Genetic and epigenetic susceptibility to endogenous retrovirus-induced lymphomas in SL mice.
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Animals↗
Biomedical subjects
T Kamoto
Publications and source records attributed to T Kamoto.
Vasculitis-susceptible genes in mice with a deficit in Fas-mediated apoptosis.
Autoimmune diseases show complex pathological manifestations, which frequently involve systemic vasculitis. This complication is understood to be a manifestation of advanced disease, or to represent distinct entities, restricted by genetic and/or environmental factors. An MRL/Mp strain of mice bearing the Fas deletion mutant gene, lpr (MRL/lpr), spontaneously develop systemic vasculitis coincidentally with glomerulonephritis, arthritis and sialoadenitis, but a C3H/HeJ-lpr/lpr (C3H/lpr) strain does not. Thus, this is a suitable model for analyzing the genetic basis of vasculitis in autoimmune diseases. To genetically dissect these complex pathological manifestations, a linkage analysis of each lesion with polymorphic microsatellite markers was performed by using MRL/lpr x (MRL/lpr x C3H/lpr)F1 backcross mice. Vasculitis-susceptible gene loci were mapped on chromosomes 3 and 4, which were not associated with glomerulonephritis, arthritis and sialoadenitis. These results indicate that systemic vasculitis in MRL/lpr mice may be under the control of host genes which are different from those for other autoimmune diseases.
Animals↗
Quantitative trait loci affecting 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in the rat.
The incidence of tongue carcinomas (TCs) induced by oral administration of 4-nitroquinoline 1-oxide in rats is strain dependent. The inbred Dark-Agouti (DA) strain showed a much higher susceptibility to large mass-forming infiltrative TCs than did the Wistar-Furth (WF) strain. Our previous study (M. Kitano et al, Jpn. J. Cancer Res., 87: 1097-1101, 1996) on crosses between these two strains postulated a dominant susceptibility gene in DA and a dominant resistance gene in WF rats. The present study mapped these loci by analyzing the backcrosses to each parent with simple sequence repeat polymorphisms. Five quantitative parameters were analyzed: (a) the number of TCs > 5 mm in diameter; (b) the total number of TCs per rat; (c) the diameter of the largest TCs (DTCmax values); (d) the number of non-TC cancers per rat; and (e) and the number of cancers of any site per rat. All of these parameters were closely correlated (P < 0.0001). DA rats had a semidominant gene (Stc1) favoring the development of 4-nitroquinoline 1-oxide-induced cancers on chromosome 19, closely linked to D19Mit9. Peak linkage was observed 4 cM distal from D19Mit9, with a logarithm of the odds (lod) score of 5.72 for the number of large TCs and 6.08 for the DTCmax. On the other hand, WF rats had a semidominant gene (Rtc1) mapped between D1Mit1 and D1Mit3, approximately 20 cM from D1Mit1, with a peak lod score of 3.30 for both the number of large TCs and the DTCmax. The main effect of Rtc1 seemed to be to reduce the size of the TCs. The action of these genes was dose dependent and cooperative. The final incidence of TC in DA, WF, F1, and backcross rats seemed to be explained by combinations of genotype at these two loci. Possible candidate genes for Stc1 and Rtc1 are discussed.
4-Nitroquinoline-1-oxide↗
Host genes affecting survival period of chemically induced bladder cancer in mice.
Treatment of C57BL/6 J (B6) and NON male mice with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) resulted in a high incidence of bladder cancer. The mean survival period, however, differed significantly by strain: 481+/-219 days in B6 (n = 31) and 203+/-119 days in NON (n = 30) (P < 0.0001). Major causes of death were renal failure due to obstruction of the urinary tract, or local invasion of tumors. The fact that the BBN-treated NON x B6 reciprocal F1 mice had survival periods as short as those of the parental NON mice suggests a genetically dominant susceptibility in NON or recessive resistance in B6. A linkage analysis of 248 back-cross mice to B6 suggested at least two quantitative trait loci determining the length of the survival period: one was mapped close to D2Mit260 (logarithm of odds, LOD, score 2.21), a microsatellite marker locus 83 cM from the centromere on chromosome 2, and another was close to D6Mit159, 7 cM from the centromere on chromosome 6 (LOD score 2.51).
