Adult T-cell leukemia( ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system( CNS) involvement. CNS involvement significantly re...Adult T-cell leukemia( ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system( CNS) involvement. CNS involvement significantly reduces survival and there are no effective treatments for CNS involvement. Therefore, an appropriate animal model is required to evaluate the inhibitory effects of novel drugs on the progression of ATL with CNS involvement. Here, we established a mouse model of ATL with CNS involvement using NOD.Cg-Prkdc~ (scid) Il2 rg ^(tm1Wjl)/SzJ mice inoculated with ATL cells intramuscularly in the postauricular region, and these mice showed paraparesis. Of the 10 mice inoculated with ATL cells intramuscularly(I.M.) at 5 weeks of age, 8(80%) showed paraparesis, whereas none of the 10 mice inoculated with ATL cells subcutaneously(S.C.) showed paraparesis. In the I.M. group, PCR detected HTLV-1-specific genes in the thoracic and lumbar vertebrae; however, in the S.C. group, the vertebrae were negative for HTLV-1 genes. Histological analysis revealed a particularly high incidence of tumors, characterized by accumulation of the injected cells, in the thoracic vertebrae of mice in the I.M. group. Tumor cell infiltration was relatively high in the bone marrow. Spinal cord compression caused by invasion of the tumor mass outside the pia mater was observed in the thoracic vertebrae of the spinal cord. In conclusion, we have reported a mouse model of tumor growth with paraparesis that may be used to assess novel therapeutic agents for ATL with CNS involvement.展开更多
Cdgler-Najjar syndrome type Ⅰ （CN-I） is the most severe type of hereditary unconjugated hyperbilirubinemia. It is caused by homozygous or compound heterozygous mutations of the UDP-glycuronosyltransferase gene （UG...Cdgler-Najjar syndrome type Ⅰ （CN-I） is the most severe type of hereditary unconjugated hyperbilirubinemia. It is caused by homozygous or compound heterozygous mutations of the UDP-glycuronosyltransferase gene （UGT1A1） on chromosome 2q37. Two patients clinically diagnosed with CN-I were examined in this paper. We sequenced five exons and their flanking sequences, specifically the promoter region of UGT1A 1, of the two patients and their parents. Quantitative real-time polymerase chain reaction （qRT-PCR） was used to determine the UGT1A1 gene copy number of one patient. In patient A, two mutations, c.239_245delCTGTGCC （p.Pro80HisfsX6; had not been reported previously） and c.1156G〉T （p.Va1386Phe）, were identified. In patient B, we found that this patient had lost heterozygosity of the UGTIA1 gene by inheriting a deletion of one allele, and had a novel mutation c.1253delT （p.Met418ArgfsX5） in the other allele. In summary, we detected three UGTIA 1 mutations in two CN-I patients： c.239_ 245delCTGTGCC （p.Pro80HisfsX6）, c.1253delT （p.MeH18ArgfsX5）, and c.1156G〉T （p.Va1386Phe）. The former two mutations are pathogenic; however, the pathogenic mechanism of c.1156G〉T （p.Va1386Phe） is unknown.展开更多
基金Japan Leukemia Research FundGrant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science,Grant/Award Number:No.24500493
文摘Adult T-cell leukemia( ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system( CNS) involvement. CNS involvement significantly reduces survival and there are no effective treatments for CNS involvement. Therefore, an appropriate animal model is required to evaluate the inhibitory effects of novel drugs on the progression of ATL with CNS involvement. Here, we established a mouse model of ATL with CNS involvement using NOD.Cg-Prkdc~ (scid) Il2 rg ^(tm1Wjl)/SzJ mice inoculated with ATL cells intramuscularly in the postauricular region, and these mice showed paraparesis. Of the 10 mice inoculated with ATL cells intramuscularly(I.M.) at 5 weeks of age, 8(80%) showed paraparesis, whereas none of the 10 mice inoculated with ATL cells subcutaneously(S.C.) showed paraparesis. In the I.M. group, PCR detected HTLV-1-specific genes in the thoracic and lumbar vertebrae; however, in the S.C. group, the vertebrae were negative for HTLV-1 genes. Histological analysis revealed a particularly high incidence of tumors, characterized by accumulation of the injected cells, in the thoracic vertebrae of mice in the I.M. group. Tumor cell infiltration was relatively high in the bone marrow. Spinal cord compression caused by invasion of the tumor mass outside the pia mater was observed in the thoracic vertebrae of the spinal cord. In conclusion, we have reported a mouse model of tumor growth with paraparesis that may be used to assess novel therapeutic agents for ATL with CNS involvement.
文摘Cdgler-Najjar syndrome type Ⅰ （CN-I） is the most severe type of hereditary unconjugated hyperbilirubinemia. It is caused by homozygous or compound heterozygous mutations of the UDP-glycuronosyltransferase gene （UGT1A1） on chromosome 2q37. Two patients clinically diagnosed with CN-I were examined in this paper. We sequenced five exons and their flanking sequences, specifically the promoter region of UGT1A 1, of the two patients and their parents. Quantitative real-time polymerase chain reaction （qRT-PCR） was used to determine the UGT1A1 gene copy number of one patient. In patient A, two mutations, c.239_245delCTGTGCC （p.Pro80HisfsX6; had not been reported previously） and c.1156G〉T （p.Va1386Phe）, were identified. In patient B, we found that this patient had lost heterozygosity of the UGTIA1 gene by inheriting a deletion of one allele, and had a novel mutation c.1253delT （p.Met418ArgfsX5） in the other allele. In summary, we detected three UGTIA 1 mutations in two CN-I patients： c.239_ 245delCTGTGCC （p.Pro80HisfsX6）, c.1253delT （p.MeH18ArgfsX5）, and c.1156G〉T （p.Va1386Phe）. The former two mutations are pathogenic; however, the pathogenic mechanism of c.1156G〉T （p.Va1386Phe） is unknown.
