis significantly decreased. HP infection was more prevalent in perforated ulcer (92%) than hemorrhagic ulcer (55%) or stenotic ulcer (45%). The grades of HP infection were 3.0 +/- 0.14 (mean +/- SEM) in perforated ulcer, 2.3 +/- 0.34 in hemorrhagic ulcer, and 2.5 +/- 0.22 in stenotic ulcer. Perforated ulcer was associated with significantly more severe HP infection and gastritis changes than hemorrhagic ulcer or stenotic ulcer. CONCLUSIONS: This study indicates that patients with perforated ulcer were infected with HP more severely than those with hemorrhagic ulcer or stenotic ulcer at the time of surgery. A close relationship was observed between the perforated ulcer and the density of HP infection determined semiquantitatively using immunohistochemical stain.
Colorectal cancer during pregnancy is very rare. We report two additional cases of rectal carcinoma. A 34-year-old woman with an obstructive adenocarcinoma of the rectal region was diagnosed at labor. A 35-year-old woman with an adenocarcinoma of the rectal region was diagnosed at 32 weeks of gestation and underwent a cesarean section and rectal resection at 35 weeks of gestation. A retrospective review of the Japanese literature was performed to identify patients who appeared to have primary colorectal cancer during pregnancy. Thirty-six patients with colon cancer (75.0%), 10 (20.8%) with rectal cancer, and two (4.2%) of unknown sites have been reported in Japanese series. The average age of the mother was 32.2 years. The calculated incidence of colorectal cancer among Japanese pregnant women was one case per 502,316 live births during the years between 1986 through 1995. Although the majority of colorectal cancers diagnosed during pregnancy are rectal carcinomas, the patients in Japan were predominantly complicated by colon cancer. The fetal risk seems small, because there were no cases of colorectal cancer metastatic to the products of conception.
OBJECTIVES: Several methods are used to detect Helicobacter pylori (HP) infection. However, few reports have evaluated the accuracy of each method and compared the grade of HP infection with the severity of histological changes. HP infection was evaluated semiquantitatively in relation to the severity of gastritis, and the sensitivity, specificity, and accuracy of several methods to detect HP infection were compared. METHODS: Biopsy specimens, obtained from a total of 64 patients who underwent endoscopy for evaluation of gastroduodenal diseases, were studied using a rapid urease test, culture, and histological assessment. An immunohistochemical method was used as the gold standard and graded according to the number of individual bacteria seen, as follows: 0 = 0; 1+ = <10; 2+ = 10-29; 3+ = 30-99; 4+ = >100. The severity of gastritis was evaluated histologically in each specimen and compared with the grade of HP infection. RESULTS: The rapid urease test had a sensitivity of 53%, specificity of 100%, and accuracy of 73%. The culture method had a sensitivity of 75%, specificity of 100%, and accuracy of 86%. Sensitivities of the rapid urease test and the culture method decreased in a positive correlation with the decrease in total number of HP bacteria counted. Using the rapid urease test, sensitivity was <30% when the grade of HP infection was < or =2+, whereas 100% sensitivity was obtained when the grade of HP infection was 4+. On the other hand, sensitivity of the culture method remained between 80% and 90% when HP infection was > or =2+. The severity of gastritis determined with Rauws scores increased in a positive correlation with the grade of HP infection as evaluated by immunohistochemical stain. CONCLUSIONS: The rapid urease test and culture of HP may result in false-negative tests for a mild infection, although they had high sensitivity and specificity for moderate to severe infection. Immunohistochemical stain provides a reliable semiquantitative diagnosis of HP infection and a positive correlation with histological changes. Clinicians should be aware of the characteristics of each method to detect HP infection and select the appropriate one(s) for their purposes.
OBJECTIVE: The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has made a strong impact on the strategy of peri-operative antibiotic prophylaxis, since MRSA has become one of the most common causative organisms of nosocomial infection in recent years. In this study, we conducted a bacteriological evaluation of surgical drains before and after introducing strategies to decrease MRSA infection rates. DESIGN AND PATIENTS: Between January 1987 and December 1994, we performed a total of 2, 755 surgical operations on inpatients, including 1,635 major and 1, 120 minor operations. Almost all surgical drains were examined bacteriologically when they were removed. The number of drains examined was 460 +/- 47 (mean +/- SEM) per year. Since the increased incidence of MRSA infection, we started exclusively using a closed drainage system and first-generation cephalosporins in 1991. The strategy was evaluated by comparing the positive rates of drain cultures, changes in bacteriological features, and incidence of MRSA infection for the 4-year periods before and after 1991. RESULTS: The positive rate of bacteria in the drains decreased significantly (p < 0.01) from 25 +/- 2 to 16 +/- 1%. Bacteriologically, the positive rate of Staphylococcus spp. decreased significantly (p < 0.05) from 7 +/- 2 to 3 +/- 0.3%. Positive rates of MRSA decreased significantly (p < 0.05) from 2.1 +/- 0.3 to 1.3 +/- 0.3%. Streptococcus declined dramatically from 3.0 +/- 0.3 to 0.3 +/- 0.1%. Of gram-negative strains, Pseudomonas and Escherichia coli were most often isolated. They showed no significant difference in positive rates between the terms. CONCLUSION: A closed drainage system and thorough use of the first-generation cephalosporins for prophylaxis were effective in decreasing positive bacterial culture of drains and reducing the incidence of MRSA on drains after surgery.
