Identification of eight novel NSD1 mutations in Sotos syndrome.
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Abnormalities, Multiple↗
Biomedical subjects
K Miyakawa
Publications and source records attributed to K Miyakawa.
Accuracy of contrast-enhanced computed tomography in the prediction of residual breast cancer after neoadjuvant chemotherapy.
Determination of the extent of residual disease after neoadjuvant chemotherapy is sometimes inaccurate by conventional diagnostic methods. The purpose of this study was to evaluate the accuracy of contrast-enhanced computed tomography (CE-CT) in depicting the extent of residual carcinomas. Fifty-seven patients with breast carcinomas of 3 cm diameter or more received neoadjuvant chemotherapy with four cycles of AT (doxorubicin and docetaxel). Before surgery, the patients underwent clinical examination, mammogram (MMG), ultrasonography (US), and CE-CT. Thirteen patients were not evaluated by CE-CT before surgery. Enhancement patterns on CE-CT were classified into multiple spots, tumor and spots, solid tumor type, and no enhancement. When all types of cancers were included in the analysis, clinical examination showed the best correlation with the pathology of the extent of residual carcinomas. However, except in invasive lobular carcinoma (ILC) and inflammatory breast carcinoma (IBC), CE-CT showed the best correlation (R insertion mark2 = 0.537). More than half of the residual microcalcifications on MMG after neoadjuvant chemotherapy suggested residual viable tumor. In conclusion, CE-CT is the most accurate noninvasive technique for identifying the extent of the residual carcinoma after neoadjuvant chemotherapy if cases of IBC and ILC are excluded.
Adult↗
Contrast-enhanced computed tomography for diagnosing the intraductal component and small invasive foci of breast cancer.
It is important to eliminate local residual cancer to avoid local recurrence after breast conserving treatment. Many efforts have been made to detect extensive intraductal components (EICs) and small invasive foci of breast cancer by diagnostic imaging including MRI and contrast-enhanced computed tomography (CE-CT). The abilities and limitations of CE-CT are reviewed in this article. The sensitivity of EIC detection by CE-CT ranges from 76% to 88%, and specificity from 79% to 89%. The sensitivity for detecting EIC and cancerous lesions were significantly higher for CE-CT than for US or MMG. The enhanced patterns of CE-CT demonstrating EIC and small invasive foci were classified into diffuse, spotty, linear and multiple types. The differences of the size of cancerous extension by CE-CT from the pathological EIC were within 2 cm in almost all cases. CE-CT is useful for visualizing EIC and small invasive foci of breast cancer.
Breast Neoplasms↗
Two special types of breast cancer presenting as progressive disease after neoadjuvant chemotherapy with docetaxel plus doxorubicin.
Seventy-eight patients with primary breast cancer over 3 cm in diameter in stages II A, II B, III A and III B according to the UICC classification received neoadjuvant chemotherapy from August 1, 1998 to June 30, 2000 at the Breast Division of the National Cancer Center Hospital. Neoadjuvant chemotherapy consisted of doxorubicin (Adriamycin: ADM) 50 mg/m(2) and docetaxel (Taxotere: DOC) 60 mg/m(2) every three weeks. The overall clinical response to this regimen was 88% (69/78). Although neoadjuvant chemotherapy with this regimen achieved good responses in patients with breast cancer, 2 patients presented with progressive disease (PD) after treatment. One patient had inflammatory breast cancer (IBC) and the other had primary squamous cell carcinoma (SCC) of the breast. There were 4 cases of IBC and one case of SCC of the breast who received neoadjuvant chemotherapy in this series. Our observations suggest that this regimen might not be effective for these types of breast cancer.
Adult↗
Diabetic mastopathy: a case report with reference to the findings of enhanced computed tomography.
We report a case of insulin-dependent diabetic fibrous mastopathy with special reference to the findings of computed tomography (CT). The patient was a 27-year-old woman with a history of insulin-dependent diabetes mellitus from childhood who presented with a right breast tumor. Physical examination showed a stony-hard, ill-defined but freely movable mass under the nipple of the right breast without nipple discharge. Mammography revealed a high-density mass shadow without microcalcifications or spicular formation. Ultrasonographic examination revealed an irregularly-shaped hypoechoic lesion with marked posterior acoustical shadowing. Contrast-enhanced CT revealed poor early phase contrast enhancement and slight delayed phase heterogeneous enhancement. Since core needle biopsy revealed fibrocystic disease, the lesion was suspicious for diabetic mastopathy. Incisional biopsy of the right breast lump was performed. On histopathological examination, the lesion showed fibrosis with dense lymphocytic infiltration around the lobules. Diabetic fibrous mastopathy was diagnosed. Physicians should be aware of the association of long-standing diabetes mellitus with the development of fibrous mastopathy. CT is considered a useful tool to differentiate diabetic mastopathy from breast cancer.
