RESUMEN
Jumping is a rapid locomotory mode widespread in terrestrial organisms. However, it is a rare specialization in ants. Forward jumping has been reported within four distantly related ant genera: Gigantiops, Harpegnathos, Myrmecia, and Odontomachus. The temporal engagement of legs/body parts during jump, however, varies across these genera. It is unknown what morphological adaptations underlie such behaviors and whether jumping in ants is solely driven directly by muscle contraction or additionally relies on elastic recoil mechanism. We investigated the morphological adaptations for jumping behavior by comparing differences in the locomotory musculature between jumping and non-jumping relatives using X-ray micro-CT and 3D morphometrics. We found that the size-specific volumes of the trochanter depressor muscle (scm6) of the middle and hind legs are 3-5 times larger in jumping ants, and that one coxal remotor muscle (scm2) is reduced in volume in the middle and/or hind legs. Notably, the enlargement in the volume of other muscle groups is directly linked to the legs or body parts engaged during the jump. Furthermore, a direct comparison of the muscle architecture revealed two significant differences between jumping vs. non-jumping ants: First, the relative Physiological Cross-Sectional Area (PCSA) of the trochanter depressor muscles of all three legs were larger in jumping ants, except in the front legs of Odontomachus rixosus and Myrmecia nigrocincta; second, the relative muscle fiber length was shorter in jumping ants compared to non-jumping counterparts, except in the front legs of O. rixosus and M. nigrocincta. These results suggest that the difference in relative muscle volume in jumping ants is largely invested in the area (PCSA), and not in fiber length. There was no clear difference in the pennation angle between jumping and non-jumping ants. Additionally, we report that the hind leg length relative to body length was longer in jumping ants. Based on direct comparison of the observed vs. possible work and power output during jumps, we surmise that direct muscle contractions suffice to explain jumping performance in three species, except for O. rixosus, where the lack of data on jumping performance prevents us from drawing definitive conclusions for this particular species. We suggest that increased investment in jumping-relevant musculature is a primary morphological adaptation that separates jumping from non-jumping ants. These results elucidate the common and idiosyncratic morphological changes underlying this rare adaptation in ants. ã¾ã¨ã ã¿ (Okinawan language-Uchinaaguchi) (Japanese) Ð ÐÐЮÐÐ (Kazakh) ZUSAMMENFASSUNG (German).
RESUMEN
A 2.9 kg Miniature Schnauzer was referred to our clinic, the Emergency & Critical Care Medicine Service at the Michigan State University Veterinary Teaching Hospital, following a dog fight. Physical examination findings upon admission included multiple thoracic wounds, absence of hindlimb deep pain, and marked Schiff-Sherrington syndrome. Computed tomography imaging revealed thoracic wall penetration and a comminuted T5 vertebral fracture. Thoracic exploration and thoracic wall repair were performed through a median sternotomy. The vertebral fracture was exposed and stabilised intra-thoracically through the same approach using pins and polymethylmethacrylate. The pins were placed percutaneously into the vertebral bodies of the adjacent vertebrae. Recovery was uncomplicated and fracture healing was documented eight weeks postoperatively. Spinal trauma secondary to dog fights is relatively common. The presence of concurrent penetrating thoracic injury negatively affects prognosis and necessitates thoracic exploration as soon as feasible. The approach should allow complete thoracic exploration to repair parietal and visceral damage, thus indicating the need for median sternotomy rather than an intercostal approach. The present case report suggested that median sternotomy can be used to safely apply stabilisation devices for the treatment of concurrent spinal trauma. Direct visualisation of the vertebral bodies permitted optimal implant anchorage as compared to potentially more hazardous techniques such as dorsal pinning.
