Fabry disease is an X-linked recessive inborn metabolic disorder caused by a deficiency of the lysosomal enzyme α-galactosidase A (EC 3.2. throughout the 7 exons of the α-galactosidase A gene (GLA). Mutation hotspots for Fabry disease do not exist. We examined 62 Fabry patients in Japan and found 24 GLA mutations, including 11 novel ones. A potential treatment reported for Fabry disease is active site specific chaperone (ASSC) therapy using 1-deoxygalactonojirimycin (DGJ), an inhibitor of α-galactosidase A, at subinhibitory concentrations. We transfected COS-7 cells with the 24 mutant GLAs and analyzed the α-galactosidase A activities. We then treated the transfected COS-7 cells with DGJ and analyzed its effect on the mutant enzyme activities. The activity of 11 missense mutants increased significantly with DGJ. Although ASSC therapy is useful only for misfolding mutants and therefore not applicable to all cases, it may be useful for treating many Japanese patients with Fabry disease. © 2007 Wiley-Liss, Inc.KEY WORDS: α-galactosidase A; GLA; lysosomal storage disease; 1-deoxygalactonojirimycin; chaperone therapy INTRODUCTIONFabry disease (FD; MIM# 301500) is a pan-ethnic, X-linked, lysosomal storage disorder caused by a deficiency in the lysosomal enzyme α-galactosidase A (EC 3.2.1.22) (Brady et al., 1967). Human α-galactosidase A is a homodimeric glycoprotein with three N-linked oligosaccharide chains on each subunit. Enzyme deficiency results in a systemic lysosomal accumulation of glycolipids, primarily globotriosylceramide (Gb3), in the vascular endothelium and other tissues. In the classical form of the disease, the patient develops angiokeratoma, hypohidrosis, and episodic pain crises in the extremities during childhood or adolescence. With advancing age, the morbidity of renal failure, cardiac disease, and early onset of stroke increases. The severity of the clinical manifestations depends on the amount of residual α-galactosidase A activity. Hemizygous male patients with no or very low α-galactosidase A activity usually have severe clinical symptoms and die as young adults. Heterozygous female Fabry patients exhibit a wide range of severity, from a virtually symptom-free course (Marguery et al., 1993) to one comparable to that of their male counterparts (Whybra et al., 2001), although they usually have no symptoms or very mild manifestations.We examined Fabry patients in Japan and sequenced the patients' α-galactosidase A gene (GLA) (MIM# 300644). To analyze the mutant α-galactosidase A activities, we transfected COS-7 cells with the mutant GLAs. In addition, since 1-deoxygalactonojirimycin (DGJ) stabilizes the α-galactosidase A conformation and improves its stability (Asano et al., 2000;Ishii et al., 2000;Yam et al., 2006), we added DGJ to the incubation medium and examined its effect on the mutant α-galactosidase A activities. MATERIALS AND METHODS PatientsWe examined 62 Fabry patients from 31 unrelated families. Diagnosis was based on reduced or absent α-galactosidase A activity and typical signs an...

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Promising outcomes of salvage chemotherapy after nivolumab therapy have been reported; however, little is known about the detailed clinical and immunologic features in lung cancer patients in whom nivolumab is unsuccessful. We report two cases of nivolumab‐refractory lung cancer, in which chemotherapy resulted in rapid regression of the lung cancer. Upon initial diagnosis, the biopsy specimens showed PD‐ligand 1 (PD‐L1)‐expressing cancer cells, accompanied by tumor‐infiltrating lymphocytes with a favorable CD8/CD4 ratio. Immunosuppressive regulatory T cells and cells positive for TIM‐3 were also observed. Physicians should take caution in treating lung cancer patients after progression on nivolumab. Further studies with a large cohort are warranted to identify the patients that may benefit from salvage chemotherapy.

Abstract. We conducted physical therapy for patients suffering from lumbago (n=37) with highfrequency hyperthermia equipment by a capacitive electric transfer method, MD-303 (0.65 ± 0.05 MHz), which is employed in Europe and America. The 37 patients comprised 13 with lumbar spondylosis deformans, 7 with lumbar spinal canal stenosis, 5 with lumbar disc herniation, 4 with lumbar spondylolysis/spondylolisthesis, 4 with lumbar discopathy, and 4 with other diseases accompanied by lumbago. The electricity was used 10 times in total, for 20 minutes per time. A rise in skin temperature was observed even 15 minutes after treatment, with no occurrence of adverse reactions, and this therapy was highly effective in relieving pain, with an efficacy rate of 81.1%. This paper reports the results of the use of this therapy.