Are exon 19 deletions and L858R EGFR mutations in non-small-cell lung cancer clinically different?
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Antineoplastic Agents↗
Biomedical subjects
S Kobayashi
Publications and source records attributed to S Kobayashi.
Substance P stimulates late-stage rat osteoblastic bone formation through neurokinin-1 receptors.
Substance P (SP) is a widely distributed neuropeptide that works as a neurotransmitter and neuromodulator. Recently, SP receptors, particularly neurokinin-1 receptors (NK(1)-Rs) that have a high affinity for SP, have been observed not only in neuron and immune cells, but also in other peripheral cells, including bone cells. To identify the role of SP in bone formation, we investigated the expression of NK(1)-Rs in osteoblastic cells and the effects of SP on bone formation by rat calvarial osteoblastic cells. Rat calvarial osteoblastic cells were isolated and cultured for 3 weeks in alpha-MEM containing 10% serum, ascorbic acid, dexamethasone, and beta-glycerophosphate. We then investigated NK(1)-R expression, SP effects on osteoblastic bone formation, and osteocalcin mRNA expression in osteoblastic cells. RT-PCR and immunocytochemistry showed that NK(1)-R mRNA was expressed and NK(1)-R was present in 14-day, but not 7-day, cultured calvarial osteoblasts. Bone formation by cultured osteoblastic cells significantly increased after the addition of 10(-8)-10(-6)MSP. During 3 weeks of culture, the addition of SP in the first week did not significantly increase bone formation, whereas adding SP during the first and second week or all 3 weeks significantly increased calvarial osteoblastic bone formation. Furthermore, semi-quantitative RT-PCR indicated that SP stimulated osteocalcin mRNA expression in the osteoblasts at day 14 or day 21, whereas SP did not stimulated the runX2 or type I collagen mRNA expression at day 7 but stimulated them at day 14. These results indicate that SP stimulates bone formation by osteoblastic cells via NK(1)-Rs at late-stage bone formation. These effects were dependent on the expression of NK(1)-R in osteoblastic cells. Our findings suggest that SP secreted from sensory neurons may modulate bone formation after the expression of SP receptors.
Animals↗
Minority spin condensate in the spin-polarized superfluid 3He A1 phase.
The magnetic properties of (3)He in its various phases originate from the interactions among the nuclear spins. The spin-polarized 'ferromagnetic' superfluid (3)He A(1) phase (which forms below 3 mK between two transition temperatures, T(c1) and T(c2), in an external magnetic field) serves as a material in which theories of fundamental magnetic processes and macroscopic quantum spin phenomena may be tested. Conventionally, the superfluid component of the A(1) phase is understood to contain only the majority spin condensate, having energetically favoured paired spins directed along the external field and no minority spin condensate having paired spins in the opposite direction. Because of difficulties in satisfying both the ultralow temperature and high magnetic field required to produce a substantial phase space, there exist few studies of spin dynamics phenomena that could be used to test the conventional view of the A(1) phase. Here we develop a mechanical spin density detector that operates in the required regime, enabling us to perform measurements of spin relaxation in the A(1) phase as a function of temperature, pressure and magnetic field. Our mechanical spin detector is based in principle on the magnetic fountain effect; spin-polarized superfluid motion can be induced both magnetically and mechanically, and we demonstrate the feasibility of increasing spin polarization by a mechanical spin filtering process. In the high temperature range of the A(1) phase near T(c1), the measured spin relaxation time is long, as expected. Unexpectedly, the spin relaxation rate increases rapidly as the temperature is decreased towards T(c2). Our measurements, together with Leggett-Takagi theory, demonstrate that a minute presence of minority spin pairs is responsible for this unexpected spin relaxation behaviour. Thus, the long-held conventional view that the A(1) phase contains only the majority spin condensate is inadequate.
Journal Article↗
Optimal low-energy laser irradiation causes temporal G2/M arrest on rat calvarial osteoblasts.
