RESUMEN
OBJECTIVE: Many systemic lupus erythematosus patients display a type I interferon (IFN) signature, and IFNα levels positively correlate with disease severity. Previous studies blocking the type I IFN pathway systemically in lupus models showed some beneficial effects. However, its effects on neuropsychiatric manifestations have yet to be carefully assessed, even though IFNα has been associated with induction of depression. Our aim was to investigate whether disrupting the type I IFN pathway would attenuate the development of murine neuropsychiatric lupus. METHODS: Female MRL/lpr mice were administered an antitype I IFN receptor (IFNAR) antibody or a control antibody intraperitoneally three times weekly for 12 weeks starting at age 4-5 weeks. Behavior was assessed during and at the end of the treatment schedule. RESULTS: No significant differences were seen between the anti-IFNAR- and control-treated mice when assessing for depression-like behavior or cognitive dysfunction, although anti-IFNAR antibody-treated mice displayed significant decreases in levels of IFN-stimulated genes. Anti-IFNAR treatment also did not significantly improve brain histology, cellular infiltration, or blood-brain barrier integrity. CONCLUSIONS: Surprisingly, our results showed no improvement in neuropsychiatric disease and suggest that the role of IFNAR signaling in the pathogenesis of neuropsychiatric lupus continues to need to be carefully assessed.
Asunto(s)
Anticuerpos/administración & dosificación , Lupus Eritematoso Sistémico/terapia , Vasculitis por Lupus del Sistema Nervioso Central/terapia , Receptor de Interferón alfa y beta/inmunología , Animales , Anticuerpos/inmunología , Conducta Animal , Disfunción Cognitiva/etiología , Disfunción Cognitiva/terapia , Depresión/etiología , Depresión/terapia , Modelos Animales de Enfermedad , Femenino , Interferón Tipo I/inmunología , Interferón-alfa/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/fisiopatología , Vasculitis por Lupus del Sistema Nervioso Central/inmunología , Vasculitis por Lupus del Sistema Nervioso Central/fisiopatología , Ratones , Ratones Endogámicos MRL lpr , Índice de Severidad de la EnfermedadRESUMEN
Two balanced reciprocal chromosome translocations, t(8;12)(p21;p13. 1) and t(15;16)(q24;q22), characterized a rare hemangiopericytoma in a newborn. Chromosome painting with a chromosome microdissection-derived whole-chromosome 8 probe confirmed that the t(8;12) was due to a reciprocal translocation. To the best of our knowledge, these chromosome findings are unique to this unusual case of a pediatric hemangiopericytoma.
Asunto(s)
Hemangiopericitoma/genética , Enfermedades del Recién Nacido/genética , Bandeo Cromosómico , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Cariotipificación , Masculino , Translocación GenéticaRESUMEN
The acute promyelocytic leukemia (APL M3)-associated translocation (15;17) has been described as having breakpoints variably located between 15q22 and 15q26, and 17q11 and 17q25. Most of the recent studies using DNA probes (fluorescence in situ hybridization [FISH]) for analysis have indicated the chromosome 15 breakpoint to be in 15q22. We have utilized a combination of G-banding, FISH, and chromosome microdissection/reverse ISH to precisely map the breakpoint to t(15;17)(q24;q21.1).
Asunto(s)
Cromosomas Humanos Par 15 , Cromosomas Humanos Par 17 , Hibridación in Situ/métodos , Leucemia Promielocítica Aguda/genética , Translocación Genética , Bandeo Cromosómico , Fragilidad Cromosómica , Humanos , CariotipificaciónRESUMEN
Supernumerary ring chromosomes varying with respect to both size and number were found as the primary cytogenetic anomaly in a rare benign soft tissue chondroma resected from the floor of the mouth of a 3-year-old girl. Reverse fluorescence in situ hybridization paint probes prepared by polymerase chain reaction from microdissected rings produced fluorescent signal over two large but discontinuous parts of the chromosome 12 long arm, subdivided into four regions. This case expands the spectrum of mesenchymal neoplasms in which ring chromosomes have been described as the primary genetic anomaly. A review of the literature reporting similar findings in other soft tissue tumors further supports the possibility that low-level amplification of chromosome 12 long-arm regions may contribute to abnormal cellular proliferation in a variety of mesenchymal tumors. Genes implicated in the control of the cell cycle such as sarcoma amplified sequence (SAS), the human homolog of the murine double-minute type 2 gene (MDM-2), proto-oncogenes CHOP/GADD153, GLI, A2MR, cyclin-dependent kinase (CDK4), and the high mobility group (HMGIC) gene implicated in mesenchymal tumorigenesis are all located on the long arm of chromosome 12. Chromosomal abnormalities involving the 12q13-q15 region are associated with a wide range of benign soft tissue tumors and sarcomas.
