[Acute exacerbation of Hashimoto's thyroiditis].
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Acute-Phase Reaction↗
Biomedical subjects
Takashi Ishihara
Publications and source records attributed to Takashi Ishihara.
Palladium-catalyzed regio- and stereoselective formate reduction of fluorine-containing allylic mesylates. A new entry for the construction of a tertiary carbon attached with a fluoroalkyl group.
The regioselective palladium-catalyzed formate reduction of gamma-fluoroalkylated allylic esters is described. Reduction of the allylic esters under the influence of palladium with a monodentate phosphine ligand proceeded preferentially at the gamma position, the corresponding reduction products with a fluoroalkyl group at the tertiary carbon being afforded in high yields. When the chiral allylic ester was employed, complete chirality transfer was observed, leading to the optically active materials in high yields.
Allyl Compounds↗
Highly stereoselective TiCl4-Catalyzed Evans-aldol and Et3Al-mediated Reformatsky reactions. Efficient accesses to optically active syn- or anti-alpha-trifluoromethyl-beta-hydroxy carboxylic acid derivatives.
[reaction: see text] The TiCl(4)-catalyzed Evans-aldol reaction of optically active 3,3,3-trifluoropropanoic imide gave the non-Evans syn product stereoselectively, whereas the Reformatsky reaction of 2-bromo-3,3,3-trifluoropropanoic imide in the presence of Et(3)Al led to the Evans anti product. These new approaches enabled us to synthesize all stereoisomers of trifluoromethylated aldol products for the first time.
Journal Article↗
Optimization of elution salt concentration in stepwise elution of protein chromatography using linear gradient elution data. Reducing residual protein A by cation-exchange chromatography in monoclonal antibody purification.
Our simple method for optimization of the elution salt concentration in stepwise elution was applied to the actual protein separation system, which involves several difficulties such as detection of the target. As a model separation system, reducing residual protein A by cation-exchange chromatography in human monoclonal antibody (hMab) purification was chosen. We carried out linear gradient elution experiments and obtained the data for the peak salt concentration of hMab and residual protein A, respectively. An enzyme-linked immunosorbent assay was applied to the measurement of the residual protein A. From these data, we calculated the distribution coefficient of the hMab and the residual protein A as a function of salt concentration. The optimal salt concentration of stepwise elution to reduce the residual protein A from the hMab was determined based on the relationship between the distribution coefficient and the salt concentration. Using the optimized condition, we successfully performed the separation, resulting in high recovery of hMab and the elimination of residual protein A.
Antibodies, Monoclonal↗
Novel synthesis of (Z)-difluoroacrylates via a highly stereoselective addition-elimination reaction.
On treating readily prepared benzyl 2,3,3-trifluoroacrylate with various Grignard reagents, e.g., aryl-, alkyl-, or alkenylmagnesium halide, in the presence of a catalytic amount of copper(I) salt in THF at -78 degrees C for 1 h, the corresponding alpha,beta-difluoroacrylates were obtained in 54-98% yields with high Z-selectivity.
Journal Article↗
Oxygen therapy prevents ventricular arrhythmias in patients with congestive heart failure and sleep apnea.
BACKGROUND: Although ventricular arrhythmia is critical for the prognosis of patients with severe congestive heart failure (CHF), it is difficult to control the arrhythmia using conservative therapies. However, many CHF patients also have sleep apnea syndrome (SAS) and oxygen supply improves their prognosis. The beneficial effects of oxygen treatment for ventricular arrhythmia have not yet been clarified, so the present study was designed to evaluate the effects of oxygen treatment for premature ventricular contraction (PVC). METHODS AND RESULTS: Patients with CHF and SAS were divided into 3 groups: (1) the "PVC declined" group that included patients who had frequent PVCs and oxygen treatment that suppressed the number of PVC; (2) the "PVC not affected" group that included patients who had frequent PVCs and oxygen treatment did not affect the number of PVC; and (3) the "few PVC" group that included patients who had no or few PVCs. The group 1 patients showed higher apnea-hypopnea index, standard deviation of all R-R intervals, left ventricular ejection fraction, and brain natriuretic peptide levels than the patients in group 2. Oxygen treatment in group 3 did not affect the PVC frequency. CONCLUSIONS: Oxygen treatment may be useful for preventing ventricular arrhythmia in selected patients with CHF and SAS.
Aged↗
Evaluation of a 1 step TRAb assay for the detection of high-affinity components to hTSHR: evidences indicating superiority of the assay in the lower TRAb range.