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Clavos Ortopédicos/veterinaria , Perros/lesiones , Fijación Interna de Fracturas/veterinaria , Fracturas Conminutas/veterinaria , Polimetil Metacrilato/uso terapéutico , Esternotomía/veterinaria , Animales , Enfermedades de los Perros/cirugía , Fijación Interna de Fracturas/métodos , Fracturas Conminutas/cirugía , Columna Vertebral/patología , Esternotomía/métodosRESUMEN
Lineage commitment in B lymphopoiesis remains poorly understood due to the inability to clearly define newly committed B lineage progenitors and their multipotential descendants. We examined the potential of three recently described progenitor populations in adult mouse bone marrow to differentiate into each hematopoietic lineage. The earliest of these, termed fraction (Fr.) A0, exhibited myeloid, erythroid, and B and T lymphoid progenitor activity and included individual cells with myeloid/B lymphoid potential. In sharp contrast, two later populations, termed Frs. A1 and A2 and characterized by surface B220 expression and transcription of the germline immunoglobulin heavy chain (IgH) locus, lacked progenitor activity for all hematopoietic lineages except B lymphocytes. These observations, together with single cell polymerase chain reaction analysis showing a lack of DHJH rearrangements in each population and experiments showing identical precursor potentials when these populations were derived from recombination activating gene (Rag)-1(-/-) and JH-/- mice, demonstrate that commitment to the B lymphoid lineage occurs before and independently of VHDHJH recombination.
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Linfocitos B/citología , Linaje de la Célula , Reordenamiento Génico de Cadena Pesada de Linfocito B , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/citología , Animales , Diferenciación Celular , ADN Nucleotidiltransferasas/metabolismo , Células Precursoras Eritroides/citología , Femenino , Genes de Inmunoglobulinas , Cadenas Pesadas de Inmunoglobulina/genética , Células Asesinas Naturales/citología , Macrófagos/citología , Ratones , Ratones Congénicos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Monocitos/citología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/citología , VDJ RecombinasasRESUMEN
Notch1 signaling is required for T cell development. We have previously demonstrated that expression of a dominant active Notch1 (ICN1) transgene in hematopoietic stem cells (HSCs) leads to thymic-independent development of CD4(+)CD8(+) double-positive (DP) T cells in the bone marrow (BM). To understand the function of Notch1 in early stages of T cell development, we assessed the ability of ICN1 to induce extrathymic T lineage commitment in BM progenitors from mice that varied in their capacity to form a functional pre-T cell receptor (TCR). Whereas mice repopulated with ICN1 transduced HSCs from either recombinase deficient (Rag-2(-/)-) or Src homology 2 domain--containing leukocyte protein of 76 kD (SLP-76)(-/)- mice failed to develop DP BM cells, recipients of ICN1-transduced Rag-2(-/)- progenitors contained two novel BM cell populations indicative of pre-DP T cell development. These novel BM populations are characterized by their expression of CD3 epsilon and pre-T alpha mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2(-/)- mice with a TCR beta transgene restored ICN1-induced DP development in the BM within 3 wk after BM transfer (BMT). At later time points, this population selectively and consistently gave rise to T cell leukemia. These findings demonstrate that Notch signaling directs T lineage commitment from multipotent progenitor cells; however, both expansion and leukemic transformation of this population are dependent on T cell-specific signals associated with development of DP thymocytes.
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Proteínas de Unión al ADN/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Receptores de Superficie Celular , Linfocitos T/fisiología , Factores de Transcripción , Animales , Médula Ósea/fisiología , Linaje de la Célula , Proteínas de Unión al ADN/metabolismo , Células Madre Hematopoyéticas/fisiología , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Leucemia de Células T/genética , Ratones , Ratones Transgénicos , Receptor Notch1 , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/metabolismo , Transducción de Señal , Timo/citologíaRESUMEN
The gene encoding the BCL-6 transcriptional repressor is frequently translocated and mutated in diffuse large cell lymphoma. Mice with a disrupted BCL-6 gene developed myocarditis and pulmonary vasculitis, had no germinal centers, and had increased expression of T helper cell type 2 cytokines. The BCL-6 DNA recognition motif resembled sites bound by the STAT (signal transducers and activators of transcription) transcription factors, which mediate cytokine signaling. BCL-6 could repress interleukin-4 (IL-4)-induced transcription when bound to a site recognized by the IL-4-responsive transcription factor Stat6. Thus, dysregulation of STAT-responsive genes may underlie the inflammatory disease in BCL-6-deficient mice and participate in lymphoid malignancies.
