Treatment with gefitinib after erlotinib-induced liver injury: a case report

INTRODUCTION: Gefitinib and erlotinib have minor differences in their chemical structures, and thus it remains unclear whether the hepatotoxicity induced by one compound is affected by the other. The case of a patient who developed erlotinib-induced liver injury and was then treated with gefitinib without hepatic toxicity or disease progression is presented. CASE PRESENTATION: A 31-year-old Japanese woman, who never smoked and who was diagnosed as having lung adenocarcinoma with carcinomatous meningitis, was treated with erlotinib. She developed erlotinib-induced liver injury after four weeks of treatment. The treatment was stopped right away, but the symptoms of meningitis re-appeared immediately. Gefitinib treatment was started and continued without recurrence of drug-induced liver injury. CONCLUSION: Gefitinib appears to be a potential treatment option after erlotinib-induced liver injury

三角線維軟骨複合体損傷における尺側手根伸筋腱と遠位橈尺関節のMRI画像分析

BACKGROUND: We compared the incidence of extensor carpi ulnaris (ECU) tendon and distal radioulnar joint (DRUJ) abnormalities using magnetic resonance imaging (MRI) between patients with triangular fibrocartilage complex (TFCC) tears and subjects without ulnar wrist pain. Additionally, we aimed to identify potential predictors of these MRI lesions. METHODS: The TFCC group comprised 70 consecutive patients with TFCC tears. The control group comprised 70 age- and sex-matched subjects without ulnar wrist pain. We evaluated the presence or absence of fluid collection in the DRUJ and ECU peritendinous area and longitudinal ECU tendon splitting. Dimensions of the fluid collection area around the ECU tendon were measured to evaluate the severity. The incidences of these abnormal MRI findings were compared between the two groups. We analyzed the correlation between the presence of ECU tendon and DRUJ lesions and variables including age, magnitude of ulnar variance, and type of TFCC tear. RESULTS: Significant differences were found between the two groups in the incidence of fluid collection of the DRUJ and ECU peritendinous area, and longitudinal ECU tendon splitting. Among the 70 patients with TFCC tears, age and the magnitude of ulnar variance were significantly correlated with the severity of fluid collection around the ECU tendon. The magnitude of ulnar variance in patients with DRUJ fluid collection was significantly larger than that in patients without fluid collection. There was a significant correlation between the presence of disc tears and DRUJ fluid collection. CONCLUSION: We found a higher incidence of accompanying abnormal MRI findings of the ECU tendon and DRUJ in patients with TFCC tears than in the control group. The presence of disc tears, the magnitude of ulnar variance, and age may be risk factors for these MRI lesions associated with TFCC tears.博士（医学）・甲第690号・平成30年11月30日Copyright © 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved

三角線維軟骨複合体損傷における尺側手根伸筋腱と遠位橈尺関節のMRI画像分析

BACKGROUND: We compared the incidence of extensor carpi ulnaris (ECU) tendon and distal radioulnar joint (DRUJ) abnormalities using magnetic resonance imaging (MRI) between patients with triangular fibrocartilage complex (TFCC) tears and subjects without ulnar wrist pain. Additionally, we aimed to identify potential predictors of these MRI lesions. METHODS: The TFCC group comprised 70 consecutive patients with TFCC tears. The control group comprised 70 age- and sex-matched subjects without ulnar wrist pain. We evaluated the presence or absence of fluid collection in the DRUJ and ECU peritendinous area and longitudinal ECU tendon splitting. Dimensions of the fluid collection area around the ECU tendon were measured to evaluate the severity. The incidences of these abnormal MRI findings were compared between the two groups. We analyzed the correlation between the presence of ECU tendon and DRUJ lesions and variables including age, magnitude of ulnar variance, and type of TFCC tear. RESULTS: Significant differences were found between the two groups in the incidence of fluid collection of the DRUJ and ECU peritendinous area, and longitudinal ECU tendon splitting. Among the 70 patients with TFCC tears, age and the magnitude of ulnar variance were significantly correlated with the severity of fluid collection around the ECU tendon. The magnitude of ulnar variance in patients with DRUJ fluid collection was significantly larger than that in patients without fluid collection. There was a significant correlation between the presence of disc tears and DRUJ fluid collection. CONCLUSION: We found a higher incidence of accompanying abnormal MRI findings of the ECU tendon and DRUJ in patients with TFCC tears than in the control group. The presence of disc tears, the magnitude of ulnar variance, and age may be risk factors for these MRI lesions associated with TFCC tears.博士（医学）・甲第690号・平成30年11月30日Copyright © 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved

Double knockdown of α1,6-fucosyltransferase (FUT8) and GDP-mannose 4,6-dehydratase (GMD) in antibody-producing cells: a new strategy for generating fully non-fucosylated therapeutic antibodies with enhanced ADCC