Adult↗
Role of granulocyte/macrophage colony-stimulating factor in zymocel-induced hepatic granuloma formation.
To examine the role of granulocyte/macrophage colony-stimulating factor (GM-CSF) in inflammatory granuloma formation, we injected GM-CSF-deficient (GM-CSF(-/-)) mice and wild-type (GM-CSF(+/+)) mice intravenously with 2 mg of zymocel, and mice were killed at various intervals for examination. In GM-CSF(-/-) mice, we demonstrated a marked delay of zymocel-induced hepatic granuloma formation until 5 days after zymocel injection with a rapid reduction in numbers of granulomas at 10 days until their disappearance. In the early phase of granuloma formation, monocyte infiltration and differentiation of monocytes into macrophages were impaired in GM-CSF(-/-) mice compared with GM-CSF(+/+) mice. The percentages of [(3)H]thymidine-labeled macrophages at 2 days after zymocel injection were lower in the GM-CSF(-/-) mice than in the GM-CSF(+/+) mice. The DNA nick-end-labeling method demonstrated increased numbers of apoptotic cells in and around hepatic granulomas of GM-CSF(-/-) mice from 8 days after zymocel injection, and electron microscopy detected apoptotic bodies. Granuloma macrophage digestion of glucan particles and activation of macrophages were similar in the two types of mice. In situ hybridization demonstrated expression of GM-CSF mRNA in the endothelial cells, hepatocytes, and some granuloma cells in the GM-CSF(+/+) mice but not in the GM-CSF(-/-) mice. These results provide evidence that GM-CSF is important for the influx of monocytes into hepatic granulomas, for differentiation of monocytes into macrophages, and for proliferation and survival of macrophages within hepatic granulomas.
Animals↗
Glutathione S-transferase Pi is a dopamine-inducible suppressor of dopamine-induced apoptosis in PC12 cells.
The finding that the neurotransmitter dopamine induces apoptosis in neurons implies the existence of a cellular mechanism by which dopaminergic neurons protect themselves from dopamine-induced apoptosis. By profiling the expression of a number of genes in differentiating PC12 cells which exhibit elevated levels of dopamine biosynthesis, we found that expression of glutathione S-transferase class Pi (GSTp) mRNA was selectively up-regulated. Interestingly, dopamine added to the culture medium of PC12 cells also augmented their expression of GSTp mRNA. Suppression of GSTp expression by transfection of its antisense expression vector augmented dopamine-induced apoptosis of PC12 cells. Conversely, overexpression of GSTp made the resultant PC12 transfectants highly resistant to dopamine-induced apoptosis. Transfection of the antisense or sense GSTp expression vectors also resulted in corresponding augmentation or suppression of dopamine-induced activation of cell-associated Jun-N-terminal kinase (JNK), which has been suggested to mediate dopamine-induced apoptosis in neuronal cells. These results indicate that GSTp is a dopamine-inducible suppressor of dopamine-induced apoptosis in PC12 cells, and suggest that this activity is exerted through inhibition of JNK activity.
Animals↗
Characterizations of critical processes in liquid-liquid phase separation of the elastomeric protein-water system: microscopic observations and light scattering measurements.
Biological self-assembly process of tropoelastin in an extracellular space, viewed as a key step of the elastogenesis, can be mimicked by the temperature-dependent coacervation of the elastin-related polypeptide-water system. Early and late stages of the phase separation behavior of the bovine neck ligamental alpha-elastin-water system were examined respectively by the laser light scattering photometry and phase contrast microscopy. Changes in the hydrodynamic size of molecular assemblies and visible microcoacervate droplet size were traced as a function of the concentration of alpha-elastin and temperature. Near the critical point, alpha-elastin concentration of 0.11 mg/mL and temperature of 21.5 degrees C, the phase separation was initiated after fast increase of the hydrodynamic size of primary aggregates as scattering particles and followed by the appearance of larger microcoacervate droplets with a broad size distribution. Whereas in the off-critical region, slow decrease of the hydrodynamic size of primary particles induced phase separation with smaller droplets of a narrow size distribution. Observation of the phase separation processes in the alpha-elastin-water system with metal chlorides and hydrophobic synthetic model polypeptide-water system indicated that the fast and slow molecular assembly processes were based on the fundamental hydrophobic interactions and involvements of electrostatic interactions between charged amino acid residues, respectively.
