RESUMEN
PURPOSE: Quality of life (QoL), appetite, cachexia, and biomarkers [albumin, hemoglobin (Hb), neutrophils, lymphocytes, platelets, C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), interleukin 8 (IL-8), C-X-C motif chemokine ligand 5 (CXCL5) and citrullinated histoneH3 (H3Cit)] were compared for 40 cases with advanced cancer and 40 healthy controls. Baseline differences and significant relationships were explored for biomarkers with QoL, appetite, and cachexia. METHODS: In a prospective case-control, age and sex matched study, the European Organisation for the Research and Treatment of Cancer Quality of Life-C30 questionnaire (EORTC-QLQ-C30) for QoL, the Functional Assessment of Anorexia and Cachexia Therapy assessment (FAACT A/CS-12) for appetite, and a five-factor cachexia assessment tool for cachexia assessment were performed. Routine hematological measurements and blood chemistry analyses together with ELISA procedures and a Multiplex® bead array platform, were used for biomarker analysis. Descriptive statistics and regression analyses were undertaken. P < 0.05 defined statistical significance. RESULTS: Global health status (QL-G), functional scales (QL-FS), and symptom scales (QL-SS) differed for cases and controls (p < 0.01). In cases, differences were observed for QL-G (p < 0.01), QL-FS (p < 0.01), and QL-SS (p = 0.01) compared to standardized references values. FAACT A/CS-12 scores differed significantly between cases and controls (p < 0.01) and 30% of cases scored "poor" appetites. Cachexia was present in 60% of cases. Albumin, lymphocytes, platelets, Hb, platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), CRP, TNFα, all at p < 0.01, neutrophil to lymphocyte ratio (NLR) (p = 0.02), IL-6 (p < 0.04), and IL-8 (p = 0.02) differed significantly between cases and controls. No difference was found for CXCL5 or H3Cit. Albumin NLR, Hb, PLR, SII, TNFα, IL-8, and CRP showed significant relationships with all aspects of QoL. QL-FS was significantly related to CXCL5 (p = 0.04), significant relationships with FAACT A/CS-12 included: NLR (p = 0.002), Hb (p < 0.001), and PLR (p < 0.01). NLR, PLR, SII, TNFα, IL-6, IL-8, and CRP correlated positively to cachexia and albumin while Hb and lymphocyte count correlated negatively to cachexia. CONCLUSION: CXCL5 and H3Cit were not reliable biomarkers for cancer cachexia, nor significantly related to QoL, appetite or cachexia. Albumin, NLR, Hb, PLR, SII, TNFα, IL-8, and CRP were reliable indicators of QoL, appetite, and cachexia. Future research should include other novel biomarkers namely growth differentiation factor-15 (GDF-15), fibroblast growth factor 21 (FGF-21), fractakline, interferon gamma (IFN-y), IL-16, macrophage colony stimulating factor (M-CSF), and macrophage procoagulant-inducing factor (MPIF).
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Apetito , Biomarcadores , Caquexia , Neoplasias , Calidad de Vida , Humanos , Caquexia/etiología , Masculino , Femenino , Persona de Mediana Edad , Neoplasias/complicaciones , Estudios de Casos y Controles , Estudios Prospectivos , Anciano , Apetito/fisiología , Biomarcadores/sangre , Encuestas y Cuestionarios , AdultoRESUMEN
NOD.H2h4 mice are the most commonly used model for human autoimmune thyroiditis. Because thyroid autoimmunity develops slowly (over months), NOD.H2h4 mice are usually exposed to excess dietary iodide to accelerate and amplify the process. However, unlike the female bias in human thyroid autoimmunity, autoantibodies to thyroglobulin (TgAb) are reported to be similar in male and female NOD.H2h4 . We sought evidence for sexual dimorphism in other parameters in this strain maintained on regular or iodized water. Without iodide, TgAb levels are higher in males than in females, the reverse of human disease. In humans, autoantibodies to thyroid peroxidase (TPOAb) are a better marker of disease than TgAb. In NOD.H2h4 mice TPOAb develop more slowly than TgAb, being detectable at 6 months of age versus 4 months for the latter. Remarkably, unlike TgAb, TPOAb levels are higher in female than male NOD.H2h4 mice on both regular and iodized water. As previously observed, serum T4 levels are similar in both sexes. However, thyroid-stimulating hormone (TSH) levels are significantly higher in males than females with or without iodide exposure. TSH levels correlate with TgAb levels in male NOD.H2h4 mice, suggesting a possible role for TSH in TgAb development. However, there is no correlation between TSH and TPOAb levels, the latter more important than TgAb in human disease. In conclusion, if the goal of an animal model is to closely reflect human disease, TPOAb rather than TgAb should be measured in older female NOD.H2h4 mice, an approach requiring patience and the use of mouse TPO protein.
