Prospective Study of Gefitinib Readministration After Chemotherapy in Patients With Advanced Non-Small-Cell Lung Cancer Who Previously Responded to Gefitinib

The present study was designed to prospectively evaluate the clinical efficacy of gefitinib readministration in patients with advanced non-small cell lung cancer who responded well to initial gefitinib, followed by cytotoxic chemotherapy. Twenty subjects were enrolled, and 3 and 6 patients achieved partial response and stable disease, respectively. These findings provide valuable information for the management of previous gefitinib responders. Introduction: Salvage treatment for acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor in patients with non-small-cell lung cancer is a matter of clinical concern. Several retrospective reports have indicated the usefulness of epidermal growth factor receptor tyrosine kinase inhibitor readministration; however, there have been few prospective studies. Materials and Methods: This study was designed to prospectively evaluate the clinical efficacy of gefitinib readministration in patients with advanced or metastatic non-small-cell lung cancer who responded well to initial gefitinib treatment. The subjects received at least 1 regimen of cytotoxic chemotherapy after progressive disease with the initial gefitinib therapy. Gefitinib administration (250 mg/d, orally) was started after progressive disease with the previous chemotherapeutic regimen. The primary endpoint in the present study was the response rate. Results: Twenty patients were enrolled between April 2007 and May 2011. Three patients achieved partial response, and 6 showed stable disease. Thus, the overall response rate and disease control rate of gefitinib readministration were 15% (95% Cl, 3.21-37.9) and 45% (95% Cl, 23.1-68.5), respectively. Median progression-free survival and overall survival from the start of gefitinib readministration were 2.0 months (95% Cl, 0.9-3.1 months) and 12.0 months (95% Cl, 8.0-16.0 months), respectively. Conclusion: These results suggest that gefitinib readministration may be an option, albeit with a low response rate and short progression-free survival, for patients who responded well to initial gefitinib followed by systemic chemotherapy. These findings provide valuable information for the management of previous gefitinib responders.ArticleCLINICAL LUNG CANCER. 13(6):458-463 (2012)journal articl

A case in which water intoxication due to excessive water ingestion did not inhibit the secretion of arginine vasopressin

We experienced a case of water intoxication due to excessive water ingestion that was complicated by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). A 60-year-old Japanese woman with nervous depression drank too much lemon tea within several hours, vomited ten times, and developed disturbed consciousness and dysarthria. Her plasma arginine vasopressin (AVP) concentration was not inhibited,although her plasma osmolality was low. Nausea and/or stress may stimulate AVP secretion regardless of the hypo-osmolality. We believe that dilatation of her stomach due to excessive liquid ingestion and cerebral edema due to hypo-osmolality brought on her nausea. Stress induced by a psychiatric problem and/or admission to a hospital may also stimulate AVP secretion by the central nervous system. Treatingnausea and stress may help reduce AVP secretion and resolve hyponatremia

Non-covalent forces tune the electron transfer complex between ferredoxin and sulfite reductase to optimize enzymatic activity.

Although electrostatic interactions between negatively-charged ferredoxin (Fd) and positively-charged sulfite reductase (SiR) have been predominantly highlighted to characterize complex formation, the detailed nature of intermolecular forces remains to be fully elucidated. We herein investigated interprotein forces for formation of an electron-transfer complex between Fd and SiR and their relationship to SiR activity using various approaches over NaCl concentrations between 0 and 400 mM. Fd-dependent SiR activity assays revealed a bell-shaped activity curve with a maximum around 40-70 mM NaCl and a reverse bell-shaped dependence of interprotein affinity. Meanwhile, intrinsic SiR activity, as measured in a methyl viologen-dependent assay, exhibited saturation above 100 mM NaCl. Thus, two assays suggested that interprotein interaction is crucial in controlling Fd-dependent SiR activity. Calorimetric analyses showed the monotonic decrease in interprotein affinity on increasing NaCl concentrations, distinguished from a reverse bell-shaped interprotein affinity observed from Fd-dependent SiR activity assay . Furthermore, Fd:SiR complex formation and interprotein affinity were thermodynamically adjusted by both enthalpy and entropy through electrostatic and non-electrostatic interactions. A residue-based NMR investigation on addition of SiR to 15N-labeled Fd at the various NaCl concentration also demonstrated that a combination of electro- and non-electrostatic forces stabilized the complex with similar interfaces and modulated the binding affinity and mode. Our findings elucidate that non-electrostatic forces are also essential for the formation and modulation of the Fd:SiR complex. We suggest that a complex configuration optimized for maximum enzymatic activity near physiological salt conditions is achieved by structural rearrangement through controlled non-covalent interprotein interactions

Visualization of Dust Generation in Outdoor Workplaces Using A Wearable Particle Monitor and Global Navigation Satellite System

We manufactured a wearable particle monitor (WPM), which is a simple and low-cost dust monitor. We aimed to evaluate the usefulness of the device by using it and location information of a Global Navigation Satellite System (GNSS) to measure dust generation in outdoor workplaces. We used nine WPMs and a particle counter KC-52 to measure in parallel the dust concentration diffusing standard particles in a dust exposure apparatus to evaluate the measurability of the WPM, and visualized dust generation in outdoor workplaces to evaluate its usability. We obtained location information using a GNSS in parallel with measuring with the WPM. The measured values of the WPM followed the measured values of the KC-52, with a strong correlation of the values between the KC-52 and each WPM. The discrepancy among devices tended to increase, however, because the measured values of the WPMs increased. For outdoor measurements, we could create a heat map of the relative values of dust generation by combining two data of the WPM and the GNSS. The methods of using the WPM could overview the conditions needed to produce dust emissions in dust-generating workplaces

Physicochemical nature of interfaces controlling ferredoxin NADP+ reductase activity through its interprotein interactions with ferredoxin

AbstractAlthough acidic residues of ferredoxin (Fd) are known to be essential for activities of various Fd-dependent enzymes, including ferredoxin NADP+ reductase (FNR) and sulfite reductase (SiR), through electrostatic interactions with basic residues of partner enzymes, non-electrostatic contributions such as hydrophobic forces remain largely unknown. We herein demonstrated that intermolecular hydrophobic and charge–charge interactions between Fd and enzymes were both critical for enzymatic activity. Systematic site-directed mutagenesis, which altered physicochemical properties of residues on the interfaces of Fd for FNR /SiR, revealed various changes in activities of both enzymes. The replacement of serine 43 of Fd to a hydrophobic residue (S43W) and charged residue (S43D) increased and decreased FNR activity, respectively, while S43W showed significantly lower SiR activity without affecting SiR activity by S43D, suggesting that hydrophobic and electrostatic interprotein forces affected FNR activity. Enzyme kinetics revealed that changes in FNR activity by mutating Fd correlated with Km, but not with kcat or activation energy, indicating that interprotein interactions determined FNR activity. Calorimetry-based binding thermodynamics between Fd and FNR showed different binding modes of FNR to wild-type, S43W, or S43D, which were controlled by enthalpy and entropy, as shown by the driving force plot. Residue-based NMR spectroscopy of 15N FNR with Fds also revealed distinct binding modes of each complex based on different directions of NMR peak shifts with similar overall chemical shift differences. We proposed that subtle adjustments in both hydrophobic and electrostatic forces were critical for enzymatic activity, and these results may be applicable to protein-based electron transfer systems