Animals↗
Changes in findings of mammography, ultrasonography and contrast-enhanced computed tomography of three histological complete responders with primary breast cancer before and after neoadjuvant chemotherapy: case reports.
We report the changes in the findings of imaging examinations (mammography, ultrasonography and contrast-enhanced computed tomography) of three patients with primary breast cancer before and after neoadjuvant chemotherapy, who obtained histologically complete responses after the chemotherapy. The neoadjuvant chemotherapy consisted of four cycles of doxorubicin and docetaxel. All patients were clinically judged as partial responders, because of the remaining tumorous lesions in the imaging examinations. However, these tumorous lesions could be related to the chemotherapy-induced fibrosis and tumor necrosis or the remaining fibrocystic changes. In this study, it was considered very difficult to estimate the extent of residual tumors accurately in patients with primary breast cancer after neoadjuvant chemotherapy by any type of imaging examination.
Aged↗
Chemical waves in self-oscillating gels
The behaviors of a poly(N-isopropyl acrylamide) (PNIPA) gel coupled with the Belousov-Zhabotinsky (BZ) reaction has been investigated as a function of temperature and catalyst concentration. In this type of gel, the chemical oscillation in the BZ reaction induces periodic and autonomous swelling-shrinking volume changes of the gel, and conversely a volume change of the PNIPA gel affects the propagation of the chemical wave. Our attention was focused on the effects of mechanical changes on the chemical wave by utilizing the thermally driven volume phase transition of the gel. Both the velocity and the frequency of the chemical wave increased with increasing temperature, and abruptly decreased at the volume transition temperature of the gel, T(c). The diffusion of HBrO2, which is essential for wave propagation, was hindered with increasing temperature. The diffusion of HBrO2 through the gel network in the low temperature region was explained in the same way as a simple diffusion of inactive molecules through a restricted environment.
Journal Article↗
Close association between high serum ALT and more rapid recurrence of hepatocellular carcinoma in hepatectomized patients with HCV-associated liver cirrhosis and hepatocellular carcinoma.
We investigated whether or not a high serum alanine aminotransferase (ALT) level is associated with a more rapid recurrence of hepatocellular carcinoma (HCC) in hepatectomized patients with hepatitis C virus (HCV)-associated liver cirrhosis (LC) (HCV-LC) and HCC. Thirty-three hepatectomized patients with HCV-LC and HCC of a single nodule who had no histologic evidence of portal or hepatic vein invasion and who had been followed up for more than 3 years were included in the study. They were subdivided into two groups according to their serum ALT levels, ALT being a well-known marker of inflammatory necrosis in the liver. Seventeen patients whose serum ALT levels showed several peaks or plateaus above 80 international units (IU) were designated as the high ALT group, and 16 patients whose serum ALT levels showed a sustained low level below 80 IU until the first recurrence were designated as the low ALT group, and the interval between hepatectomy and the first recurrence was observed. In the high ALT group, HCC recurred within 3 years in 70.6% of the patients. In contrast, it recurred in only 18.8% of the low ALT group within the same period (p < 0.05). There was a significant difference (p = 0.0201) between the two groups in the cumulative nonrecurrence rate. The mean interval in recurrent patients between hepatectomy and the first recurrence in the high ALT group (23.6 +/- 2.8 months; mean +/- SE) was significantly (p < 0.02) shorter than that in the low ALT group (49.3 +/- 9.7 months). The expected interval between hepatectomy and recurrence was as short as 2.8 +/- 0.5 years (mean +/- SE) in the high ALT group, compared with 5.8 +/- 0.7 years in the low ALT group (p < 0.05). These results showed that the recurrence of HCC was accelerated in the high ALT group, suggesting that suppression of the rise in ALT level after hepatectomy by treatment with anti-inflammatory drugs may prolong the interval until recurrence by about 2 years in hepatectomized patients with HCC and HCV-LC.