Asunto(s)
Condroma/genética , Cromosomas Humanos Par 12 , Neoplasias de la Boca/genética , Cromosomas en Anillo , Preescolar , Condroma/patología , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Neoplasias de la Boca/patologíaRESUMEN
We describe an infant with trisomy of (5)(p10p13.1) resulting from a de novo marker chromosome. The marker's origin was identified by chromosome microdissection and reverse in situ hybridization. The clinical findings are compared to those of other partial and complete 5p duplications. This case further defines the critical region of 5p trisomy syndrome to proximal 5p.
Asunto(s)
Cromosomas Humanos Par 5/genética , Trisomía , Anomalías Múltiples/genética , Adulto , Bandeo Cromosómico , Análisis Citogenético , Femenino , Fertilización In Vitro , Marcadores Genéticos , Humanos , Lactante , Recién Nacido , Masculino , Síndrome , TrillizosRESUMEN
To more precisely determine the nature of chromosome 3 rearrangements in small cell lung carcinomas (SCLCs), we have applied molecular cytogenetic technologies to a newly characterized SCLC tumor and five SCLC cell lines. Fluorescent in situ hybridization, chromosome microdissection, and, on the previously uncharacterized tumor, spectral karyotyping was utilized to determine chromosome 3 rearrangements. In all cases, our studies were performed on previously G-banded chromosomes in a sequential manner to facilitate a direct comparison. A consistent breakpoint on the long arm of chromosome 3 at band 3q13.2 was identified in all six tumors. This breakpoint was commonly the result of complex chromosomal rearrangements. Loss of the entire short arm of a chromosome 3 was noted in all six tumor cultures. Two of these cell lines had two sublines, one of which contained a 3q13.2 rearrangement and the other of which contained a chromosome rearrangement that resulted in loss of a chromosome 3 short arm. This consistent rearrangement at chromosome band 3q13.2, as demonstrated by molecular cytogenetic methods, may indicate the location of a gene important in the tumorigenesis of SCLC.
Asunto(s)
Carcinoma de Células Pequeñas/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 3 , Neoplasias Pulmonares/genética , Anciano , Deleción Cromosómica , Humanos , Hibridación Fluorescente in Situ , Masculino , Poliploidía , Translocación Genética , Células Tumorales CultivadasRESUMEN
Low-grade B-cell lymphoproliferative disorders are frequently associated with an extra copy of chromosome 12. This well-documented acquired anomaly is one of the most specific numerical chromosome alterations to occur in human hematological malignancies. We have cytogenetically characterized bone marrow and peripheral blood cells from a patient with B-cell chronic lymphocytic leukemia (CLL) having a unique acquired translocation involving chromosomes 6 and 12, t(6;12) (p21.3;q13), which implicates band 12q13 as the site of the gene(s) important in this lymphoproliferative B-cell disorder. Aneuploidy, in the form of trisomy of chromosome 12, is not a requirement for neoplastic transformation in B-cell CLL, but gene rearrangement (present case) or nondisjunctional acquisition of additional copies of defective genes on chromosome 12 at band q13 may be involved in the genesis or progression of this disorder.