<p>Abstract</p> <p>Background</p> <p>Antibody-dependent cellular cytotoxicity (ADCC) is greatly enhanced by the absence of the core fucose of oligosaccharides attached to the Fc, and is closely related to the clinical efficacy of anticancer activity in humans <it>in vivo</it>. Unfortunately, all licensed therapeutic antibodies and almost all currently-developed therapeutic antibodies are heavily fucosylated and fail to optimize ADCC, which leads to a large dose requirement at a very high cost for the administration of antibody therapy to cancer patients. In this study, we explored the possibility of converting already-established antibody-producing cells to cells that produce antibodies fully lacking core fucosylation in order to facilitate the rapid development of next-generation therapeutic antibodies.</p> <p>Results</p> <p>Firstly, loss-of-function analyses using small interfering RNAs (siRNAs) against the three key genes involved in oligosaccharide fucose modification, i.e. α1,6-fucosyltransferase (<it>FUT8</it>), GDP-mannose 4,6-dehydratase (<it>GMD</it>), and GDP-fucose transporter (<it>GFT</it>), revealed that single-gene knockdown of each target was insufficient to completely defucosylate the products in antibody-producing cells, even though the most effective siRNA (>90% depression of the target mRNA) was employed. Interestingly, beyond our expectations, synergistic effects of <it>FUT8 </it>and <it>GMD </it>siRNAs on the reduction in fucosylation were observed, but not when these were used in combination with <it>GFT </it>siRNA. Secondly, we successfully developed an effective short hairpin siRNA tandem expression vector that facilitated the double knockdown of <it>FUT8 </it>and <it>GMD</it>, and we converted antibody-producing Chinese hamster ovary (CHO) cells to fully non-fucosylated antibody producers within two months, and with high converting frequency. Finally, the stable manufacture of fully non-fucosylated antibodies with enhanced ADCC was confirmed using the converted cells in serum-free fed-batch culture.</p> <p>Conclusion</p> <p>Our results suggest that FUT8 and GMD collaborate synergistically in the process of intracellular oligosaccharide fucosylation. We also demonstrated that double knockdown of <it>FUT8 </it>and <it>GMD </it>in antibody-producing cells could serve as a new strategy for producing next-generation therapeutic antibodies fully lacking core fucosylation and with enhanced ADCC. This approach offers tremendous cost- and time-sparing advantages for the development of next-generation therapeutic antibodies.</p

Simulation system for understanding the lag effect in fluoroscopic images

Real-time tumor tracking in external radiotherapy can be achieved by diagnostic (kV) X-ray imaging with a dynamic flat-panel detector (FPD). It is crucial to understand the effects of image lag for real-time tumor tracking. Our purpose in this study was to develop a lag simulation system based on the image lag properties of an FPD system. Image lag properties were measured on flat-field images both in direct- and indirect-conversion dynamic FPDs. A moving target with image lag was simulated based on the lag properties in all combinations of FPD types, imaging rates, exposure doses, and target speeds, and then compared with actual moving targets for investigation of the reproducibility of image lag. Image lag was simulated successfully and agreed well with the actual lag as well as with the predicted effect. In the indirect-conversion FPD, a higher dose caused greater image lag on images. In contrast, there were no significant differences among dose levels in a direct-conversion FPD. There were no relationships between target speed and amount of image blurring in either type of FPD. The maximum contour blurring and the rate of increase in pixel value due to image lag were 1.1 mm and 10.0 %, respectively, in all combinations of imaging parameters examined in this study. Blurred boundaries and changes in pixel value due to image lag were estimated under various imaging conditions with use of the simulation system. Our system would be helpful for a better understanding of the effects of image lag in fluoroscopic images. © 2012 Japanese Society of Radiological Technology and Japan Society of Medical Physics

Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans

Removal of the fucose residue from the N-glycans of the Fc portion of immunoglobulin G (IgG) results in a dramatic enhancement of antibody-dependent cellular cytotoxicity (ADCC) through improved affinity for Fcγ receptor IIIa (FcγRIIIa). Here, we present the 2.2-Å structure of the complex formed between nonfucosylated IgG1-Fc and a soluble form of FcγRIIIa (sFcγRIIIa) with two N-glycosylation sites. The crystal structure shows that one of the two N-glycans of sFcγRIIIa mediates the interaction with nonfucosylated Fc, thereby stabilizing the complex. However, fucosylation of the Fc N-glycans inhibits this interaction, because of steric hindrance, and furthermore, negatively affects the dynamics of the receptor binding site. Our results offer a structural basis for improvement in ADCC of therapeutic antibodies by defucosylation

グリーンランド氷床北西部Thule地域沿岸における高濁度海水域の変動

第6回極域科学シンポジウム分野横断セッション：[IA] 急変する北極気候システム及びその全球的な影響の総合的解明―GRENE北極気候変動研究事業研究成果報告2015―11月19日（木）　国立極地研究所１階交流アトリウ

Development of an apolipoprotein E mimetic peptide–lipid conjugate for efficient brain delivery of liposomes

Liposomes are versatile carriers that can encapsulate various drugs; however, for delivery to the brain, they must be modified with a targeting ligand or other modifications to provide blood–brain barrier (BBB) permeability, while avoiding rapid clearance by reticuloendothelial systems through polyethylene glycol (PEG) modification. BBB-penetrating peptides act as brain-targeting ligands. In this study, to achieve efficient brain delivery of liposomes, we screened the functionality of eight BBB-penetrating peptides reported previously, based on high-throughput quantitative evaluation methods with in vitro BBB permeability evaluation system using Transwell, in situ brain perfusion system, and others. For apolipoprotein E mimetic tandem dimer peptide (ApoEdp), which showed the best brain-targeting and BBB permeability in the comparative evaluation of eight peptides, its lipid conjugate with serine–glycine (SG)5 spacer (ApoEdp-SG-lipid) was newly synthesized and ApoEdp-modified PEGylated liposomes were prepared. ApoEdp-modified PEGylated liposomes were effectively associated with human brain capillary endothelial cells via the ApoEdp sequence and permeated the membrane in an in vitro BBB model. Moreover, ApoEdp-modified PEGylated liposomes accumulated in the brain 3.9-fold higher than PEGylated liposomes in mice. In addition, the ability of ApoEdp-modified PEGylated liposomes to localize beyond the BBB into the brain parenchyma in mice was demonstrated via three-dimensional imaging with tissue clearing. These results suggest that ApoEdp-SG-lipid modification is an effective approach for endowing PEGylated liposomes with the brain-targeting ability and BBB permeability