Animals↗
Incidence of lymph node metastasis and its impact on long-term prognosis in clinically localized prostate cancer.
BACKGROUND: Pelvic lymph node dissection (PLND) is an important staging method for men with clinically localized prostate cancer. We report our experience with staging PLND and the impact of lymph node metastasis on long-term prognosis. METHODS: One hundred forty-eight consecutive patients who underwent staging PLND for clinically localized prostate cancer were retrospectively studied. Patients were evaluated for the presence and number of lymph node metastases, treatment (prostatectomy vs. radiotherapy), and endocrine therapy, and analyzed with respect to disease progression and survival. The mean follow-up period was 52.9 months (range, 2.3 to 165.8 months). RESULTS: Thirty-two patients (21.6%) had pelvic lymph node metastases, the incidence of which markedly decreased from 32.3% in 1982 to 1987 to 6.7% in 1994 to 1997. The intervals to disease progression and cancer death were significantly shorter in patients with positive lymph nodes (P < 0.001). In stage D1 disease, patients who underwent a radical prostatectomy tended to be free of progression longer than those receiving radiotherapy or conservative therapy (P = 0.0546). Other factors, such as early endocrine therapy, the extent of lymph node involvement and the Gleason score of the primary tumor did not predict disease progression or survival. CONCLUSION: These data suggest a decreasing trend in the incidence of lymph node metastasis in the PSA era. Although longer disease-free intervals were observed in radical prostatectomy-treated patients, the impact of an aggressive approach to stage D1 disease awaits further studies.
Adenocarcinoma↗
[Clinical application of intraoperative ultrasonography for bilateral multilocular cystic renal cell carcinoma: a case report].
A 45-year-old man was referred to our department for further examination of the renal complicated cyst which was found incidentally by ultrasonography. Another complicated cyst in the left kidney was detected by subsequent dynamic CT and ultrasonography, which suggested bilateral cystic renal cell carcinoma. Bilateral partial nephrectomy was performed. Intraoperative ultrasonography was useful for diagnosis of multilocular cystic renal cell carcinoma (MCRCC). It disclosed multiple septa of the right renal complicated cyst which were not revealed by any preoperative examinations. It was also a useful adjunct to partial nephrectomy. It helped to identify the extent of deep intra-parenchymal lesions. The final diagnosis was bilateral synchronous multilocular cystic renal cell carcinoma. This is the second case of bilateral synchronous multilocular cystic renal cell carcinoma reported in Japan. We reviewed the clinical characteristics of 59 cases of MCRCC in the Japanese literature including the present case.
Carcinoma, Renal Cell↗
Genetic resistance to urethan-induced pulmonary adenomas in SMXA recombinant inbred mouse strains.
Development of pulmonary adenomas (PAs) in mice is under the genetic control of multiple host genes. We have established a new set of SMXA recombinant inbred strains from PA-susceptible A/J and PA-resistant SM/J mice. The number of urethan-induced PAs was variable among substrains of the SMXA recombinant inbred strains, indicating the involvement of multiple genes. SMXA24 mice were highly resistant to PA, although they had susceptible alleles at all four known susceptibility genes, including kras2 and MHC. To identify the resistance gene in SMXA24, progeny of reciprocal F1 crosses and progeny of backcrosses to A/J were given urethan at 4 weeks of age and examined for induced PA at the age of 5 months. In reciprocal F1 cross progeny, the incidence of PA was very low, indicating that the resistance was a semidominant trait. Quantitative trait analysis of the backcross generation revealed significant linkages to loci on chromosome 12 (logarithm of odds score, 6.47) and chromosome 11 (logarithm of odds score, 4.35). To date, two PA resistance (PAR) genes, Par1 (located on chromosome 11) and Par2 (located on chromosome 18), have been reported. From the map position, one of the resistance genes on chromosome 11 was indistinguishable from Par1. However, another resistance gene on chromosome 12 was new, and we named this gene Par3. A likely candidate gene for Par3 is nPKCn, which is expressed exclusively in skin and lung and is down-regulated in PA. Par1 and Par3 seemed to act synergistically.