Immunoreactive (ir)-endothelin (ET)-1 concentrations in serum samples and synovial fluids from patients with rheumatoid arthritis were higher than concentrations in sera obtained from healthy volunteers. No significant difference in ir-ET-1 concentrations in synovial fluid was observed between rheumatoid arthritis patients and osteoarthritis patients. Cultured fluids of synovial cells collected from synovial tissues and leucocytes from synovial fluids of rheumatoid arthritis patients were studied to determine the origin of ir-ET-1 in synovial fluids. Ir-ET-1 was detected in the cultured fluids of synovial macrophage-like type A cells, but not in those of fibroblast-like type B cells from the synovial tissues or leucocytes from the synovial fluids. Longitudinal studies showed that the ir-ET-1 concentration in the cultured fluid reached a peak around 24 h after starting the culture. ET-1 secreted from macrophage-like synoviocytes may be involved in the pathogenesis of inflammatory arthritis.
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We have studied the cytoplasmic mechanism that induces metaphase chromosome condensation in cell-free Xenopus egg extracts. To analyze the mechanism responsible for inducing chromosome condensation separately from those responsible for sperm chromatin remodeling and nuclear envelope disassembly, we used Xenopus sperm chromatin that had already been remodeled to nucleosomal chromatin by incubating demembranated sperm with egg extracts added with lysolecithin. We found that inhibition of cyclin B-Cdc2 with butyrolactone I abolished chromosome condensation of the remodeled sperm chromatin by M-phase egg extracts, but incubation of the chromatin with active cyclin B-Cdc2 alone did not induce chromosome condensation, indicating a requirement for cytoplasmic factor(s) in addition to cyclin B-Cdc2 for the induction of chromosome condensation. We further demonstrated that if the cyclin B-Cdc2-dependent phosphorylation state was protected against dephosphorylation by a preincubation of M-phase extracts with ATP-gamma-S, chromosome condensation and phosphorylation of chromosomal histone H1 occurred even when extracts were depleted of cyclin B-Cdc2 activity. The chromosome condensation seen in the absence of cyclin B-Cdc2 was completely inhibited with another protein kinase inhibitor, 6-dimethylaminopurine, implying that a protein kinase other than cyclin B-Cdc2 was involved in the induction of chromosome condensation. These results strongly suggest that a cyclin B-Cdc2-dependent protein kinase cascade is involved in inducing chromosome condensation and the phosphorylation of chromosomal histone H1.
We have investigated the molecular target of an antitumor agent ICRF-193, a bisdioxopiperazine derivative, in in vitro chromosome condensation system of Xenopus egg extract (XEE), where DNA topoisomerase II was previously demonstrated to play a crucial role. Demembranated Xenopus sperm head chromatin is converted to metaphase chromosome-like structure in XEE in two steps, i.e., swelling of the chromatin followed by condensation of chromosome. When ICRF-193 was added to the reaction, swelling of the chromatin was not affected but chromosome condensation was completely blocked. This blockade was reversed by exogenous supplement of calf thymus topoisomerase II, which was in turn neutralized by anti-topoisomerase II monoclonal antibody. These results demonstrate that topoisomerase II is the molecular target of the drug ICRF-193.
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A hard X-ray microbeam with zone-plate optics has been tested at the MR-BW-TL beamline on the Tristan main ring of the KEK, and preliminary experiments on scanning microscopy have also been performed. A sputtered-sliced Fresnel zone plate with an Au core and Ag/C multilayer is used as an X-ray focusing device. The outermost zone width of the zone plate is 0.25 microm. A focused spot size of approximately 0.5 mum has been achieved at an X-ray energy of 8.54 keV. In a scanning X-ray microscopy experiment, test patterns with submicrometer fine structure have been clearly resolved.
