Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.     

Rapid acetylation of native cellulose by TFAA and characterization of the products

Acetylation of cellulose (Whatman cellulose powder CF-11 and Egyptian cotton fiber) by the use of the TFAA “impelling” method was examined, and the decrease in the degree of polymerization (DP) during the reaction was determined. Cellulose triacetate can be readily prepared by the TFAA method. When Whatman cellulose powder was used, the degradation of cellulose during acetylation was not observed in reaction times up to 5 hr, and a slight decrease in the degree of polymerization was detected in samples after reaction for more than 12 hr. The number of chain scissions per cellulose molecule for Egyptian cotton fiber was similar in magnitude to that for Whatman cellulose at the reaction time of 8 hr, but the value for Egyptian cotton fiber was considerably larger compared with that for Whatman cellulose after 12 hr.     

Homogeneous graft copolymerization of styrene onto cellulose in a sulfur dioxide–diethylamine–dimethyl sulfoxide cellulose solvent

Graft copolymerization of styrene onto cellulose was studied in a homogeneous system (SO₂–DEA–DMSO medium) by γ-ray mutual irradiation technique. At the same time, homopolymerization of styrene was also examined separately in DMSO, SO₂–DMSO, DEA–DMSO, and SO₂–DEA–DMSO media by the same technique. Polymerization of styrene hardly occurs on concentrations above 10 mole SO₂–DEA complex per mole glucose unit. Maximum percent grafting was obtained in concentrations of 4 mole, after which it decreased rapidly. Total conversion and percent grafting increased with the irradiation time. The value (=0.55) of the slope of the total conversion rate plotted against the dose was only a little higher than the 1/2 which was expected from normal kinetics. No retardation in homopolymerization of styrene in DMSO, SO₂–DMSO, and DEA–DMSO was evident, while the retardation of homopolymerization in the SO₂–DEA–DMSO medium was measurable. Sulfur atoms were detected in the polymers obtained in both of SO₂–DMSO and SO₂–DEA–DMSO solutions. All of the molecular weights of polymers obtained in the present experiment were very low (3.9 × 10³?1.75 × 10⁴).     

Cloning and mapping of the U2af1-rs2 gene with a high transmission distortion in interspecific backcross progeny

We have cloned and analyzed the mouse U2af1-rs2 gene based on its sequence similarity to the imprinted gene U2af1-rs1 (SP2). Sequence analysis of this U2af1-rs2 cDNA revealed that it contained an open reading frame encoding a protein of 462 amino acid residues. The predicted amino acid sequence showed 72.7 and 35.8% identity to the U2af1-rs1 and U2 small nuclear ribonucleoprotein auxiliary factor, respectively. Interspecific backcross analysis showed this gene to map to the distal region of the X chromosome and also indicated that there was significant distortion of transmission ratio of the U2af1-rs2 allele in the backcrossed progeny from (C57BL/6J x Mus spretus)F1 females mated to Mus spretus males.     

A new analysis method for disposition kinetics of enterohepatic circulation of diclofenac in rats

The pharmacokinetics of diclofenac, which is definitely subject to enterohepatic circulation in rats, was evaluated. The pharmacokinetic model for enterohepatic circulation was constructed in the Laplace-transformed domain by means of the transfer function method of the signal flow. The transformed equations were simultaneously fitted to the time courses of plasma concentration averaged over two groups of rats [i.e. one with an intact enterohepatic circulation and the other without an enterohepatic circulation by means of the bile duct cannula (double-lines fitting)]. The transformed equations were also fitted to each plasma time course in the individual rat (single-line fitting). It was demonstrated that the estimated pharmacokinetic parameters by the single-line fitting almost coincided with those by the double-lines fitting. The local moments for a single pass through enterohepatic circulation were also calculated from the time courses of both the plasma concentration and the amount excreted into the bile. In the nonanesthetized group, the recirculation ratio (Fc) and the mean recirculation time (tc) of diclofenac were estimated to be 21.1% and 4.5 hr, respectively. The absorption ratio (Fa) and the mean absorption time (ta) from the intestinal tract were 52.2% and 4.29 hr, respectively. The experiments using bile duct cannulation revealed that the total amounts excreted into the bile were 14.4% in the anesthetized group and 40.4% in the nonanesthetized group of rats, and that diclofenac was excreted 95% as the glucuronide form and 5% as the intact form in both groups.     

Triiodothyronine resuscitates the impaired liver function after Pringle's maneuver

OBJECTIVE: To evaluate the changes in thyroid hormone levels and the effectiveness of exogenous triiodothyronine (T3) in shock caused by prolonged use of Pringle's maneuver (cross-clamping of hepatic triads). DESIGN: Pringle's maneuver was performed on dogs for 1 hour. In the T3 group (n = 7), 1 microgram/kg per hour of T3 was administered intravenously for 3 hours after declamping. In the control group (n = 7), the same volume of saline solution without T3 was administered. MAIN OUTCOME MEASURES: Serum T3, reverse T3, thyroxine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the ketone body ratio (AKBR), which reflect the hepatic energy charge, were measured. Tissue blood flow, tissue blood velocity, and tissue blood mass of the liver were measured by means of a laser Doppler flowmeter. Oxygen saturation of the hemoglobin in the liver tissue was measured by tissue near-infrared spectroscopy. Dogs were observed until the seventh postoperative day. RESULTS: In the control group, the low T3 syndrome was observed. None of the dogs recovered from the shock and none survived for more than 24 hours. In the T3 group, all dogs recovered from the shock and survived. In the control group, hepatic tissue blood flow and oxygen saturation of hemoglobin in liver tissue were decreased, and the AKBR was deteriorated. In the T3 group, however, these parameters were markedly improved. CONCLUSION: It is suggested that T3 administration is beneficial in managing the critical resuscitation period of liver function after Pringle's maneuver is performed in dogs.     