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Citocinas/biosíntesis , Proteínas de Unión al ADN/fisiología , Centro Germinal/inmunología , Inflamación/inmunología , Proteínas Proto-Oncogénicas/fisiología , Factores de Transcripción/fisiología , Animales , Linfocitos B/inmunología , Células Cultivadas , Proteínas de Unión al ADN/genética , Ficoll/análogos & derivados , Ficoll/inmunología , Haptenos , Hemocianinas/inmunología , Inmunoglobulinas/biosíntesis , Inflamación/patología , Interferón gamma/biosíntesis , Interleucina-4/metabolismo , Interleucinas/biosíntesis , Interleucinas/metabolismo , Activación de Linfocitos , Ratones , Miocarditis/inmunología , Miocarditis/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Receptores de IgE/genética , Factor de Transcripción STAT6 , Transducción de Señal , Bazo/inmunología , Linfocitos T/inmunología , Células Th2/inmunología , Transactivadores/metabolismo , Factores de Transcripción/genética , Transcripción Genética , Trinitrobencenos/inmunología , Vasculitis/inmunología , Vasculitis/patologíaRESUMEN
Developing alphabeta T cells diverge into the CD4 and CD8 lineages as they mature in the thymus. It is unclear whether lineage commitment is mechanistically distinct from the process that selects for the survival of T cells with useful T cell receptor (TCR) specificities (positive selection). In HD mice, which lack mature CD4+ T cells, major histocompatibility complex (MHC) class II-restricted T cells are redirected to the CD8 lineage independent of MHC class I expression. However, neither TCR-mediated signaling nor positive selection is impaired. Thus, the HD mutation provides genetic evidence that lineage commitment may be mechanistically distinct from positive selection.
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Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Linaje de la Célula , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Subgrupos de Linfocitos T/citología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Cruzamientos Genéticos , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Masculino , Ratones , Ratones Mutantes , Ratones Transgénicos , Fenotipo , Fosforilación , Quimera por Radiación , Transducción de Señal , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Lymphocyte development is critically influenced by self-antigens. T cells are subject to both positive and negative selection, depending on their degree of self-reactivity. Although B cells are subject to negative selection, it has been difficult to test whether self-antigen plays any positive role in B cell development. A murine model system of naturally generated autoreactive B cells with a germ line gene-encoded specificity for the Thy-1 (CD90) glycoprotein was developed, in which the presence of self-antigen promotes B cell accumulation and serum autoantibody secretion. Thus, B cells can be subject to positive selection, generated, and maintained on the basis of their autoreactivity.
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Autoanticuerpos/biosíntesis , Autoantígenos/inmunología , Subgrupos de Linfocitos B/inmunología , Antígenos Thy-1/inmunología , Envejecimiento/inmunología , Animales , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Antígenos CD5/análisis , Genes de Inmunoglobulinas , Hibridomas , Inmunidad Innata , Vigilancia Inmunológica , Ratones , Ratones SCID , Ratones Transgénicos , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal , Linfocitos T/inmunologíaRESUMEN
In 2007, UNAIDS issued a guidance note on HIV and sex work, the tone and contents of which angered sex workers, activists and public health workers worldwide. In this article, based on presentations at the conference, M. Seshu et al describe the problems with the guidance note, discuss the reaction to its publication, and explain how a group of activists got together to develop a reworked version of the guidance note.