Asunto(s)
Cromosomas Humanos Par 12 , Cromosomas Humanos Par 6 , Leucemia Linfocítica Crónica de Células B/genética , Translocación Genética , Células de la Médula Ósea/citología , Pintura Cromosómica , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Ganglios Linfáticos/patología , Metástasis Linfática/genética , Linfocitos/citología , Masculino , Metafase , Persona de Mediana Edad , Células Tumorales CultivadasRESUMEN
Williams syndrome (WS) is a developmental disorder affecting connective tissue and the central nervous system. A common feature of WS, supravalvular aortic stenosis, is also a distinct autosomal dominant disorder caused by mutations in the elastin gene. In this study, we identified hemizygosity at the elastin locus using genetic analyses in four familial and five sporadic cases of WS. Fluorescent in situ hybridization and quantitative Southern analyses confirmed these findings, demonstrating inherited and de novo deletions of the elastin gene. These data indicate that deletions involving one elastin allele cause WS and implicate elastin hemizygosity in the pathogenesis of the disease.
Asunto(s)
Enfermedades del Tejido Conjuntivo/genética , Discapacidades del Desarrollo/genética , Elastina/genética , Adulto , Alelos , Estenosis de la Válvula Aórtica/genética , Arterias/anomalías , Southern Blotting , Niño , Preescolar , Cromosomas Humanos Par 7 , Genes , Genotipo , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Linaje , Eliminación de Secuencia , SíndromeRESUMEN
Supravalvular aortic stenosis (SVAS) is an autosomal dominant disorder characterized by abnormalities of development of the great vessels. SVAS is also commonly part of Williams syndrome. Linkage to the elastin gene on chromosome 7q11 has recently been reported in two kindreds with SVAS. Previous reports of patients with 7q11 deletions have noted great vessel abnormalities in some. We report on a family in which SVAS is cosegregating with a balanced reciprocal translocation, t(6:7) (p21.1;q11.23), providing further evidence that SVAS is the result of a mutation of elastin at 7q11.23 region. The propositus of the translocation family has some minor anomalies which occur in Williams syndrome, suggesting that elastin abnormalities may cause some of the abnormalities found in Williams syndrome.
Asunto(s)
Estenosis de la Válvula Aórtica/genética , Cromosomas Humanos Par 6 , Cromosomas Humanos Par 7 , Elastina/genética , Translocación Genética , Adulto , Anciano , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Niño , Preescolar , Femenino , Humanos , Recién Nacido , Cariotipificación , Masculino , Linaje , Síndrome , UltrasonografíaRESUMEN
A patient is described with 18p- syndrome and hypopituitarism. This is the first patient with this syndrome who has been shown to benefit from growth hormone therapy. Patients with this syndrome who have growth deficiency should be considered for evaluation for hypopituitarism, if the quality of their lives would improve with an increase in stature.
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 18/ultraestructura , Cromosomas Humanos Par 21/ultraestructura , Enanismo Hipofisario/genética , Hipopituitarismo/genética , Translocación Genética , Preescolar , Enanismo Hipofisario/tratamiento farmacológico , Hormona del Crecimiento/análogos & derivados , Hormona del Crecimiento/uso terapéutico , Hormona de Crecimiento Humana , Humanos , Discapacidades para el Aprendizaje/genética , MasculinoRESUMEN
A 10-year-old girl and a 10-month-old girl, both with ambiguous genitalia, were found to have 45,X/46,X,mar and 45,X/46,X,r(?) mosaicism. The marker chromosomes in both girls were very small. Polymerase chain reaction, with synthetic oligonucleotide primers from Y-specific DNA sequences pY-80 and pY53.3 containing the sex-determining region Y(SRY), proved the marker chromosomes to contain the Y short arm material. In situ hybridization with probe pY-80 confirmed that the marker chromosomes included the Y short arms. These findings, together with ambiguous genitalia in the girls, indicate that the marker chromosomes include the testis-determining factor gene.