Low-energy laser irradiation (LELI) accelerates wound healing and is thought to accelerate bone formation. However, the mechanism of laser healing is not clear. To clarify the biological mechanism of LELI healing, we investigated the effects of LELI on rat osteoblasts in vitro. Osteoblastic cells from 3-day-old Wistar rat calvaria were irradiated using a low-energy gallium-aluminum-arsenide (Ga-Al-As) diode laser. Bone formation, osteoblast differentiation, and cell proliferation were evaluated by von Kossa staining, reverse-transcription polymerase chain reaction, alkaline phosphatase (ALP) staining, 5-bromo-2'-deoxyuridine (BrdU) uptake, and fluorescence-activated cell sorter (FACS) analysis. At 21 days after LELI, the greatest bone formation was observed with irradiation energy of 3.75 J/cm2 and the first week after seeding. LELI (3.75 J/cm2) induced an increased number of cells at day 3. LELI-stimulated differentiation in osteoblastic cells was demonstrated by the increases of Runx2 expression and ALP-positive colonies. By contrast, at 1 day after laser irradiation, the number of cells in the irradiation group was significantly lower than that in the control group. BrdU uptake indicated lower proliferation 12 and 24 hours after irradiation compared with the control. Furthermore, FACS data demonstrated a higher proportion of cells in the G2/M phase of the cell cycle 12 hours after irradiation compared with the control. G2/M arrest was confirmed by the appearance of G2/M arrest marker 14-3-3-sigma or phospho-p53. These results demonstrate that LELI induces not only acceleration of bone formation but also initial G2/M arrest, which may cause wound healing like tissue repair.
Alkaline Phosphatase↗
Detailed images of asteroid 25143 Itokawa from Hayabusa.
Rendezvous of the Japanese spacecraft Hayabusa with the near-Earth asteroid 25143 Itokawa took place during the interval September through November 2005. The onboard camera imaged the solid surface of this tiny asteroid (535 meters by 294 meters by 209 meters) with a spatial resolution of 70 centimeters per pixel, revealing diverse surface morphologies. Unlike previously explored asteroids, the surface of Itokawa reveals both rough and smooth terrains. Craters generally show unclear morphologies. Numerous boulders on Itokawa's surface suggest a rubble-pile structure.
Journal Article↗
No effect of a traditional Chinese medicine, Hochu-ekki-to, on antibody titer after influenza vaccination in man: a randomized, placebo-controlled, double-blind trial.
BACKGROUND: It was shown that a traditional Chinese medicine, Hochu-ekki-to (HET), had adjuvant effects in influenza vaccination in an animal experiment. This, however, could not be assessed in a clinical study. METHODS: Thirty-two healthy subjects were randomly assigned to two groups (control and HET groups) in a double-blind manner. HET subjects (n=17) took 7.5 g of HET/day for two weeks; control subjects took the same amount of indistinguishable placebo. Then subjects were vaccinated against influenza (H1N1, H3N2 and B/Shandong). Hemagglutinin titers and natural killer (NK) activity were measured at weeks 0, 1, 2, 4, and 12. RESULTS: Antiinfluenza titers against the three viruses were increased continuously for the first two weeks and leveled off. However, there were no significant differences in any titers between the two groups. NK activity peaked at week 2 without any inter-group differences. CONCLUSION: We could not find any adjuvant effects of HET in this experimental condition.
Adjuvants, Immunologic↗
Projection patterns of lamina VIII commissural neurons in the lumbar spinal cord of the adult cat: an anterograde neural tracing study.