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Guías como Asunto , Infecciones por VIH , Trabajo Sexual , Naciones Unidas , HumanosRESUMEN
In up to 45% of reported cases of the non-Hodgkin's lymphoma, diffuse large cell lymphoma, there are translocations of the BCL-6 gene, which are presumed to deregulate its expression. The BCL-6 protein, which is unmutated in these lymphomas, contains six Krüppel-like zinc fingers at its carboxy terminus and a 121 amino acid domain at its amino terminus, termed the POZ domain, which bears homology with amino terminal domains in a subset zinc finger transcription factors. In this study, we tested whether BCL-6 regulates transcription and if the POZ domain has a role in this function. The BCL-6 POZ domain, when fused to the GAL4 DNA binding domain, strongly repressed transcriptional activation initiated from several different promoters including the SV40 enhancer/promoter. Repression was also observed when the fusion protein was bound at a distance of 200 bp 5' of the promoter. When the GAL4/BCL6 POZ domain fusion protein was expressed in yeast, it was able to homodimerize in the nucleus. Nevertheless, in contrast with mammalian cells, the fusion protein did not repress transcription. To test the ability of the full length BC1-6 protein to repress transcription when bound to DNA through its zinc finger DNA binding domain, high affinity BCL-6 binding sites were selected from a pool of random oligonucleotides. Full length BCL-6 was able to strongly repress transcription when bound to its cognate site cloned upstream of the thymidine kinase promoter. This repression was mediated, in large measure, by the POZ domain, although a variant of BCL-6 lacking the POZ domain was able to repress transcription modestly. The ability of BCL-6 to function as a transcriptional repressor may contribute to its ability to transform B lymphocytes in diffuse large cell lymphoma.
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Proteínas de Unión al ADN/fisiología , ADN/metabolismo , Proteínas Proto-Oncogénicas/fisiología , Proto-Oncogenes/fisiología , Factor de Transcripción Sp1/fisiología , Factores de Transcripción/fisiología , Activación Transcripcional , Dedos de Zinc/fisiología , Secuencia de Bases , Sitios de Unión , Proteínas de Unión al ADN/química , Vectores Genéticos , Células HeLa , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas c-bcl-6 , Proteínas Recombinantes de Fusión , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae , Factor de Transcripción Sp1/metabolismo , Factores de Transcripción/químicaRESUMEN
PURPOSE: Capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes that results in the preferential release of 5-FU at the tumor site. PATIENTS AND METHODS: In this phase I study, capecitabine was administered twice daily as outpatient therapy, each cycle administered for 2 weeks followed by 1 week of rest. Thirty-four patients with solid tumors, all of whom except three patients were pretreated, were treated at dose levels from 502 to 3,514 mg/m2 daily. RESULTS: The median treatment duration was four cycles (85 days; range, 14 to 833+ days). Two patients continue on treatment at 686 and 833+ days. Capecitabine 3,000 mg/m2 daily was not tolerable, with dose-limiting toxicities of diarrhea with hypotension, abdominal pain, and leukopenia. Palmar-plantar erythrodysesthesia (PPE) became evident at higher dose levels after prolonged treatment. Evidence of objective tumor response was reported in four patients at 2,510 mg/m2 daily and greater (one complete response [CR] and three partial responses [PRs]) with subjective minor tumor responses in a further seven patients. Pharmacokinetic studies showed rapid gastrointestinal absorption of capecitabine, followed by extensive conversion into 5'-deoxy-5-fluorouridine (5'-DFUR), with only low systemic 5-FU levels. CONCLUSION: Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.
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Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Desoxicitidina/análogos & derivados , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: Dolasetron is a 5-HT3 antagonist antiemetic with active oral and intravenous formulations. The effects of this class are enhanced when combined with dexamethasone. This study tested the ability of the combination of oral dolasetron 200 mg and oral dexamethasone 20 mg to prevent acute emesis in cancer patients receiving initial cisplatin at doses > or = 70 mg/m2. Additionally, patients were randomly assigned to receive a second dosage of the regimen 16 hours later to improve control of acute symptoms. PATIENTS AND METHODS: A total of 75 patients were entered, with 38 randomized to the two-dose regimen. Thirty-five percent were women and 77% had lung cancer. RESULTS: Overall, the regimen prevented acute vomiting in 76% (95% confidence interval, 65% to 85%), including 74% of 35 patients who received cisplatin at doses > or = 100 mg/m2. There was no observed difference in emesis prevention between the one-dose (76%) and two-dose (76%) regimens (95% confidence interval for the difference, -20% to 19%). The median time to the onset of emesis was 19 hours for the one-dose regimen and 17 hours for the two-dose regimen in those patients with emesis. Headache occurred in 11% who received one dose and 16% who received two doses. CONCLUSION: The combination of oral dolasetron 200 mg and dexamethasone 20 mg given only once prevented acute emesis in 76% of patients who received cisplatin > or = 70 mg/m2. Administration of a second dose of the regimen did not improve the observed prevention rate or delay the time to emesis. This one-dose oral regimen has comparable or better effectiveness than reported results of intravenous combination regimens in preventing cisplatin-induced vomiting and merits further study and use.