Adenoma↗
Expression of LECAM-1 and LFA-1 on pre-B lymphoma cells but not on preneoplastic pre-B cells in SL/KH mice.
The pre-B lymphoma-prone inbred strain SL/Kh mice showed a polyclonal expansion of BP-1+ pre-B cells in bone marrow early in life. Preneoplastic pre-B cells did not express adhesion molecules LECAM-1 and LFA-1, whereas neoplastic pre-B cells consistently expressed both molecules. There were two types of pre-B lymphomas in SL/Kh with distinct in vivo behavior. One infiltrated lymph nodes and spleen and another, predominantly bone marrow. However, lymphoma cells of both types expressed BP-1, LECAM-1 and LFA-1. Expression of these adhesion molecules on BP-1+ cells, therefore, may represent an important consequence of pre-B lymphomagenesis in SL/Kh strain, but is not sufficient to explain the in vivo behavior of the pre-B lymphoma cells.
Animals↗
An autopsy case of angioimmunoblastic T-cell lymphoma with a high content of epithelioid cells in the lymph node: immunohistochemical and genomic analyses.
A 79-year-old female developed red papulonodular eruptions on her extremities, facial erythema, generalized lymphadenopathy and high fever. Histopathology of an affected lymph node showed the features of angioimmunoblastic T-cell lymphoma with a high content of epithelioid cells. She died about two years after the onset despite therapy. Genomic Southern blotting and immunostaining of the lymph nodes were performed twice. In August of 1993, Southern blotting did not show any rearrangement of the immunoglobulin or the T-cell receptor (TCR) gene. Small or medium-sized lymphoid cells were positive for CD4 or CD8 (CD4:CD8 = 2:1). However, in September of 1994 (at autopsy), rearrangements of TCK C beta 1, J beta 2 and J gamma genes were observed. Small or medium-sized lymphoid cells were positive for CD4, but negative for CD8. Several large cells were positive for Latent Membrane Protein 1 (LMP1) of the Epstein-Barr virus (EBV). Our results proved that selective oligoclonal proliferation of tumor cells (probably CD4+) accompanied the disease progress.
Aged↗
Quantitative trait loci associated with promoting effects of sodium L-ascorbate on two-stage bladder carcinogenesis in rats.
In the two-stage rat bladder carcinogenesis model using N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiator and sodium L-ascorbate (SA) as a promoter, we found a notable strain difference between F344/DuCrj (F344) and WS/Shi (WS) rats in susceptibility to the promoting effect of SA. Twenty each of F344, WS and reciprocal F1 hybrid rats were given 0.05% BBN in their drinking water for 4 weeks and then a basal diet with (BBN-SA group) or without (BBN group) a 5% SA supplement for 32 weeks. In F344 and also in reciprocal F1 hybrids, the number of tumors per rat was significantly higher in the BBN-SA group than in the BBN group (P < 0.0001). In contrast, WS rats were not significantly affected by either treatment (P = 0.8). These findings indicate that F344 rats are highly susceptible to the promoter effect of SA, but WS rats are not. Linkage analysis of 108 WSx (WS x F344) F1 backcrosses revealed that this difference was related to a quantitative trait locus mapped on rat Chr. 17 (maximum LOD score, 3.86) named Bladder Tumor Susceptible-1 and possibly another locus on Chr. 5 (maximum LOD score, 2.39). This study has provided the first evidence that host genes influence the risk of bladder cancer development.
Animals↗
To be or not to be a T-lymphomas, that is determined by a dominant gene Tlsm-1 in mouse models.
A single dominant gene Tlsm-1 was found to determine the type of spontaneous lymphomas to be T in the cross between AKR/Ms and SL/Kh. Microsatellite analysis mapped Tlsm-1 at the position 61 cM from centromere of Chr. 7. Study of this segment of T-lymphoma prone AKXD Rl strains also showed association of Tlsm-1 with T-lymphomas. On the other hand, lymphoma latency was significantly shorten by a recessive gene lla of SL/Kh. By a quantitative trait analysis, lla was located in class II gene in MHC.
