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Biomedical subjects

S Todo

Publications and source records attributed to S Todo.

At least 55 records · Page 3Linked to original sources
PubMed2000

Detection of clonotypic IGH and TCR rearrangements in the neonatal blood spots of infants and children with B-cell precursor acute lymphoblastic leukemia.

An attractive hypothesis is that in utero exposure of hematopoietic cells to oncogenic agents can induce molecular changes leading to overt acute lymphoblastic leukemia (ALL) in infants and perhaps older children as well. Although supported by studies of identical infant twins with concordant leukemia, and of nontwined patients with MLL gene rearrangements, this concept has not been extended to the larger population of B-lineage ALL patients who lack unique nonconstitutive mutations or abnormally rearranged genes. We therefore sought to demonstrate a prenatal origin for 7 cases of B-cell precursor ALL (either CD10(+) or CD10(-)) that had been diagnosed in infants and children 14 days to 9 years of age. Using a polymerase chain reaction-based assay, we identified the same clonotypic immunoglobulin heavy-chain complementarity determining region or T-cell receptor V(D)2-D(D)3 sequences in the neonatal blood spots (Guthrie card) and leukemic cell DNAs of 2 infants with CD10(-) ALL and 2 of the 5 older patients with CD10(+) ALL. Nucleotide sequencing showed a paucity of N or P regions and shortened D germ line and conserved J sequences, indicative of cells arising from fetal hematopoiesis. Our findings strongly suggest a prenatal origin for some cases of B-cell precursor ALL lacking specific clonotypic abnormalities.

Base Sequence↗
PubMed2000

Quantum phase transition of the randomly diluted heisenberg antiferromagnet on a square lattice

Ground-state magnetic properties of the diluted Heisenberg antiferromagnet on a square lattice are investigated by means of the quantum Monte Carlo method with the continuous-time loop algorithm. It is found that the critical concentration of magnetic sites is independent of the spin size S, and equal to the two-dimensional percolation threshold. However, the existence of quantum fluctuations makes the critical exponents deviate from those of the classical percolation transition. Furthermore, we found that the transition is not universal, i.e., the critical exponents significantly depend on S.

Journal Article↗
PubMed2000

Blocking the CD28-B7 T-cell costimulatory pathway abrogates the development of obliterative bronchiolitis in a murine heterotopic airway model.

BACKGROUND: CTLA4IgG that binds to B7 effectively inhibits the signaling of CD28/B7 pathway and induces antigen-specific T-cell unresponsiveness in vitro and in vivo. We examined whether the development of obliterative bronchiolitis in a murine heterotopic airway transplantation model is T cell dependent and whether CTLA4IgG abrogates the development of obliterative bronchiolitis. METHODS: Tracheae with main bronchi from C3H/He (H2k), BALB/C (H2d), or C57BL/6 (H2b) mice were transplanted heterotopically into subcutaneous pockets on the backs of BALB/C or BALB/C nu/nu mice on day 0. Recipient mice were untreated or intraperitoneally treated with either CTLA4IgG or human IgG with different time and dose schedules. RESULTS: The development of obliterative bronchiolitis, which leads to luminal obliteration by fibrous tissue in a murine heterotopic airway transplantation model, was T cell dependent and the development of obliterative bronchiolitis was significantly abrogated by the CTLA4IgG treatment. However, the normal ciliated columnar respiratory epithelial cells in allografts were lost and replaced by flattened attenuated epithelial cells even after the CTLA4IgG treatment. We further demonstrated that CTLA4IgG treatment did not result in the induction of donor-specific unresponsiveness. CONCLUSIONS: We demonstrated that the development of obliterative bronchiolitis in a murine heterotopic airway model involves both CD28/B7-dependent and -independent processes. The luminal obliteration by fibrous tissue is clearly CD28/B7 dependent and can be inhibited by CTLA4IgG. The luminal obliteration of allografted trachea by fibrous tissues and the loss of ciliated columnar respiratory epithelial cells represent distinct disease processes.

Abatacept↗
PubMed2000

Prolongation of canine liver allograft survival by a novel immunosuppressant, FTY720: effect of monotherapy and combined treatment with conventional drugs.