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Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Dexametasona/uso terapéutico , Indoles/uso terapéutico , Quinolizinas/uso terapéutico , Vómitos/prevención & control , Enfermedad Aguda , Administración Oral , Antieméticos/administración & dosificación , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Dexametasona/administración & dosificación , Quimioterapia Combinada , Femenino , Humanos , Indoles/administración & dosificación , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Náusea/prevención & control , Neoplasias/tratamiento farmacológico , Quinolizinas/administración & dosificación , Vómitos/inducido químicamenteRESUMEN
PURPOSE: To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III. PATIENTS AND METHODS: Three capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m(2)/d bid continuously; arm B, 2,510 mg/m(2)/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m(2)/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off). RESULTS: One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response [PR] + complete response [CR]) were reported for eight patients with two CRs (21%; 95% confidence interval [CI], 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity. CONCLUSION: Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.
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Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Esquema de Medicación , Femenino , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
PURPOSE: To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil (5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m(2) administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/LV) until disease progression or unacceptable toxicity. RESULTS: The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P =.65); median time to treatment failure was 4.2 and 4.0 months (log-rank P =.89); and median overall survival was 13.2 and 12.1 months (log-rank P =.33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P <.00001) of stomatitis and alopecia, but a higher incidence of cutaneous hand-foot syndrome (P <.00001). Capecitabine also resulted in lower incidences (P <.00001) of grade 3/4 stomatitis and neutropenia, leading to a lower incidence of grade 3/4 neutropenic fever and sepsis. Only grade 3 hand-foot syndrome (P <.00001) and uncomplicated grade 3/4 hyperbilirubinemia (P <.0001) were reported more frequently with capecitabine. CONCLUSION: Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent.
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Adenocarcinoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Fluorouracilo/uso terapéutico , Profármacos/uso terapéutico , Adenocarcinoma/secundario , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Capecitabina , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Profármacos/administración & dosificación , Profármacos/efectos adversos , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
The CBA/N strain carries xid, a murine btk missense mutation that reduces peripheral B cell numbers. Using in vivo BrdU labeling and cytofluorimetry, we have compared the magnitude, production rates, and turnover rates of each B lineage subset in the marrow and periphery of CBA/Ca and CBA/N mice. Our results show the pro-B compartment is largely unaffected by xid. In contrast, the pre-B cell pool is markedly reduced, reflecting a diminished production rate and unaltered turnover time. Despite diminished pre-B cell formation, the size of the immature B cell pool is relatively normal in CBA/N mice, due to increased proportional survival of pre-B cells. In addition, we have assessed the marrow and peripheral B cell subsets of CBA/N mice transgenic for bcl-2. These results indicate that while the bcl-2 transgene promotes lengthened survival in most B cell subsets, the pro/pre-B cell losses mediated by xid are not abrogated by bcl-2 overexpression. Taken together, these findings suggest that the initial [not readable: see text] from the pro- to pre-B cell pools, and that anomalies in subsequent compartments likely reflects the action of homeostatic mechanisms compensating for compromised pre-B cell production.