Aged↗
A hydrophobic region locating at the center of fibroblast growth factor-9 is crucial for its secretion.
Fibroblast growth factor (FGF)-9 is a glycosylated neurotrophic polypeptide highly expressed in brain. The mechanism for its secretion from expressing cells is unclear, because its primary structure lacks a cleavable signal sequence. We, therefore, investigated the mechanism and structural requirements for secretion of FGF-9. As with other secreted proteins, in vitro translation of FGF-9 was inhibited by signal recognition particle, which binds to the signal sequence. When translated in vitro, full-length FGF-9 was translocated into microsomes, glycosylated, and protected from trypsin digestion. By using various FGF-9 deletion mutants, we found that two hydrophobic domains, located at the N terminus and at the center of the FGF-9 primary structure, were crucial for translocation. Examination of various point mutants revealed that local hydrophobicity of the central hydrophobic domain, but not the N terminus, was crucial for translocation. Analogous results were obtained with respect to FGF-9 secretion from transfectant cells. Upon deletion of the complete sequence preceding it, the previously uncleavable hydrophobic domain appeared to serve as a cleavable signal sequence. Our results suggest that nascent FGF-9 polypeptides translocate into endoplasmic reticulum without peptide cleavage via a co-translational pathway in which both the N terminus and the central hydrophobic domain are important; thereafter, FGF-9 is glycosylated and secreted.
Amino Acid Sequence↗
Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis.
BACKGROUND: Many studies have demonstrated in animal experiments that persistent inflammation may accelerate the development of carcinoma. In this article, the question of whether the persistent elevation of serum alanine aminotransferase (ALT) levels (which represents the inflammatory necrosis of hepatocytes) correlates with the development of hepatocellular carcinoma (HCC) was studied in patients with early stage hepatitis C virus (HCV)-associated cirrhosis. METHODS: Sixty-nine consecutive patients with biopsy proven HCV-associated cirrhosis (mostly Child's Stage A) who had been followed for >5 years for the development of HCC were studied. They were subdivided into 3 groups according to their serum ALT levels: Group A was comprised of 28 patients whose annual average serum ALT level was persistently high (>/= 80 IU) (high ALT group), Group B was comprised of 28 patients whose annual average serum ALT level was persistently low (< 80 IU) (low ALT group), and Group C was comprised of 13 unclassified patients. The patients had been studied prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography for > 5 years. RESULTS: In the high ALT group HCC developed in 71.4% of patients compared with 25.0% in the low ALT group over the observation period (P < 0.005). The 5-year rate of incidence of HCC in the high ALT group was as high as 53.6% compared with only 7.1% in the low ALT group (P < 0.001). The expected interval between the diagnosis of cirrhosis and the development of HCC was 6.0 +/- 0.7 years (mean +/- standard error) in the high ALT group and 12.7 +/- 1.2 years in the low ALT group (P < 0.001). CONCLUSIONS: The results of the current study demonstrated that the development of HCC was more rapid in the high ALT group with HCV-associated cirrhosis.
Aged↗
Granulocyte/macrophage colony-stimulating factor and interleukin-3 correct osteopetrosis in mice with osteopetrosis mutation.
Although young mice homozygous for the osteopetrosis (op) mutation usually developed prominent osteopetrosis, its severity was markedly reduced in aged op/op mice. This age-associated reversal of osteopetrosis was accompanied by the expansion of bone marrow cavities and increased numbers of tartrate-resistant acid phosphatase (TRAP)-positive cells and of macrophages in the bone marrow. The TRAP-positive cells were mononuclear and developed ruffled borders and numerous vesicles, vacuoles, and granules. Enzyme-linked immunosorbent assay demonstrated a significant elevation of serum granulocyte/ macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-3 levels in the aged op/op mice. To examine whether GM-CSF and/or IL-3 could correct osteopetrosis in young op/op mice, 5 ng of recombinant murine (rm)GM-CSF and/or 100 ng of rmIL-3 were injected daily into young op/op mice. In these treated young op/op mice, the bone marrow cavities were expanded significantly at 2 weeks after administration, associated with significantly increased numbers of TRAP-positive cells and bone marrow macrophages. TRAP-positive cells increased in number with days after injection. These results suggest that GM-CSF and IL-3 induce the development of osteoclasts to correct osteopetrosis in the op/op mice with aging.