Thermodynamics of phosphorus in carbon-saturated manganese-based alloys

The interaction coefficient of phosphorus with silicon in a Mn-Si-C_sat alloy has been measured at 1573 K, equilibrating CaC₂, C, and Ca₃P₂ in a quartz capsule to keep the phosphorus partial pressure as high as 33.7 Pa. The activity coefficient of phosphorus in the melts increases with increasing silicon content, and the interaction parameter between silicon and phosphorus in the melts at carbon saturation ε^Si_P, C_sat was found to be 10.4. The activity of phosphorus in a carbon-saturated Fe-Mn alloy was also determined at temperatures of 1573 to 1673 K using a chemical equilibration technique between BaO-BaF₂ fluxes and Fe-Mn-C_sat with manganese mass contents ranging from 0 to 85.3 %. A slight decrease in the activity coefficient of phosphorus in Fe-Mn-C_sat alloys was observed with increasing manganese content, as a reflection of a stronger interaction between manganese and phosphorus than that between iron and phosphorus. The value for e^Mn_P,Csat was found to be -0.0029 between 1573 and 1673 K.     

Coupling phenomena in the transfer of elements between a gas phase and iron melts

The simultaneous transfer of Si and C from a gas phase containing SiO and CO to liquid Fe-C alloys has been investigated. It was found that, although the silicon content of the melt increased with time as expected, the carbon content initially decreased, in spite of the fact that the carbon potential of the gas phase was above that of the liquid alloy. These phenomena are interpreted in terms of irreversible thermodynamics which shows that the overall transfer reactions are comprised of coupled reactions: SiO(g) + CO(g) →Si + CO₂(g) andC + CO₂(g) → 2CO(g). It is also shown that the simultaneous transfer of carbon and oxygen from gas mixtures of CO and CO₂ to liquid iron occurs via the coupled reactions CO₂(g) →O + CO(g) and 2CO(g) →C + CO₂. In each case there is a predominant, or driving reaction which promotes the other.     

Moment analysis of stereoselective enterohepatic circulation and unidirectional chiral inversion of ketoprofen enantiomers in rat

The stereoselective enterohepatic circulation (EHC) and the synchronous chiral inversion of ketoprofen enantiomer in rat were evaluated by moment analysis based on the recirculatory concept. (R)-(-)- and (S)-(+)-ketoprofen were independently administered into rats, and the plasma and bile concentrations of both enantiomers were determined by a column-switching HPLC. (S)-Ketoprofen was generated by the chiral inversion from (R)-ketoprofen, whereas (R)-ketoprofen was not generated from (S)-ketoprofen. Within 30 min after intravenous administrations, the plasma time courses of R- and S-enantiomers were almost the same between rats with laparotomy and those with bile-duct cannula. After 30 min, the plasma concentrations in rats with laparotomy were significantly higher than those in rats with bile-duct cannula. The Laplace-transformed equations for stereoselective EHC and the synchronous chiral inversion were derived by means of the transfer function method on the basis of the recirculatory theory. The global moments (AUC and MRT) which were derived directly from the transformed equations were related to the local moments for the single EHC. The recirculation ratios of (R)- and (S)-ketoprofen for the single EHC were estimated to be 15.4% and 63.6%, respectively. The absorption ratios of (R)- and (S)-ketoprofen for the absorption process from the gastrointestinal tract into the systemic circulation were 87.0% and 83.8%, respectively. The biliary excretion rations of (R)- and (S)-ketoprofen for the disposition process through the systemic circulation into the bile were 17.7% and 75.8%, respectively. The chiral inversion ratio from (R)-ketoprofen into (S)-ketoprofen was 59.5%. The complicated disposition of ketoprofen, i.e., the simultaneous EHC and chiral inversion, was able to be analyzed by a moment method in a simple way.     

Thermodynamics of sulfur in the BaO-MnO-SiO2 flux system

The sulfide capacity of the molten BaO-MnO-SiO₂ system was determined by measuring the sulfur partition ratio between the oxide and an Ag-S alloy in a controlled CO-CO₂-Ar gas mixture at 1573 K for two purposes. One is to develop highly basic fluxes which can extensively desulfurize manganese-based alloys, and the other is to examine the effect of BaO addition on thermodynamic properties of sulfur in the MnO-SiO₂ melts from which MnS precipitates functioning as the nucleus for subsequent γ -α transformation of steel. The sulfide capacity of the BaO-MnO-SiO₂ system strongly depends on the composition, and MnO has been found to enhance sulfide capacity to a greater extent than BaO at less basic compositions.