Asunto(s)
Aberraciones Cromosómicas Sexuales/genética , Cromosoma Y , Secuencia de Bases , Southern Blotting , Niño , Bandeo Cromosómico , Femenino , Hormonas Esteroides Gonadales/sangre , Humanos , Lactante , Datos de Secuencia Molecular , Mosaicismo , Reacción en Cadena de la Polimerasa , Aberraciones Cromosómicas Sexuales/sangreRESUMEN
Cytogenetic studies were performed on 12 involved lymph nodes from Hodgkin's disease patients utilizing conditioned medium from 12-O-tetradecanoylphorbol-13-acetate-staphylococcus enterotoxin A induced mononuclear cells. The majority of cells analyzed had a normal karyotype. An unusually high rate of nonclonal karyotypic abnormalities was noted in most cultures. Clonal abnormalities involving chromosomes 3 and 21 were noted in two patients. Cytogenetic analysis of cultures stimulated with conditioned medium or specific growth factors may lead to a better understanding of the genetic mechanisms involved in Hodgkin's disease.
Asunto(s)
Aberraciones Cromosómicas , Enfermedad de Hodgkin/genética , Ganglios Linfáticos/ultraestructura , Adulto , Células Cultivadas , Niño , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 3 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cromosomas SexualesRESUMEN
Two cell lines designated HBPC-1 and HBPC-2 have been established from hamster buccal pouch tumors induced by topical 7,12-dimethylbenz(a)anthracene (DMBA) and DMBA in conjunction with type 1 herpes simplex virus infection, respectively. The cells are epithelial in morphology, have a doubling time of approximately 18 h, and require bovine serum for optimal growth. The karyotype is aneuploid, with several marker chromosomes, and the cells produce squamous cell carcinomas when transplanted into normal hamster pouch tissues.
Asunto(s)
Carcinoma de Células Escamosas/patología , Neoplasias de la Boca/patología , Simplexvirus/fisiología , Células Tumorales Cultivadas , 9,10-Dimetil-1,2-benzantraceno , Animales , Carcinoma de Células Escamosas/inducido químicamente , División Celular , Mejilla , Cricetinae , Desmosomas/ultraestructura , Epitelio , Queratinas/análisis , Mesocricetus , Mucosa Bucal , Neoplasias de la Boca/inducido químicamente , Trasplante de Neoplasias , Células Tumorales Cultivadas/ultraestructuraRESUMEN
Although numerous genetic markers are available for studying chimerism after bone marrow transplantation (BMT), there remains a need for a practical and highly informative method that is applicable in the early posttransplantation period. Using DNA restriction-fragment-length polymorphisms (RFLPs), we have evaluated the feasibility of developing a single synthetic oligonucleotide probe to study post-BMT chimerism. We have thus tested three candidate probes, termed O-3315-32, O-3315-80, and O-AY-29, that are homologous to tandemly repetitive sequences. Our results demonstrated donor-specific and recipient-specific fragments in 11 of 11 HLA-matched sibling pairs tested using probes O-3315-32 and O-3315-80. When probe O-AY-29 was used, 14 of 17 sibling pairs showed both donor and recipient markers, one had only a recipient marker, and two were identical. We showed that each of the three synthetic probes was effective in documenting donor marrow engraftment, mixed hematopoietic chimerism, the patient's pre-BMT phenotype (by using cultured skin fibroblasts obtained after BMT), and the origin of the malignant hematopoietic cells (i.e., of donor or recipient origin) in patients who developed recurrent hematologic malignancy following BMT. Compared with the use of cloned genomic probes, there are several important advantages to the use of synthetic oligonucleotide probes in studying post-BMT chimerism. Synthetic probes have absolute hybridization specificity and can be designed to suit the purposes of an individual study, since they have adjustable specificity that can be altered by changes in the length of the probe and by changes in the hybridization temperature. A single synthetic probe analogous to several highly polymorphic loci can have a polymorphism information content sufficiently high so that all but a small percentage of BMT patients could be followed easily; for example, if a probe were complementary to three highly polymorphic unlinked loci, it would discriminate approximately 98% of sibling donor/recipient pairs. This would be accomplished using only one restriction-endonuclease digestion and only one gel electrophoresis. Since other genetic markers, e.g., red blood cell antigens, immunoglobulin allotypes, and chromosome analysis, are not uniformly informative and, in some cases, cannot be used in the early posttransplantation period, the use of synthetic oligonucleotide probes for analysis of DNA RFLP is emerging as the method of choice for studies of post-BMT chimerism. This method will allow for the development of new knowledge that has not been possible with previous methods.