The aim of this study was to develop an assay to selectively detect high-affinity components among TRAb. Using an rhTSHR-coated tube system, a 1 step TRAb assay method was developed that included 1) co-incubation with (125)I-bTSH, 2) a 50 microl serum sample, 3) an increased incubation volume (450 microl), and 4) a 1 hour incubation time. Sixty-one TRAb positive Graves' sera were studied. When the regular TRAb assay (Reg) results were quantitatively compared to the 1 step assay (1 step) results, certain dispersions and overestimations using the latter were seen. Further, some 1 step positive results were observed in the low Reg range. Overestimations were considered mostly due to the differences between TRAb standard and patients' serum TRAb in the binding competition against co-incubated (125)I-bTSH, which was shown from a modified assay mimicking the 1 step conditions. Therefore, the 1 step results were decided to be expressed by % inhibition against (125)I-bTSH. As for data dispersions, TRAb absorptions during the regular 1st incubation were studied. Individually, the absorption rates varied from 11 to 69%, and higher absorptions were observed in lower Reg range, especially in those negative by the 1 step. Observed 1 step positive results in the low Reg range were of interest, and 1 step/Reg ratios were calculated. The ratios with 1 step negative samples were significantly lower than those of 1 step positive samples. In conclusion, the 1 step assay was proved to detect a particular and biologically active TRAb, especially in those with low TRAb. The clinical significance of the 1 step results should be of future interest.
Antibody Affinity↗
Regioselective one-step synthesis of 4-fluoroalkylated isoquinolines via carbopalladation reaction of fluorine-containing alkynes.
[reaction: see text] The palladium-catalyzed annulation reaction of fluoroalkylated alkynes with various 2-iodobenzylidenamines was investigated. In the presence of a catalytic amount of Pd(PPh3)4, the reaction took place smoothly to give the corresponding 4-fluoroalkylated isoquinoline in high yield as a single isomer. No other regioisomer was detected.
Alkynes↗
Rational methods for predicting human monoclonal antibodies retention in protein A affinity chromatography and cation exchange chromatography. Structure-based chromatography design for monoclonal antibodies.
Rational methods for predicting the chromatographic behavior of human monoclonal antibodies (hMabs) in protein A affinity chromatography and cation exchange chromatography from the amino acid sequences information were proposed. We investigated the relation between the structures of 28 hMabs and their chromatographic behavior in protein A affinity chromatography and cation exchange chromatography using linear gradient elution experiments. In protein A affinity chromatography, the elution pH of the hMabs was correlated with not only the structure of the Fc region (subclass), but also that of the variable region. The elution pH of hMabs that have LYLQMNSL sequences in between the CDR2 and CDR3 regions of the heavy chain became lower among the same subclass of hMabs. In cation exchange chromatography, the peak salt concentrations IR of hMabs that have the same sequences of variable regions (or that have a structural difference in their Fc region, which puts them into a subclass) were similar. The IR values of hMabs were well correlated with the equilibrium association constant Ke, and also with the surface positive charge distribution of the variable region of the heavy chain (corrected surface net positive charge (cN) of the VH region). Based on these findings, we developed rational methods for predicting the retention behavior, which were also tested with eight additional hMabs. By considering the information on the number of binding sites associated with protein adsorption as determined experimentally, and the surface positive charge distribution from the three-dimensional structure of Mab A, we hypothesized that hMabs is separated by cation exchange chromatography as the surface positive charge distribution of the VH region is recognized.
Amino Acid Sequence↗
GC79/TRPS1 and tumorigenesis in humans.
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Adenoma↗
Optimization of monoclonal antibody purification by ion-exchange chromatography. Application of simple methods with linear gradient elution experimental data.
Simple methods for the optimization of ion-exchange chromatography of proteins in our previous papers were applied to cation-exchange chromatography purification of monoclonal antibodies (Mab). We carried out linear gradient elution experiments, and obtained the data for the peak salt concentration and the peak width. From these data, the distribution coefficient as a function of salt concentration, and the height equivalent to a theoretical plate (HETP) as a function of mobile phase velocity were calculated. The optimized linear gradient elution conditions were determined based on the relationship between buffer consumption and separation time. The optimal stepwise elution conditions were determined based on the relationship between the distribution coefficient and the salt concentration.
Antibodies, Monoclonal↗
Differences in TSH receptor binding and thyroid-stimulating properties between TSH and Graves' IgG. Slowly-acting TSH receptor antibody moieties in Graves' sera affect assay data.
We analyzed TSH receptor (TSHR) effects, both binding and thyroid-stimulation, of TSH and Graves' IgG. A new TRAb assay system utilizes rhTSHR coated tubes and is comprised of two step incubation, the first incubation with patient serum followed by a second incubation with 125I-bTSH. We called TRAb measured by this method as hTRAb. 125I-bTSH binding capacity of the tube was found close to saturation at 1 hr with 200 microl of 125I-bTSH. Up to 5 hr of first incubation for hTRAb assay revealed significant increases in all hTRAb activities. hTRAb was not affected by second incubation time or dose of 125I-bTSH. When 1 step incubation with 125I-bTSH and Graves' serum was performed, hTRAb again increased significantly with time. A simple competitive equilibrium model could not be applied to these ligands. Second, Graves' IgG and bTSH were compared for in vitro thyroid-stimulation sequentially up to 24 hr, measuring cAMP generation from cultured porcine thyrocytes. While bTSH yielded peak cAMP generation by 8 hr, TSAb revealed more cAMP generation by 24 hr than at 8 hr. We concluded that individual Graves' sera contain heterogeneous TRAb of variable avidities, and that slow-acting TRAb, which may lack biological activity, can be detected by prolonged incubation.