BACKGROUND: The immunosuppressive effect and other properties of a novel immunosuppressant, FTY720, have been studied mostly in the experimental transplantation of various extrahepatic organs. In this experiment, we evaluated the antirejection potency and adverse effects of this agent on liver grafts using a canine liver transplantation model. METHODS: Forty-eight orthotopic liver transplantations were performed by the standard technique under a veno-venous bypass. Liver recipients were divided into two studies: a single-dose study with FTY720 at various doses and a combined dose study with conventional immunosuppressants (cyclosporine or tacrolimus) alone and combined with FTY720. Survival, biochemical and hematological tests, blood levels of immunosuppressants, and postmortem histology were determined. RESULTS: The median survival of untreated control animals was 9 days, whereas treatment with FTY720 at a dose of 0.1 mg/kg/day prolonged graft survival to 49.5 days. FTY720 at 1 mg/kg/day showed a slight but insignificant prolongation to 16 days, but when the dose was increased to 5 mg/kg/day, the graft was rejected at 10 days. The combination of FTY720, 0.1 mg/kg/day, with a subtherapeutic dose of cyclosporine, 5 mg/kg/ day, prolonged median animal survival from 40 days with cyclosporine alone to 74 days. A combination of FTY720 (0.1 mg/kg/day) with tacrolimus (0.5 mg/kg/ day) compromised animal survival, reducing survival from 83.5 days with tacrolimus alone to 30.5 days due to infectious complication and emaciation by overimmunosuppression. No evident drug-induced side effects were observed. CONCLUSIONS: FTY720 has a potent immunosuppressive effect when used alone at 0.1 mg/kg/day in canine liver transplantation. FTY720 is a promising candidate for future clinical application in orthotopic liver transplantation.

Animals↗
PubMed2000

Distinct prognostic values of p53 mutations and loss of estrogen receptor and their cumulative effect in primary breast cancers.

A total of 76 primary breast cancers were screened for p53 mutations using the yeast p53 functional assay, and the mutations were determined by DNA sequencing. Clonal mutations of p53 were detected in 30 tumors (39%). Immunohistochemical staining for nuclear p53 accumulation performed on the yeast assay-positive cases clearly differentiated missense mutations in the DNA binding domain (contact mutant; 17 cases) as positive stain and nonsense-type mutations or missense mutations that may affect 3D-structure of p53 protein (structural mutant; 13 cases) as negative stain. Enzyme immunoassay revealed loss of estrogen receptor in 36 tumors (50%). Prognostic values of p53 mutation and loss of estrogen receptor were evaluated after a median follow-up period of 44 months. p53 mutations were associated with a short overall survival (log rank test, p = 0.0319), whereas it was not related to disease-free (recurrence-free) survival. Contact mutants were associated with slightly shorter survival compared with structural mutants. Inversely, loss of estrogen receptor was associated with early recurrence (p = 0.0461) but not with short overall survival. The patients with tumors harboring both p53 mutation and loss of estrogen receptor had the poorest outcome (p = 0.0019 and 0.0075 for overall and disease-free survivals, respectively), suggesting independent and additive effects of the 2 factors. The independent role of the 2 factors was confirmed by a multivariate analysis using the Cox proportional hazard model stratified according to clinical tumor stages. Although preliminary, due to the small number of patients studied and the relatively short follow-up time, our results suggest that p53 mutations and loss of estrogen receptor cooperatively affect the prognosis of primary breast cancer patients.

Adult↗
PubMed2000

Serial analysis of MLL-AF4 chimeric message through successful bone marrow transplantation in a patient with t(4;11)-positive infant-ALL.

A 28-month-old girl with acute lymphoblastic leukemia (ALL) showing a t(4;11)(q21;q23) karyotype successfully underwent allogeneic bone marrow transplantation (BMT) at relapse. The chimeric MLL-AF4 message on her bone marrow (BM) specimens, examined by reverse transcriptase-polymerase chain reaction, was detectable at diagnosis, relapse, and just before BMT but became undetectable following BMT. She has since maintained complete remission. This observation suggests that detection of the chimeric message in BM may be useful to predict clinical outcome in patients with t(4;11) ALL.

Biomarkers, Tumor↗
PubMed2000

An antibody for macrophage migration inhibitory factor suppresses tumour growth and inhibits tumour-associated angiogenesis.

To verify the role of macrophage migration inhibitory factor (MIF) in tumourigenesis, we examined the effect of an anti-MIF antibody on tumour growth and angiogenesis. We inoculated murine colon adenocarcinoma cell line colon 26 cells subcutaneously into the flank in BALB/c mice. After nine days, we treated tumour-bearing mice with an anti-rat MIF antibody by intraperitoneal injection on days 9, 11, 13, 15, 17, 19 and 21. We found significant inhibition of tumour growth by this treatment from day 15 to day 22. Next, we implanted a chamber filled with colon 26 cells, which only passes soluble factors, in the subcutaneous fascia of the flank, and treated mice with the anti-rat MIF antibody at days 1, 3 and 5. By histological examination at day 6, angiogenesis within the subcutaneous fascia in contact with the chamber was markedly suppressed. In vitro, we added an anti-human MIF antibody to human umbilical vein endothelial cells (HUVEC) to evaluate its effect on cell growth by measurement of [3H]thymidine incorporation. We observed that the anti-MIF antibody significantly suppressed [3H]thymidine uptake by HUVEC. These results suggest the possibility that MIF is involved in tumourigenesis via promotion of angiogenesis.