Asunto(s)
Trasplante de Médula Ósea , Quimera , Oligonucleótidos/genética , Médula Ósea/ultraestructura , Rechazo de Injerto , Antígenos HLA/genética , Humanos , Leucemia Mieloide/terapia , Linfoma no Hodgkin/terapia , Hibridación de Ácido Nucleico , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Recurrencia , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
Twenty-nine of 172 patients (17%) who received an allogeneic bone marrow transplant (BMT) from histocompatible sibling donors for hematologic malignancies were mixed hematopoietic chimeras; ie, they had a mixture of donor and host hematopoietic or lymphohematopoietic cells at greater than or equal to 14 days after transplantation. Twenty-four of the 29 mixed chimeras (83%) have remained in continuous complete remission for up to 116 months (greater than 9 years) following BMT. Four of the 29 patients (14%) have had recurrent leukemia, and 7 of the 29 (24%) have had moderate or severe graft-v-host disease (GVHD). Twelve of these 29 patients have persisted as stable mixed chimeras for greater than or equal to 2 years after BMT, whereas other patients converted to all donor-type hematopoiesis. The incidence of mixed chimerism was independent of the pretransplant regimen, the donor or recipient age (less than 20 v greater than 20 years), remission status (first complete remission of acute leukemia and first chronic phase of chronic myelocytic leukemia v later stages of disease), and type of leukemia. Our data indicate that mixed hematopoietic chimerism is not rare after BMT for hematologic malignancies and that its presence is compatible with long-term disease-free survival. Prospective studies of mixed chimerism after BMT are warranted to achieve better understanding of its biologic importance.
Asunto(s)
Trasplante de Médula Ósea , Quimera , Células Madre Hematopoyéticas/citología , Leucemia/terapia , Enfermedad Aguda , Antígenos de Superficie/análisis , Médula Ósea/inmunología , Eritrocitos/inmunología , Enfermedad Injerto contra Huésped , Humanos , Alotipos de Inmunoglobulinas/análisis , Trasplante HomólogoRESUMEN
Twenty patients (age range, 4 to 48 years; median age, 36 years) with de novo or drug-induced myelodysplastic syndromes or myeloproliferative disorders were treated with myeloablative immunosuppressive therapy followed by bone marrow transplantation (BMT). Four preparative regimens were used; three regimens consisted of combined total body irradiation (TBI) and chemotherapy and one of combination chemotherapy only. One patient received marrow from his identical twin brother, whereas the other 19 patients were grafted with marrow from histocompatible siblings. In 19 patients the abnormal clone was at least temporarily ablated, while in one patient the congenital myelodysplasia persisted. Eight patients are alive and well for +108 to +3,359 days post-transplantation. Nine patients died of transplant-related complications (six of interstitial pneumonia, two of gastrointestinal bleeding, and one of fungal sepsis) and three patients died with persisting or recurring disease. One patient with a late recurrence has undergone a second successful bone marrow transplant procedure. Outcome of BMT was not related to French-American-British (FAB) type, marrow fibrosis, cytogenetic abnormalities, or preparation regimen. Marrow transplantation as a means of providing long-term disease-free survival and possible cure should be considered in patients if a suitable donor is available.