This study was designed to characterize the morphology of commissural axons, with the goal of revealing some of the organizing principles of their projections in the lumbosacral cord. Axons were labeled anterogradely with biotinylated-dextran amine which was injected in the left lamina VIII and the adjoining parts of lamina VII in the lumbar segments L5-L6 in seven cats. After 3-4 weeks, commissural axons were well labeled throughout lumbosacral segments L1-S2. After crossing the midline at the injection level, labeled axons traveled rostrally and/or caudally in the contralateral ventral and lateral funiculi giving off multiple axon collaterals. The trajectories of 34 single axons were traced in their entirety from their points of origin to their distal ends. Most of these axons were thin (proximal diameter <3.5 microm) and short (<30 mm), and gave off 6 to 32 axon collaterals at short intercollateral distances (mean <2 mm) in the lumbosacral enlargement. Some thicker axons (diameter >3.5 microm) ascended as far as the thoracic level; these supplied only four to six collaterals at long intercollateral intervals ( approximately 6.5 mm). All of the axons except one projected unilaterally. The axons as a whole terminated throughout the contralateral ventral horn. However, axons that traveled in different parts of the white matter had different characteristic terminal arborizations. The collaterals of axons that traveled in the ventral funiculus terminated preferentially in laminae VII-VIII, while those in the lateral funiculus terminated in lamina IX. Although the collateral branching patterns differed from one axon to another, collaterals arising from a particular axon usually exhibited similar patterns at different rostrocaudal levels. These uniform collateral termination patterns indicate that the morphology of each neuron might be specifically related to its function. This may allow future studies to identify different functional types of commissural neurons on the basis of much less extensive reconstructions.
Animals↗
Engineering of Escherichia coli L-serine O-acetyltransferase on the basis of crystal structure: desensitization to feedback inhibition by L-cysteine.
L-Serine O-acetyltransferase (SAT) from Escherichia coli catalyzes the first step of L-cysteine synthesis in E.coli and is strictly inhibited by the second step product, L-cysteine. To establish a fermentation process to produce L-cysteine, we embarked on a mutational study of E.coli SAT to desensitize the feedback inhibition by L-cysteine. The crystal structure and the reaction mechanism of SAT from E.coli have shown that the substrate L-serine and the inhibitor L-cysteine bind to the identical region in the SAT protein. To decrease the affinity for only L-cysteine, we first built the structure model of L-serine-binding SAT on the basis of the crystal structure with bound L-cysteine and compared these two structures. The comparison showed that the Calpha of Asp92 underwent a substantial positional change upon the replacement of L-cysteine by L-serine. We then introduced various amino acid substitutions at positions 89-96 around Asp92 by randomized, fragment-directed mutagenesis to change the position of the Asp92. As a result, we successfully obtained mutant SATs which have both extreme insensitivity to an inhibition by L-cysteine (the concentration that inhibits 50% activity; IC(50) = 1,100 micromol/l, the inhibition constant; K(i) = 950.0 micromol/l) and extremely high emzymatic activities.
Amino Acid Substitution↗
Aplastic patella tissue in a patient with isolated patella aplasia-hypoplasia.
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Adult↗
Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese.
Microscopic polyangiitis (MPA) is a rare and severe form of systemic necrotizing vasculitis associated with myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibody (ANCA). We previously reported significant association of HLA-DRB1*0901 with MPA. To define the susceptibility loci within the HLA region, we determined the genotypes of HLA-DQB1, DPB1, B and C in 50 patients with MPA and 77 unrelated Japanese controls. In addition to HLA-DRB1*0901, significant association of DQB1*0303 (allele carrier frequencies 50% in MPA, 29.9% in controls, odds ratio 2.35, P = 0.017) was detected. These alleles were in strong linkage disequilibrium (D' = 0.95, r2 = 0.82). Increased frequency was also observed for DPB1*0201, B*15111 and Cw*0303, which was at least partly accounted for by linkage disequilibrium with DRB1*0901 and DQB1*0303. These results indicate that DRB1*0901-DQB1*0303 haplotype represents the primary genetic risk for MPA within the HLA region in Japanese, and provides the basis that future functional studies on the role of HLA in MPA should target DR9, DQ9 and DR53 proteins encoded by this haplotype.
Alleles↗
Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the Dialysis Outcomes and Practice Patterns Study.
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Blood Pressure↗
Growth-promoting effect on iron-sulfur proteins on axenic cultures of Entamoeba dispar.
