Readministration of gefitinib in a responder after treatment discontinuation due to gefinitib-related interstitial lung disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Gefitinib is a new molecular-targeted agent for the treatment of patients with advanced non-small cell lung cancer that fail to respond to conventional chemotherapy. Gefitinib is considered to be well tolerated and less toxic compared with conventional cytotoxic drugs. However, interstitial lung disease (ILD) has been reported as a serious adverse effect. The precise management of a gefitinib responder having severe adverse events remains unknown.</p> <p>Case Presentation</p> <p>We report the case of gefitinib readministration in a patient with lung adenocarcinoma who had once responded but in whom treatment had to be discontinued owing to gefinitib-related ILD. A dramatic response was achieved both at the time of initial treatment (250 mg/day) and at readministration of gefitinib (125 mg/day). The effectiveness of gefitinib therapy in our patient could be explained in part by the presence of an activating mutation of epidermal growth factor receptor (<it>EGFR</it>) gene, L858R in exon 21, which was identified in the primary tumor.</p> <p>Conclusion</p> <p>A reduced dose of gefitinib might be sufficient for patients having tumors with <it>EGFR </it>gene mutations, and that the currently approved dose may be excessively potent in some of these patients, thus resulting in the onset of adverse events.</p

Leptin Reduces the Expression and Increases the Phosphorylation of the Negative Regulators of GLUT4 Traffic TBC1D1 and TBC1D4 in Muscle of ob/ob Mice

Leptin improves insulin sensitivity in skeletal muscle. Our goal was to determine whether proteins controlling GLUT4 traffic are altered by leptin deficiency and in vivo leptin administration in skeletal muscle of wild type and ob/ob mice. Leptin-deficient ob/ob mice were divided in three groups: control, leptin-treated (1 mg/kg/d) and leptin pair-fed ob/ob mice. Microarray analysis revealed that 1,546 and 1,127 genes were regulated by leptin deficiency and leptin treatment, respectively. Among these, we identified 24 genes involved in intracellular vesicle-mediated transport in ob/ob mice. TBC1 domain family, member 1 (Tbc1d1), a negative regulator of GLUT4 translocation, was up-regulated (P = 0.001) in ob/ob mice as compared to wild types. Importantly, leptin treatment reduced the transcript levels of Tbc1d1 (P<0.001) and Tbc1d4 (P = 0.004) in the leptin-treated ob/ob as compared to pair-fed ob/ob animals. In addition, phosphorylation levels of TBC1D1 and TBC1D4 were enhanced in leptin-treated ob/ob as compared to control ob/ob (P = 0.015 and P = 0.023, respectively) and pair-fed ob/ob (P = 0.036 and P = 0.034, respectively) mice. Despite similar GLUT4 protein expression in wild type and ob/ob groups a different immunolocalization of this protein was evidenced in muscle sections. Leptin treatment increased GLUT4 immunoreactivity in gastrocnemius and extensor digitorum longus sections of leptin-treated ob/ob mice. Moreover, GLUT4 protein detected in immunoprecipitates from TBC1D4 was reduced by leptin replacement compared to control ob/ob (P = 0.013) and pair-fed ob/ob (P = 0.037) mice. Our findings suggest that leptin enhances the intracellular GLUT4 transport in skeletal muscle of ob/ob animals by reducing the expression and activity of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4

Gender Differences in S-Nitrosoglutathione Reductase Activity in the Lung

S-nitrosothiols have been implicated in the etiology of various pulmonary diseases. Many of these diseases display gender preferences in presentation or altered severity that occurs with puberty, the mechanism by which is unknown. Estrogen has been shown to influence the expression and activity of endothelial nitric oxide synthase (eNOS) which is associated with increased S-nitrosothiol production. The effects of gender hormones on the expression and activity of the de-nitrosylating enzyme S-nitrosoglutathione reductase (GSNO-R) are undefined. This report evaluates the effects of gender hormones on the activity and expression of GSNO-R and its relationship to N-acetyl cysteine (NAC)-induced pulmonary hypertension (PH). GSNO-R activity was elevated in lung homogenates from female compared to male mice. Increased activity was not due to changes in GSNO-R expression, but correlated with GSNO-R S-nitrosylation: females were greater than males. The ability of GSNO-R to be activated by S-nitrosylation was confirmed by: 1) the ability of S-nitrosoglutathione (GSNO) to increase the activity of GSNO-R in murine pulmonary endothelial cells and 2) reduced activity of GSNO-R in lung homogenates from eNOS−/− mice. Gender differences in GSNO-R activity appear to explain the difference in the ability of NAC to induce PH: female and castrated male animals are protected from NAC-induced PH. Castration results in elevated GSNO-R activity that is similar to that seen in female animals. The data suggest that GSNO-R activity is modulated by both estrogens and androgens in conjunction with hormonal regulation of eNOS to maintain S-nitrosothiol homeostasis. Moreover, disruption of this eNOS-GSNO-R axis contributes to the development of PH

Simulating the carbon balance of a temperate larch forest under various meteorological conditions

<p>Abstract</p> <p>Background</p> <p>Changes in the timing of phenological events may cause the annual carbon budget of deciduous forests to change. Therefore, one should take such events into account when evaluating the effects of global warming on deciduous forests. In this article, we report on the results of numerical experiments done with a model that includes a phenological module simulating the timing of bud burst and other phenological events and estimating maximum leaf area index.</p> <p>Results</p> <p>This study suggests that the negative effects of warming on tree productivity (net primary production) outweigh the positive effects of a prolonged growing season. An increase in air temperature by 3°C (5°C) reduces cumulative net primary production by 21.3% (34.2%). Similarly, cumulative net ecosystem production (the difference between cumulative net primary production and heterotrophic respiration) decreases by 43.5% (64.5%) when temperatures are increased by 3°C (5°C). However, the positive effects of CO₂enrichment (2 × CO₂) outweigh the negative effects of warming (<5°C).</p> <p>Conclusion</p> <p>Although the model was calibrated and validated for a specific forest ecosystem, the implications of the study may be extrapolated to deciduous forests in cool-temperate zones. These forests share common features, and it can be conjectured that carbon stocks would increase in such forests in the face of doubled CO₂and increased temperatures as long as the increase in temperature does not exceed 5°C.</p