Aging↗
Contrast-enhanced computed tomography detection of occult breast cancers presenting as axillary masses.
Some non-palpable breast cancers presenting as axillary metastases (occult breast cancer, OBC) are not clinically detectable by either mammography (MMG) or ultrasonography (US). We performed contrast-enhanced computed tomography (CE-CT) in order to locate the primary tumors in five cases of OBC and succeeded in locating all of them.
Aged↗
The C-terminal region of fibroblast growth factor-1 is crucial for its biological activity and high level protein expression in mammalian cells.
We have studied the role of the carboxyl(C)-terminus of fibroblast growth factor(FGF)-1 using prokaryotic and eukaryotic expression systems. The full-length FGF-1 protein and its mutants lacking 6- and 9-amino acids at the C-terminus IFGF-1 (Cdel6) and FGF-1 (Cdel9), respectively] could be expressed in E. coli cells at the similar levels. The deletion mutants bound very weakly to FGF receptor and to heparin, and did not stimulate DNA synthesis in BALB/c3T3 cells. In contrast to E. coli cells, in NIH3T3 transfectants and L6 transfectants, the protein expression level of FGF-1 (Cdel6) was significantly lower than that of FGF-1, and longer C-terminal deletions further decreased the protein expression levels. However, the level of transcripts in the transfectants and the level of translates in in vitro system were equivalent for all the FGF-1 constructs. Treatment with proteasome inhibitors of the NIH3T3 transfectants expressing FGF-1(Cdel6) increased the protein level six-fold. The results indicate that the C-terminus of FGF-I is crucial for its biological activity and high-level expression in mammalian cells and suggest that deletion of the C-terminus of FGF-1 induces its post-translational degradation by proteasome system.
3T3 Cells↗
Distinct regulation of myoblast differentiation by intracellular and extracellular fibroblast growth factor-1.
We studied the role of fibroblast growth factor (FGF)-1 in the physiology of myoblast differentiation. We found that, while endogenous FGF-1 in L6-10 rat myoblasts did not suppress the progress of differentiation, the addition of FGF-1 to the culture medium suppressed it. Moreover, L6-10 cells stably transfected with full length FGF-1 undergo enhanced differentiation. The latter was well correlated with myogenin expression and myotube formation. Constitutive expression of a mutant FGF-1 (FGF-1U) that lacked a nuclear localization signal, promoted the differentiation of the myoblasts even more strongly. Furthermore, the expression of FGF-1U in an inducible expression system enhanced myogenin expression promptly. In L6-10 transfectants expressing a dominant-negative mutant of FGF receptor, stable transfection of FGF-1 promoted differentiation as it did in parent cells. Studies with FGF receptors and MAP kinase suggest that both are involved in the effect of FGF-1 when it is supplemented to culture medium but not during the effect of endogenous FGF-1 synthesized in cells. We conclude that intracellular (endogenous) and extracellular (exogenous) FGF-1 have differential effects on the regulation of myogenic differentiation of L6-10 cells.
Amino Acid Sequence↗
Effects of recombinant human macrophage colony-stimulating factor on proliferation, differentiation and survival of Kupffer cells in the liver of adult mice.
OBJECTIVE: To investigate the effects of macrophage colony-stimulating factor (M-CSF) on the proliferation, differentiation and survival of Kupffer cells in the liver of adult mice. STUDY DESIGN: By the combined method of autoradiography with [3H]thymidine and immunohistochemistry using a monoclonal antibody against mouse macrophages (F4/80 or BM8), the labeling rate of [3H]thymidine in macrophages within the liver sinusoids was examined at various intervals after single flash labeling with [3H]thymidine in adult mice with or without daily administration of recombinant human M-CSF. RESULTS: A minor population of Kupffer cells (about 2%) possessed proliferative capacity under a normal steady state condition. With time after flash labeling, the influx of monocytes and their differentiation into macrophages were demonstrated in the liver, and their labeling rate returned to the baseline level one week later. Afterward, the labeling rate of Kupffer cells was maintained at the baseline level until the end of five weeks. Administration of M-CSF enhanced the proliferative capacity of Kupffer cells, increased the number of macrophages and delayed the time of peaking. However, it did not prolong the survival of Kupffer cells. CONCLUSION: In normal mice, Kupffer cells can survive for at least five weeks. Daily M-CSF administration induces the increased number and proliferative capacity of Kupffer cells.
Animals↗