A growth-promoting factor (GPF) that promotes the growth of Entamoeba dispar under axenic culture conditions was found in fractions of mitochondria (Mt), hydrogenosomes (Hg) and chloroplasts (Cp) obtained from cells of six different protozoan, mammalian and plant species. We were able to extract the GPF from the Cp-rich leaf cells of a plant (spiderwort: Commelina communis L.) in an acetone-soluble fraction as a complex of chlorophyll with low molecular weight proteins (molecular weight [MW] approximately 4,600). We also found that on treatment with 0.6% complexes of 2-mercapthoethanol (2ME), complexes of chlorophyll-a with iron-sulphur (Fe-S) proteins (e.g., ferredoxins [Fd] from spinach and Clostridium pasteurianum) and noncomplex rubredoxin (Rd) from C. posteurianum have a growth-promoting effect on E. dispar. These findings suggest that E. dispar may lack a sufficient quantity of some essential components of Fe-S proteins, such as Fe-S center.
Animals↗
Aging and oxidative stress in progressive supranuclear palsy.
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder, which may possibly be induced by oxidative stress. However, the age-related alteration of the endogenous antioxidant system is not well understood. To better understand this, we measured Cu/Zn-superoxide dismutase (SOD), glutathione peroxidase (GPx), and 4-hydroxynonenal (HNE)-conjugated GPx in cerebrospinal fluid of PSP patients by enzyme linked immunosorbent assay. A significant increase in the Cu/Zn-SOD level was detected in PSP group compared with controls. The levels of Cu/Zn-SOD and GPx in PSP group showed positive correlations with age. Two-thirds of total GPx was present as the HNE-conjugated form with positive correlation in PSP group. In conclusion, the endogenous antioxidant system of PSP patients appears to be activated with aging, however, it might be unable to function effectively because of conjugation with HNE.
Age Factors↗
Aberrant regulation of imprinted gene expression in Gtl2lacZ mice.
The imprinted region on mouse distal chromosome 12 covers about 1 Mb and contains at least three paternally expressed genes (Pegs: Peg9/Dlk1, Peg11/Rtl1, and Dio3) and four maternally expressed genes (Megs: Meg3/Gtl2, antiPeg11/antiRlt1, Meg8/Rian, and Meg9/Mirg). Gtl2(lacZ) (Gene trap locus 2) mice have a transgene (TG) insertion 2.3 kb upstream from the Meg3/Gtl2 promoter and show about 40% growth retardation when the TG-inserted allele is paternally derived. Quantitative RT-PCR experiments showed that the expression levels of Pegs in this region were reduced below 50%. These results are consistent with the observed phenotype in Gtl2lacZ mice, because at least two Pegs(Peg9/Dlk1 and Dio3) have growth-promoting effects. The aberrant induction of Megs from silent paternal alleles was also observed in association with changes in the DNA methylation level of a differentially methylated region (DMR) located around Meg3/Gtl2 exon 1. Interestingly, a 60 approximately 80% reduction in all Megs was observed when the TG was maternally derived, although the pups showed no apparent growth or morphological abnormalities. Therefore, the paternal or maternal inheritance of the TG results in the down-regulation in cis of either Pegs or Megs, respectively, suggesting that the TG insertion influences the mechanism regulating the entire imprinted region.
Animals↗
Estrogen-receptor-alpha-positive extramammary Paget's disease treated with hormonal therapy.
The patient was an 80-year-old man with scrotal and penile extramammary Paget's disease and prostate cancer. Both diseases were in advanced stages. Tumor cells of extramammary Paget's disease strongly expressed estrogen receptor alpha. The patient was concurrently treated with two kinds of hormonal therapy: the anti-estrogen tamoxifen (20 mg/day orally) for extramammary Paget's disease and the anti-androgen bicalutamide (80 mg/day orally) for prostate cancer. The toxicity of the therapy was mild. All of the metastatic lesions remained stable for 2 months after initiation of dual hormonal therapy. During a follow-up period of 22 months, performance status was well maintained for 17 months. Hormonal therapy may be an alternative for selected cases of advanced extramammary Paget's disease.