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Subgrupos de Linfocitos B/patología , Genes bcl-2 , Células Madre Hematopoyéticas/patología , Síndromes de Inmunodeficiencia/patología , Proteínas Tirosina Quinasas/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Agammaglobulinemia Tirosina Quinasa , Animales , Subgrupos de Linfocitos B/inmunología , Médula Ósea/patología , Muerte Celular , Diferenciación Celular , Supervivencia Celular , Femenino , Regulación del Desarrollo de la Expresión Génica , Hematopoyesis/genética , Células Madre Hematopoyéticas/inmunología , Homeostasis , Humanos , Síndromes de Inmunodeficiencia/enzimología , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Activación de Linfocitos , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos CBA , Ratones Transgénicos , Mutación Missense , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/genética , Bazo/patologíaRESUMEN
Capecitabine (Xeloda) is a novel rationally designed fluoropyrimidine carbamate. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes resulting in preferential release of 5-fluorouracil (5-FU) at the tumor site. Preclinical studies indicated an enhancement of the therapeutic index when capecitabine was combined with leucovorin. This Phase I trial was designed to determine the safety profile, maximal tolerated dose, and pharmacokinetic profile of the combination of capecitabine plus a fixed dose of p.o. leucovorin (60 mg/day) during administration to patients with refractory advanced cancers. The intention was to administer both drugs continuously, but the starting dose of capecitabine was also the maximum tolerated dose (1004 mg/m2/day) in six patients treated with this regimen. A cycle of treatment was then redefined as leucovorin and capecitabine given p.o., twice daily for 2 consecutive weeks followed by a 1-week rest period. Capecitabine doses from 1004 mg/m2/day to 2510 mg/m2/day were evaluated with the intermittent schedule over approximately 80 courses in an additional 25 patients. The dose-limiting toxicities that defined the maximum tolerated dose at 2000 mg/m2/day were diarrhea, nausea, vomiting, and palmar plantar erythrodysesthesia. The recommended Phase II dose using this schedule was 1650 mg/m2/day of capecitabine plus leucovorin 60 mg/day. Plasma concentrations of capecitabine, intermediate metabolites, and 5-FU were measured in 26 patients on days 1 and 14 of therapy. The pharmacokinetics of capecitabine were characterized by rapid GI absorption, with Cmax at 1 h, followed by conversion to active drug. The coadministration of leucovorin had no effect on the pharmacokinetics of capecitabine. Two patients with colorectal cancer, both previously treated with 5-FU, had partial responses. Phase II studies have confirmed the promising antitumor activity of this drug, and capecitabine is currently in Phase III evaluation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Femenino , Fluorouracilo/análogos & derivados , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucovorina/farmacocinética , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Capecitabine (Ro 09-1978) is a novel oral fluoropyrimidine carbamate that was rationally designed to generate 5-fluorouracil (5-FU) selectively in tumors. The effect of food on the pharmacokinetics of capecitabine and its metabolites was investigated in 11 patients with advanced colorectal cancer using a two-way cross-over design with randomized sequence. Patients received repeated doses of 666 or 1255 mg/m2 of capecitabine twice daily. On study days 1 and 8, drug was administered following an overnight fast or within 30 min after consumption of a standard breakfast, and serial blood samples were collected. Concentrations of capecitabine and its metabolites [5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), 5-FU, dihydro-5-fluorouracil (FUH2), and alpha-fluoro-beta-alanine (FBAL)] in plasma were determined by high-performance liquid chromatography or liquid chromatography/mass spectroscopy. Intake of food prior to the administration of capecitabine resulted in pharmacokinetic changes of all compounds involved. The extent of these changes, however, varied considerably between the various compounds. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) values were decreased after food, and time until the occurrence of Cmax values were increased. In contrast, the apparent elimination half-life was not affected by food intake. The extent of change in Cmax and AUC was highest for capecitabine and decreased with the order of formation of the metabolites. The "before:after food" ratios of the Cmax values were 2.47 for capecitabine, 1.81 for 5'-DFCR, 1.53 for 5'-DFUR, 1.58 for 5-FU, 1.26 for FUH2, and 1.11 for FBAL. The before: after food ratios of the AUC values were 1.51 for capecitabine, 1.26 for 5'-DFCR, 1.15 for 5'-DFUR, 1.13 for 5-FU, 1.07 for FUH2, and 1.04 for FBAL. The results show that food has a profound effect on the AUC of capecitabine, a moderate effect on the AUC of 5'-DFCR, and only a minor influence on the AUC of the other metabolites in plasma. In addition, a profound influence on Cmax of capecitabine and most of its metabolites was found. Detailed information on the relationship between concentration and safety/efficacy is necessary to evaluate the clinical significance of these pharmacokinetic findings. At present, it is recommended that capecitabine be administered with food as this procedure was used in the clinical trials.