Adenocarcinoma↗
PubMed2000

Somatic mutations of the APC gene in primary breast cancers.

APC gene mutations play an important role in the initiation step of colorectal carcinogenesis in both familial adenomatous polyposis (FAP) patients and non-FAP patients. Although the APC gene is expressed in most tissues, including the lung, liver, kidney, and mammary gland, its somatic mutations have rarely been found in primary tumors affecting these organs. We have developed a sensitive yeast-based assay for screening almost the entire coding region of the APC gene. By this method, we have been able to detect somatic mutations of the APC gene in 57% of colorectal cancers and none in non-small cell lung cancers. Interestingly, the assay detected somatic APC gene mutations in 18% of breast cancers, in which APC gene mutation was previously considered rare. In the breast cancers, most of the APC mutations were distributed outside the mutation cluster region that has been advocated for colorectal cancers. We also noted a difference in the mutation pattern of the APC between colorectal and breast cancers. In colorectal cancers, all base substitutions were observed at C residues (5 of 5), whereas in breast cancers the majority of them were found at G residues (4 of 5). Furthermore, APC mutations were observed at a significantly high frequency in advanced stages of primary breast cancers (TNM classification, P < 0.05; T category, P < 0.01). Our data suggest that the etiology of the APC mutations and their biological role in carcinogenesis may differ between colorectal and breast cancers.

Adenomatous Polyposis Coli↗
PubMed2000

Sequential observation of liver cell regeneration after massive hepatic necrosis in auxiliary partial orthotopic liver transplantation.

The morphogenesis of hepatocytes after massive hepatic necrosis to recovery through liver cell regeneration has not been fully understood. Sequential biopsies were performed on the native liver of a 22-year-old man who underwent auxiliary partial orthotopic liver transplantation 1 month after fulminant hepatitis. Auxiliary partial orthotopic liver transplantation was successful, and the biopsy samples permitted us to examine the regenerating process of hepatocytes after massive necrosis. At the time of auxiliary partial orthotopic liver transplantation (postoperative day 0), 95% of hepatocytes were lost and a few ductules were found in the portal areas. The ductules stained with cytokeratin 19. At postoperative day 7, the ductules began to increase in size and number and became dilated over a period of 1 month, when individual hepatocytes with clear cytoplasm appeared from the ductules. As the differentiation of hepatocytes increased, the expression of cytokeratin 19 was found to decrease. From 2 to 3 months, all of the ductules were transformed into hepatocytes, and they began to form round cell clusters. From 3 to 6 months, the round cell clusters became organized into trabecula with fibrosis. From 6 to 12 months, a lobular architecture was established, and by 14 months, the necrotic liver was fully recovered to normal. This study by examination of sequential biopsies demonstrates the progression of the regenerating process from total hepatic necrosis to complete recovery.

Adult↗
PubMed2000

FK506-induced intractable leukoencephalopathy following allogeneic bone marrow transplantation.

FK506-related leukoencephalopathy has been reported to be reversible and readily treated by discontinuation or reduction of FK506. We describe two pediatric cases of FK506-related leukoencephalopathy following allogeneic bone marrow transplantation, which could not be readily controlled. These cases show that FK506-related leukoencephalopathy is not always reversible, and patients may develop epilepsy. Bone Marrow Transplantation (2000) 25, 331-334.

Acute Disease↗
PubMed2000

Splenectomy in haemophagocytic lymphohistiocytosis: report of histopathological changes with CD19+ B-cell depletion and therapeutic results.

The pathogenesis of haemophagocytic lymphohistiocytosis (HLH) in children without a known familial pattern of inheritance is often difficult to establish. Splenic enlargement, one of the main clinical findings in this disorder, has led to the use of splenectomy for uncontrollable coagulopathy, persistent cytopenia or both. This procedure is also thought to be a useful tool in making a differential diagnosis in cases of the immunochemotherapy-resistant HLH. We report here five cases of splenectomized childhood HLH, in which subsets of mononuclear spleen cells were analysed either by flow cytometry or immunohistochemistry, and the results were compared with those from cases of hereditary spherocytosis (controls). There was a statistically significant depletion of CD19+ B cells in the HLH cases (3.8 +/- 3.2% vs. 52.6 +/- 4.5%, P < 0. 0001) associated with an increase of T cells in three cases and of natural killer cells in another. The histopathological findings included atrophic white pulps, B-cell depletion with fibrosis and haemosiderosis in all five cases. Despite temporary therapeutic benefits, three of the HLH patients had a rapidly deteriorating post-splenectomy course and all three eventually died. These results demonstrate striking depletion of B cells in the enlarged spleens of children with HLH, which may be an intrinsic feature of HLH pathogenesis. Further study is needed to establish the therapeutic value of splenectomy in this disease.