Aged, 80 and over↗
Calreticulin as a new histone binding protein in mitotic chromosomes.
Calreticulin (CRT) is a multifunctional Ca(2+)-binding protein that mainly functions in the endoplasmic reticulum as a molecular chaperone for newly synthesized proteins. Recently we reported the protein composition of human metaphase chromosomes (Uchiyama et al., 2004), which included CRT. Here we describe new characteristics of CRT in vitro as well as its localization on the surface of metaphase chromosomes in vivo. CRT was detected in the chromosomal fraction by Western blotting and its binding partners were identified as core and linker histones by ligand overlay assay. Surface plasmon resonance sensor analyses revealed that CRT is bound to chromatin fibers. Moreover, we found that CRT has both supercoiling activity, which assists core histone assembly into chromatin fibers, and binding ability to histone H2A/H2B dimers and histone H3/H4 tetramers. Unlike the chromosome scaffold proteins, indirect immunofluorescent staining revealed that CRT is located on the surface of metaphase chromosomes. These results suggest that CRT plays a role which involves chromatin dynamics on the surface of mitotic chromosomes.
Calreticulin↗
Effect of prenatal exposure to bisphenol A on the serum testosterone concentration of rats at birth.
In the rat, testosterone (T) in the neonatal period plays an important role in sexual differentiation and there is a serum T surge in male rats 2 hours after birth. Pregnant female rats were exposed to various doses of bisphenol A (BPA) from gestational day 1 (GD1) through 2 hours after parturition. About half of the BPA-exposed and control dams were subjected to cesarean section on GD22. The male fetuses on GD22 were immediately sacrificed and blood was collected. The other half of the BPA-treated and control dams delivered at GD23 (parturition day). The male pups were sacrificed 2 hours after birth. Serum T concentration was determined by radioimmunoassay (RIA). The BPA concentration in the fetal serum on GD22 increased inversely to the T levels in the serum. The T concentration in the pups' serum 2 hours after birth decreased inversely to the BPA concentration in the serum. However, there were no differences in the serum T concentration among the various doses of BPA. These results suggest that exposure to BPA in utero inhibits the T surge in the neonatal period and we speculate that exposure to BPA in utero disrupts the endocrine environment in the neonatal male.
Animals↗
Stat5 expression predicts response to endocrine therapy and improves survival in estrogen receptor-positive breast cancer.
Constitutively activated signal transducers and activators of transcription (Stats), in particular Stat3 and Stat5, have been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis in various cancers. Stat3 is essential in mammary gland epithelial cell apoptosis and involution, whereas Stat5 is well established as a key factor in mammary epithelial cell growth and differentiation. Crosstalk between Stats and estrogen receptor (ER) has been demonstrated by several laboratories and we have focused on the role of Stat5 in ER-positive breast cancer. Using immunohistochemical techniques, we examined the expression of Stat3 and Stat5 in 517 human breast cancer tissues and analyzed their significance for prognosis and prediction of response to endocrine therapy. Stat5 expression was significantly correlated with histological grade (P<0.0001), ER (P=0.02), and progesterone receptor (P=0.026) expression. There was no difference between Stat3 expression and clinicopathological factors. In 346 patients with ER-positive breast cancer, patients with Stat5 positive tumors had significantly increased overall survival (P=0.0009) in multivariate analysis. There were 70 patients who received endocrine therapy as first-line treatment for metastatic breast cancer at relapse. The patients whose primary breast tumors were Stat5 positive, had significantly better response to endocrine therapy (P=0.04), and longer survival after relapse (P=0.0003), than those whose tumors were Stat5 negative. The present study demonstrates for the first time that Stat5 is a predictive factor for endocrine therapy response and a strong prognostic molecular marker in ER-positive breast cancer. Our data suggest that the expression of Stat5 is helpful in selecting patients who may benefit from endocrine therapy.
Adult↗