Animals↗
[Neoadjuvant CYVADIC (cyclophosphamide, vincristine, adriamycin and dacarbazine) therapy for retroperitoneal leiomyosarcoma: a case report].
Retroperitoneal leiomyosarcoma is often too large to be completely removed. We report a 67-year-old woman successfully treated with neoadjuvant CYVADIC (cyclosphosphamide, vincristine, adriamycin and dacarbazine). The tumor was removed with the right kidney and ureter and a part of the vena cava after 2 courses of CYVADIC. The tumor recurred at the duodenum 7 years later and was completely removed following neoadjuvant CYVADIC. Neoadjuvant chemotherapy could be helpful for the complete resection of advanced leiomyosarcoma.
Aged↗
Host modifier genes affect mouse autoimmunity induced by the lpr gene.
A defect in apoptotic signal transmission through CD95 is an essential genetic mechanism for lymphoproliferation and autoimmunities in lpr or gld mice. However, disease manifestations are largely affected by the host genetic background. To identify and map such host genes modifying lpr gene effect, ie, the lpr modifier (Lprm) genes, 82 MRL/lpr x (MRL/lpr x C3H/lpr) F1 mice were subjected to immunopathological and genetical analyses. High-grade vasculitis and glomerulonephritis among backcross mice were observed in separate groups of mice. Microsatellite analysis revealed that there were two host genes affecting the occurrence of vasculitis, Lprm1 (chromosome 4) and Lprm2 (chromosome 3). A recessive MRL allele at Lprm1 enhanced vasculitis to occur in both sexes, whereas that of Lprm2 inhibited its development selectively in females. Genotype combinations of these two genes explained the severity of vasculitis in crosses of MRL/lpr and C3H/lpr mice and also the vasculitis-prone recombinant inbred strain McH5/lpr. A recessive MRL allele at Lprm3 (chromosome 14) suppressed glomerulonephritis. The weight of the spleen was increased by a recessive MRL allele at Lprm4 (chromosome 5) yielding a logarithm of odds score of 2.02 in a quantitative trait locus analysis. In contrast, the weight of axillary lymph nodes was increased by a recessive MRL allele at a locus on chromosome 2, but its presence was not supported by the quantitative trait locus analysis. The titer of anti-dsDNA autoantibody was controlled by the locus Lprm5 on chromosome 16, which had an logarithm of odds score of 3.41. Possible candidate genes for Lprm genes deduced from their map locations are discussed and compared with the autoimmunity genes reported thus far. In conclusion, autoimmune disease manifestations by the lpr mutation are affected by multiple host genes separately.
Animals↗
Mapping of rupture of lens cataract (rlc) on mouse chromosome 14.
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Animals↗
Two dominant host resistance genes to pre-B lymphoma in wild-derived inbred mouse strain MSM/Ms.
To explore possible host genes suppressing spontaneous B-lymphomagenesis in the mouse, expression of ecotropic murine leukemia virus (E-MuLV) and lymphoma development were observed in crosses between the pre-B lymphoma-prone SL/Kh and low-lymphoma strains of mice. E-MuLV expression was intensely inhibited in F1 hybrids with the strains either with the Fv-1b allele (BALB/C, C57BL/10, and A/J) or with the Fv-1nr allele (NZB). In these F1 mice, no lymphoma developed by 18 months of age. On the other hand, F1 hybrids with the strains with the Fv-1n allele [C3H/He, CBA/N, SJL, DBA/2, and MSM/Ms (hereafter referred to as MSM)], high or intermediate levels of E-MuLV expression were observed. Lymphoma incidence in these F1 hybrids, however, was low. This observation suggests the presence of non-Fv-1 dominant resistance genes in these strains. In an attempt to characterize such host genes, we analyzed crosses between SL/Kh mice and a wild mouse-derived inbred strain, MSM/Ms. The latter was susceptible to N-tropic virus expression, but (SL/Kh x MSM)F1 hybrids, did not develop and lymphomas. Of 60 SL/Kh x (SL/Kh x MSM)F1 hybrids, 14 B-lineage lymphomas, including 13 pre-B and 1 follicular center cell lymphoma, developed by 18 months of age. This was compatible with the hypothesis of two independently segregating dominant genes of MSM suppressing lymphomagenesis. By scanning all chromosomes for linkage of lymphoma susceptibility with polymorphic microsatellite loci, one significant linkage disequilibrium was found in the proximal segment of chromosome 17, containing D17MIT44 (map position 15.0) to D17MIT150 (position 33.3), and another linkage disequilibrium, in the midproximal segment of chromosome 18, containing D18MIT90 (map position 28.0) and D18MIT140 (37.0). All 13 pre-B lymphoma-bearing backcross mice were homozygous for SL/Kh-derived alleles at these loci. We named the gene on chromosome 17 Msmr1 (for MSM resistance 1) and that on chromosome 18 Msmr 2 (for MSM resistance 2).