Asunto(s)
Trasplante de Médula Ósea , Síndromes Mielodisplásicos/terapia , Trastornos Mieloproliferativos/terapia , Adolescente , Adulto , Niño , Preescolar , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/radioterapia , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/radioterapia , Recurrencia , Donantes de Tejidos , Irradiación Corporal TotalRESUMEN
Patients with acute lymphoblastic leukemia who have poor prognostic features at diagnosis usually have a short disease-free survival in spite of successful remission induction. Those poor risk features are: age over 30 years, a white blood cell count over 25,000/microliter, certain translocations of chromosomes, and requirement for more than six weeks of induction chemotherapy to attain a complete remission. We have used high-dose radiochemotherapy to prepare 39 patients with acute lymphoblastic leukemia in first complete remission (1 infant and 38 adults; median age 23 years) for bone marrow transplantation from histocompatible sibling donors. Thirty-one of the 39 patients in this study had one (n = 23) or more (n = 8) poor risk features: age (n = 7); high white blood cell count (n = 19); translocations (n = 4), or resistance to initial induction therapy (n = 11). Currently, 26 patients are surviving for 4-72 months (median 18 months) following marrow grafting and are in complete remission. One of the surviving patients had two marrow transplant procedures because of recurrent leukemia. Actuarial survival in complete remission is 63% for the entire group of 39 patients and is 60% if the eight patients who had no poor risk features are excluded from analysis. The following causes for failure were observed: leukemic relapse was encountered in four patients between 3 and 17 months after BMT for an actuarial relapse rate of 16%; bacterial sepsis was the cause of death in two patients; graft-versus-host disease and/or interstitial pneumonia led to the demise of seven patients, and one patient died with leukoencephalopathy. It appears that high-dose radiochemotherapy followed by bone marrow transplantation from a histocompatible sibling donor during first complete remission can result in a high disease-free survival rate for younger adults with poor-risk acute lymphoblastic leukemia. This concept needs to be tested in prospective trials comparing bone marrow transplantation with chemotherapy.
Asunto(s)
Trasplante de Médula Ósea , Leucemia Linfoide/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Estudios de Evaluación como Asunto , Femenino , Humanos , Leucemia Linfoide/tratamiento farmacológico , Leucemia Linfoide/radioterapia , Masculino , Complicaciones Posoperatorias , Riesgo , Trasplante Homólogo , Irradiación Corporal TotalRESUMEN
We have studied the feasibility of using DNA restriction fragment-length polymorphisms (RFLP) to study marrow engraftment in 27 patients after allogeneic bone marrow transplantation, and have compared these results with those obtained using red blood cell antigens, cytogenetics, and immunoglobulin allotypes. Using highly polymorphic DNA probes, we have documented stable chronic mixed hematopoietic chimerism, have identified transient mixed chimeras, have excluded mixed chimerism with high probability in retrospective studies even when a pretransplant DNA sample was not available, have documented marrow engraftment in the early posttransplant period, and have studied the origin of leukemic cells in patients with recurrent disease. We have evaluated the advantages and disadvantages of several genetic markers and have developed tentative statements concerning the prognosis of patients with mixed chimerism. We conclude that DNA RFLP are powerful and practical genetic markers in bone marrow transplantation studies and that further studies of mixed hematopoietic chimerism are warranted.
Asunto(s)
Trasplante de Médula Ósea , Quimera , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Antígenos de Superficie/análisis , ADN de Neoplasias/análisis , Eritrocitos/inmunología , Femenino , Marcadores Genéticos , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/análisis , Humanos , Alotipos de Inmunoglobulinas/análisis , Leucemia/genética , Leucemia/terapia , Masculino , Recurrencia , Estudios RetrospectivosRESUMEN
Nonrandom associations between the sex chromosomes of the brush-tailed possum, Trichosurus vulpecula, were found to be due to association of nucleolar organizer regions (NOR's) on the X and Y chromosomes. NOR association was also observed between an autosome and the X chromosome. These findings, based on silver staining, are in contrast to the report of MURRAY (1977), who observed sex-chromosome association in this animal and indicated that these nonrandom associations may reflect an association between heterochromatic regions during interphase. We observed only two pairs of NOR's per cell in this animal, one autosomal and one on the sex chromosomes, rather than the several such regions observed by MURRAY, who used an N-banding technique. We discuss the problem of nonhomologous chromosome association in mammalian cells as influenced by heterochromatin and NOR's and find little support for nonhomologous chromosome associations at mitotic metaphase due to heterochromatin association.