Asunto(s)
Antineoplásicos/farmacocinética , Neoplasias Colorrectales/metabolismo , Desoxicitidina/análogos & derivados , Interacciones Alimento-Droga , Administración Oral , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Área Bajo la Curva , Capecitabina , Estudios Cruzados , Desoxicitidina/administración & dosificación , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Método Doble Ciego , Femenino , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Mutations of the androgen receptor (AR) cause defects in virilization and can result in a spectrum of phenotypic abnormalities of male sexual development that includes patients with a completely female phenotype (complete testicular feminization) and individuals with less severe defects of virilization, such as Reifenstein syndrome. These phenotypes are not specific for mutations of the AR gene, however, and defects in other genes can also result in similar abnormalities of male development. For this reason, the diagnosis of an AR defect is laborious and requires data from endocrine studies, the family history, and in vitro binding experiments. To assist in the evaluation of patients with possible AR defects, we previously employed the use of a recombinant adenovirus to deliver an androgen-responsive gene into fibroblast cultures to assay AR function in normal subjects and patients with complete forms of androgen resistance. Although these studies demonstrated measurable differences between these two groups of subjects, we did not assay samples from patients with partial defects of androgen action. In the current study, we have modified this method to examine AR function in three groups of patients with known or suspected defects of AR function: patients with Reifenstein syndrome, patients with spinobulbar muscular atrophy, and patients with severe forms of isolated hypospadias. When assayed using this method, the AR function of patients with Reifenstein syndrome was intermediate between that of normal control subjects and that of patients with complete testicular feminization. Using the parameters established by the aforementioned experiments, we found that defective AR function can be detected in fibroblasts established from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including two with a normal AR gene sequence. These results suggest that this method may have some utility in screening samples to detect defects of AR function, particularly when viewed in the context of other AR assays results.
Asunto(s)
Adenoviridae/genética , Genes Reporteros , Genitales , Receptores Androgénicos/fisiología , Piel/metabolismo , Femenino , Fibroblastos/metabolismo , Humanos , Hipospadias/metabolismo , Masculino , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patología , Recombinación Genética , Valores de Referencia , Piel/citología , Síndrome , Virilismo/metabolismo , Virilismo/patologíaRESUMEN
More than 95% of newly formed B cells die in the short interval spanning sIgM acquisition in the bone marrow and entry into the long-lived pool, suggesting that selective events dictating B cell longevity occur at this stage. These likely include both ligand-induced deletion as well as discrete events that mediate recruitment to the long-lived recirculating pool. We are probing these events through the examination of normal B cell differentiation during this critical period: the characterization of a natural mutation that blocks late maturation, an irradiation/autoreconstitution model of marrow-derived B cell differentiation, and the identification of life span regulatory genes whose expression changes within this window.
Asunto(s)
Linfocitos B/inmunología , Células de la Médula Ósea/inmunología , Médula Ósea/inmunología , Animales , Linfocitos B/citología , Células de la Médula Ósea/citología , Diferenciación Celular/inmunología , Humanos , Inmunoglobulina M/análisis , MutaciónRESUMEN
The androgen receptor (AR) and closely related members of the steroid receptor family have proven difficult to obtain in native form in large quantities. In the case of the human AR (hAR), high-level expression in prokaryotic or non-mammalian cells leads to the synthesis of a high proportion of non-binding, insoluble, or degraded forms of the receptor protein. To circumvent these difficulties, we have constructed a recombinant adenovirus that directs the expression of hAR under the control of a potent, constitutive promoter. Infection of eukaryotic cells with this recombinant virus leads to the synthesis of large quantities of the intact AR. In contrast to expression methods designed to direct the full-length AR in bacteria, yeast, and insect cells, AR expressed in mammalian cells using this adenoviral vector accumulates at high levels, retains many properties of the native AR, and is not rapidly proteolyzed. This method will prove useful for large-scale preparations of hAR for use in functional and structural studies.