BACKGROUND AND OBJECTIVES: The present study compared the effects of sequential methotrexate and fluorouracil followed by leucovorin rescue (MFL), as an adjuvant chemotherapy versus a combination of tegafur (UFT) and mitomycin C (MMC), on patient survival and recurrence after surgery for colorectal carcinoma. METHODS: Between January 1990 and December 1995, a total of 46 patients with advanced colorectal cancer were treated postsurgically by adjuvant chemotherapy using MFL or UFT-MMC. Surgical treatment was performed according to standardized procedures for radical resection of colorectal cancer. The patients were stratified into two groups after surgery. The MFL regimen consisted of MTX (100 mg/m2) and 5-FU (600 mg/m2) at hour 24, followed by leucovorin rescue. The UFT-MMC regimen consisted of MMC (12 mg/m2) intraoperatively and MMC (6 mg/m2) ever other week after surgery for 2 months and oral UFT (375 mg/m2/day), a combination of tegafur and uracil in a molar ratio of 1:4, was continued for 3 years or longer depending on the patients tolerance. RESULTS: The overall survival rates after surgery was significantly (P < 0.05) higher in the MFL than the UFT-MMC group. Recurrence rates were significantly lower in the MFL than the UFT-MMC Group, especially for liver recurrence. Disease-free survival was significantly (P < 0.05) higher in the MFL than the UFT-MMC group. CONCLUSIONS: The present results demonstrated the superiority of MFL therapy for improving postsurgical survival in patients with advanced colorectal cancer, in particular for those patients with a high risk of recurrence following potential curative resection.
The crystal structure of the Escherichia coli replication-terminator protein (Tus) bound to terminus-site (Ter) DNA has been determined at 2.7 A resolution. The Tus protein folds into a previously undescribed architecture divided into two domains by a central basic cleft. This cleft accommodates locally deformed B-form Ter DNA and makes extensive contacts with the major groove, mainly through two interdomain beta-strands. The unusual structural features of this complex may explain how the replication fork is halted in only one direction.
Ryudocan, a heparan sulfate proteoglycan, was isolated from human endothelium-like EAhy926 cells by a combination of ion-exchange and immunoaffinity chromatography. Purified human ryudocan has biochemical properties similar to those of rat ryudocan isolated from microvascular endothelial cells. Human ryudocan contains only heparan sulfate (HS) glycosaminoglycan chains along with a core protein with an apparent molecular mass of 30 kDa. We evaluated the interactions between purified human ryudocan and several extracellular ligands by using a solid-phase binding assay. We found that basic fibroblast growth factor (bFGF), midkine (MK), and tissue factor pathway inhibitor (TFPI) exhibit significant ryudocan binding. Heparitinase (but not chondroitin ABC lyase) treatment destroyed the ability of ryudocan binding to bFGF, MK, and TFPI. Heparin and HS, but not chondroitin sulfate, inhibited such ryudocan binding. Thus, the HS chains of ryudocan appear to be responsible for its binding to bFGF, MK, and TFPI. The apparent dissociation constants for purified ryudocan were as follows: bFGF, 0.50 nM; MK, 0.30 nM; and TFPI, 0.74 nM. Immunohistochemical analysis revealed that ryudocan was expressed in fibrous connective tissues, peripheral nerve tissues, and placental trophoblasts. These findings suggest that ryudocan may possess multiple biological functions, such as bFGF modulation, neurite growth promotion, and anticoagulation, via HS-binding effectors in the cellular microenvironment.
A new powder diffractometer for synchrotron radiation with six detector arms has been constructed. Five detector arms are attached radially at intervals of 25 degrees to the 2theta axis and form a multiple-detector system. Five scintillation counters coupled with flat Ge(111) crystal analyzers on the respective arms can simultaneously record the whole powder pattern divided into five segments, each with an equal 2theta span. The optics design is based on flat-specimen reflection geometry using a parallel beam. The intensity data are collected using a 2theta step-scan technique in asymmetric diffraction at a fixed incident angle. A sixth multi-purpose detector arm can be used in the conventional single-arm scan mode. It can be equipped with various kinds of analyzers such as long horizontal parallel slits, a fiat or channel-cut crystal analyzer, a receiving slit and a solid-state detector. Test operations of the multiple-detector system, conducted at the Photon Factory in Tsukuba, recorded a full width at half maximum of 0.022 degrees and a peak maximum intensity of more than 40000 counts s(-1) for the (111) reflection from Si powder. The whole powder pattern of Mg(2)SiO(4) over a 2theta range of 130 degrees could be step-scanned at a step interval of 0.004 degrees (2theta) in just 4 h. Results of whole-powder-pattern decomposition and Rietveld refinement of the Mg(2)SiO(4) pattern are given.