Animals↗
Immeasurably low and non-TRH-stimulatable TSH associated with normal I-123 uptake in two goitrous euthyroid patients: possible existence of other thyroid-hormone regulated thyroid stimulators other than TSH.
We described two euthyroid patients with normally functioning goiters, but with persistently undetectable and non-stimulatable TSH levels. Subject 1 was a 64-year-old woman with a large diffuse goiter who has been clinically and biochemically euthyroid without any medication for at least 19 years. Subject 2 was a 31-year-old woman with a small diffuse goiter who has been euthyroid for 4 years. Both patients had persistently undetectable levels of serum TSH, TSH receptor antibodies (TRAb) and thyroid stimulating antibodies (TSAb). Their basal TSH levels were very low and their T3 responses to TRH were very diminished or absent. In contrast, the basal levels of the other pituitary hormones and their responses to LHRH, GRH and CRH stimulation were all within normal limits in both patients. MRI images of pituitary glands, 123I thyroid uptake, and thyroid scans were normal. Ectopic thyroids were not detected on (99m)TcO4- and 123I total body scans. Factors interfering with the measurement of TSH were excluded by recovery studies. In subject 1 a T3-suppression test was positive and a perchlorate discharge test was negative. In subject 2 a T3-suppression test was negative. Euthyroid Graves' disease, subclinical hyperthyroidism, destructive thyroiditis, thyrotoxicosis of extrathyroid origin, central hypothyroidism, and nonthyroidal illness were all ruled out by these observations. These results suggest that an unknown factor, such as thyrostimulin, but not TSH or TSAb, stimulates the thyroid and maintains euthyroidism, and may have a role in the regulation of the hypothalamus-pituitary-thyroid axis.
Adult↗
A facile regiocontrol in the palladium-catalyzed annulation of fluorine-containing internal alkynes with variously substituted 2-iodoanilines: a new regioselective synthesis of 2- or 3-fluoroalkylated indole derivatives.
Treatment of various types of fluoroalkylated alkynes with o-iodoaniline in the presence of Pd(PPh(3))(4) in DMF at 80 degrees C for 8 h mainly gave 2-fluoroalkylated indoles in high yields. The use of P(o-Tol)(3) instead of PPh(3) as a ligand led to the preferential formation of 3-fluoroalkylated indoles in high yields. Interestingly, the reaction of trifluoromethylated alkynes bearing a benzylic substituent afforded 2- or 3-trifluoroethylated indole derivatives in good yields.
Alkynes↗
Highly diastereoselective reductive coupling of 2-bromo-2,3,3,3-tetrafluoropropanamide with aldehydes promoted by triphenylphosphine-titanium(IV) isopropoxide. An efficient route to the synthesis of erythro-alpha-fluoro-alpha-(trifluoromethyl)-beta-hydroxy amides.
The reductive coupling reaction of N-methoxy-N-methyl-2-bromo-2,3,3,3-tetrafluoropropanamide (Weinreb amide) with various aldehydes under the influence of the combined reagent, 1.2 equiv each of triphenylphosphine and titanium(IV) isopropoxide, took place smoothly at ambient temperature to give the corresponding alpha-fluoro-alpha-(trifluoromethyl)-beta-hydroxy amides in a highly erythro-selective manner. The high erythro selectivity was also obtained even by employing a combination of triphenylphosphine (1.2 equiv) and a catalytic amount of titanium(IV) isopropoxide.
Journal Article↗
Highly regio- and stereoselective carbostannylation reaction of fluorine-containing internal acetylenes with allylstannanes.
Carbostannylation of fluoroalkylated alkynes with various allylstannanes in the presence of AIBN was investigated. In the case of the allylstannane having an electron-withdrawing group at the beta position, the reaction proceeded highly regio- and stereoselectively to give the corresponding allylstannylated products in high yields. Even in the absence of AIBN, the reaction took place smoothly in a highly regio- and stereoselective manner under an atmosphere of air. Thus-obtained vinylstannanes were subjected to the Migita-Kosugi-Stille coupling reaction conditions, affording the tetrasubstituted alkenes in excellent yields.
Journal Article↗
A highly regio- and stereoselective carbocupration of fluoroalkylated internal alkynes: a short total synthesis of the antiestrogenic drug panomifene.
[reaction: see text] A highly regio- and stereoselective carbometalation reaction of fluoroalkylated internal alkynes with organocopper reagents is described. This reaction is utilized successfully in the short, stereoselective total synthesis of the antiestrogenic drug panomifene.
Journal Article↗
A sequential highly stereoselective hydroboration and Suzuki-Miyaura cross-coupling reaction of fluoroalkylated internal acetylenes: a practical one-pot synthesis of fluoroalkylated trisubstituted alkenes.
The one-pot synthesis of trisubstituted alkenes starting from fluoroalkylated internal alkynes was investigated. Hydroboration of the alkynes proceeded in a highly regio- and stereoselective manner to give the corresponding vinylboranes in excellent yields. Without isolation, treatment of the vinylboranes with various aryl halides under the Suzuki-Miyaura cross-coupling conditions gave the fluoroalkylated trisubstituted alkenes in high yields with complete retention of the olefinic geometry.
Journal Article↗