Animals↗
A quantitative trait locus in major histocompatibility complex determining latent period of mouse lymphomas.
The effects of two host genes on retrovirus-induced murine lymphoma were evaluated by studying 114 F2 intercross mice between SL/Kh and AKR/Ms mice. Out of 47 T-lymphoma-bearing F2 mice, 45 had the AKR-derived dominant allele at Tism-1. The length of the lymphoma latent period was not related to type of tumor. Instead, it was significantly shortened by a recessive SL/Kh-derived allele at a major histocompatibility complex (MHC)-linked locus on Chr. 17. A quantitative trait analysis of the latent period yielded a maximal logarithm of likelihood ratio for linkage (LOD) score of 7.06 at a class II gene within MHC. The SL/Kh-derived recessive gene was named lla (lymphoma latency acceleration).
Alleles↗
The origin of SL family mice.
The origin of SL family mice was studied by analyzing 100 microsatellite loci, the major histocompatibility complex, the Mx gene, murine leukemia provirus, and mammary tumor provirus. From the genetic profile of family members and their history, we assumed the existence of a proto-SL mouse, an ancestor of all SL family members. Many alleles were contributed to the proto-SL by the ancestors related to strains A2G and CF#1, and/or some wild mice. Among four existing family members, SL/Am and SL/Ni mice were almost identical and presumably closest to the proto-SL. The SL/Kh mouse was derived from a cross of the proto-SL and AKR mice, because SL/Kh mice inherited a considerable number of genes from AKR mice, the most outstanding of which were those of the provirus Emv-11 and Thy-1.1. The SL/QDj mice seemed to be a recombinant inbred strain between SL/Am and SL/Kh mice, because their alleles at all 100 microsatellite loci were shared by SL/Am or SL/Kh strains or both. All four SL family members shared the major histocompatibility complex haplotype q.
Animals↗
T lymphomagenesis is determined by a dominant host gene thymic lymphoma susceptible mouse-1 (TLSM-1) in mouse models.
Susceptibility to T lymphomas in mice is determined by a number of viral and host genetic factors. We analyzed the types and latent period of lymphomas spontaneously occurring in crosses between AKR/Ms, a T lymphoma-prone mouse strain, and SL/Kh, a pre-B lymphoma-prone strain. The incidence of T lymphomas in the F1 hybrids backcross to SL/Kh as well as F2 generation mice indicated that a dominant host gene thymic lymphoma susceptible mouse-1 (Tlsm-1) of AKR/Ms determined the type of lymphomas to be thymic. Linkage analysis with microsatellite markers assigned Tlsm-1 to the map position 61 cM from centromere of the chromosome 7. Close scrutiny of this region of AKXD recombinant inbred strains for spontaneous T lymphomas revealed the presence of Tlsm-1-like gene most likely between D7MIT71 (map position 62) and D7MIT13 (map position 70). On the other hand, a SL/Kh-derived recessive allele at a major histocompatibility complex (MHC)-linked locus accelerated development of both T and B lymphomas.
Animals↗