Antigens, CD19↗
PubMed2000

Living donor liver transplantation in adults: outcome in Japan.

1. Twenty centers in Japan performed 308 living donor liver transplants (LDLT) in adults. 2. Right lobe grafts were used in the minority of cases (27.1%); most had left lobe grafts (72.9%). Survival was not influenced by the type of graft. 3. There were no donor deaths (0%); 9.3% of donors experienced mild to moderate complications. Biliary complications were the most frequent. 4. Overall recipient survival was 72.4%.

Adult↗
PubMed2000

A novel hydroxyl radical scavenger, nicaraven, protects the liver from warm ischemia and reperfusion injury.

BACKGROUND: Reactive oxygen species have been considered to be involved in liver injury at the procurement, preservation, and transplantation from donors without beating hearts. A novel hydroxyl radical scavenger, nicaraven with hydrophilic and lipophilic properties, infiltrates both intracellular and extracellular spaces where it effectively scavenges reactive oxygen species. Protection by nicaraven against ischemia and reperfusion damage of the brain, heart, and kidneys has been shown. The effect of this agent on the liver remains unclear. METHODS: Two-hour total hepatic vascular exclusion was used. Eighteen beagle dogs were randomly assigned to 2 groups: 12 animals were not treated (group I) and 6 were treated with nicaraven (group II). Nicaraven was administered intravenously (2mg/kg/min) for 60 minutes before ischemia and for 3 hours, starting 30 minutes before reperfusion. RESULTS: Two-week survival rates were 25% in group I and 100% in group II (P <.01). Nicaraven inhibited lipid peroxidation in the liver, improved hepatic and systemic hemodynamics and energy metabolism, and suppressed liver enzyme release, endothelin-1 elevation in hepatic venous blood, histologic damage, and neutrophil infiltration into the liver. CONCLUSIONS: Nicaraven exerted hepatic protection against warm ischemia and reperfusion injury. This may indicate nicaraven as a potential candidate to attenuate liver injury from warm ischemia and preservation in transplantation from donors without beating hearts.

Adenine Nucleotides↗
PubMed2000

Tibiofemoral movement 3: full flexion in the living knee studied by MRI.

We studied active flexion from 90 degrees to 133 degrees and passive flexion to 162 degrees using MRI in 20 unloaded knees in Japanese subjects. Flexion over this arc is accompanied by backward movement of the medial femoral condyle of 4.0 mm and by backward movement laterally of 15 mm, i.e., by internal rotation of the tibia. At 162 degrees the lateral femoral condyle lies posterior to the tibia.

Adult↗
PubMed2000

Molecular analysis of latent membrane protein 1 in patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Japan.

Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is considered to be an oncoprotein because it is crucial for B-lymphocyte transformation. Since a 30 base pair (bp) deletion in the carboxy-terminal portion of the LMP1 gene was found in a CAO cell line derived from nasopharyngeal carcinoma containing EBV, an association between EB viral genetic alteration and tumorigenicity has been postulated. In this study we have analyzed LMP1 DNA isolated from 10 Japanese patients with EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). In all HLH patients, we found the 30 bp deletion and 4-8-tandem repeats of the sequence DNGPQDPDNTD in the LMP1 gene. Furthermore, detailed amino acid (aa) sequence analysis revealed that 7 aa substitutions identical to those found in CAO-LMP1 but not in B95.8 cell line-LMP1 were found in all the HLH cases. NF-kappaB assay revealed that HLH-LMP1 activated NF-kappaB significantly more than that of B95.8-LMP1 (p=0.032). We conclude that EBV from all of our HLH cases shared common genetic characteristics with EBV obtained from the CAO cell line, which is distinct from the wild-type EBV isolated from the B95.8 cell line. These data suggest that the mutational changes of the LMP1 gene may play an important role in the pathogenesis of these fatal EBV-related disorders.

Adolescent↗
PubMed2000

Correlation between elevated intratumoral thymidine phosphorylase and prognosis of node-positive breast carcinoma undergoing adjuvant doxifluridine treatment.

We determined intratumoral thymidine phosphorylase (dThdPase) activity in 213 patients with T2N0M0 or T2N1M0 breast cancer. After surgery doxifluridine, an intermediate metabolite of capecitabine, and tamoxifen were given by mouth. According to dThdPase activity the examined patients were classified as: A, high activity group; tumors with the activity not less than the mean value and B, low activity group; tumors with activity less than the mean value. Group A had a better prognosis than group B in node-positive patients (disease-free survival, p=0.0446; overall survival, p=0.0788). Intratumoral dThdPase activity might be a useful marker for predicting responsiveness to doxifluridine treatment in the adjuvant setting.

Adult↗