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Envejecimiento/inmunología , Yoduro Peroxidasa/inmunología , Factores Sexuales , Tiroiditis Autoinmune/inmunología , Animales , Formación de Anticuerpos , Autoanticuerpos/metabolismo , Dietoterapia , Modelos Animales de Enfermedad , Femenino , Humanos , Yoduros/administración & dosificación , Masculino , Ratones , Ratones Endogámicos NOD , Caracteres Sexuales , Tiroglobulina/inmunología , Tiroiditis Autoinmune/diagnóstico , Tirotropina/sangreRESUMEN
The thyrotrophin receptor (TSHR) A-subunit is the autoantigen targeted by pathogenic autoantibodies that cause Graves' hyperthyroidism, a common autoimmune disease in humans. Previously, we reported that pathogenic TSHR antibodies develop spontaneously in thyroiditis-susceptible non-obese diabetic (NOD).H2h4 mice bearing a human TSHR A-subunit transgene, which is expressed at low levels in both the thyroid and thymus (Lo-expressor transgene). The present study tested recent evidence that high intrathymic TSHR expression protects against the development of pathogenic TSHR antibodies in humans. By successive back-crossing, we transferred to the NOD.H2h4 background a human TSHR A-subunit transgene expressed at high levels in the thyroid and thymus (Hi-expressor transgene). In the sixth back-cross generation (> 98% NOD.H2h4 genome), only transgenic offspring produced spontaneously immunoglobulin (Ig)G class non-pathogenic human TSHR A-subunit antibodies. In contrast, both transgenic and non-transgenic offspring developed antibodies to thyroglobulin and thyroid peroxidase. However, non-pathogenic human TSHR antibody levels in Hi-expressor offspring were lower than in Lo-expressor transgenic mice. Moreover, pathogenic TSHR antibodies, detected by inhibition of TSH binding to the TSHR, only developed in back-cross offspring bearing the Lo-expressor, but not the Hi-expressor, transgene. High versus low expression human TSHR A-subunit in the NOD.H2h4 thymus was not explained by the transgene locations, namely chromosome 2 (127-147 Mb; Hi-expressor) and chromosome 1 (22.9-39.3 Mb; low expressor). Nevertheless, using thyroiditis-prone NOD.H2h4 mice and two transgenic lines, our data support the association from human studies that low intrathymic TSHR expression is associated with susceptibility to developing pathogenic TSHR antibodies, while high intrathymic TSHR expression is protective.
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Inmunoglobulinas Estimulantes de la Tiroides/biosíntesis , Receptores de Tirotropina/genética , Receptores de Tirotropina/inmunología , Timo/metabolismo , Glándula Tiroides/inmunología , Tiroiditis Autoinmune/inmunología , Tiroiditis Autoinmune/fisiopatología , Animales , Autoanticuerpos/sangre , Enfermedad de Graves/inmunología , Humanos , Inmunoglobulinas Estimulantes de la Tiroides/inmunología , Yoduro Peroxidasa/inmunología , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Tiroglobulina/inmunología , Glándula Tiroides/citología , Glándula Tiroides/patología , Tiroiditis Autoinmune/patologíaRESUMEN
BACKGROUND: To establish the role of antiemetic therapy with neurokinin-1 (NK1) receptor antagonists (RAs) in nonanthracycline and cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC) regimens, this study evaluated single-dose intravenous (i.v.) fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with non-AC MEC. PATIENTS AND METHODS: In this international, phase III, double-blind trial, adult cancer subjects scheduled to receive ≥1 non-AC MEC on day 1 were randomized to a regimen comprising single-dose i.v. fosaprepitant 150 mg or placebo along with ondansetron and dexamethasone on day 1; control regimen recipients received ondansetron on days 2 and 3. Primary end points were the proportion of subjects achieving a complete response (CR; no vomiting and no use of rescue medication) in the delayed phase (25-120 h after MEC initiation) and safety. Secondary end points included CR in the overall and acute phases (0-120 and 0-24 h after MEC initiation, respectively) and no vomiting in the overall phase. Nausea and the Functional Living Index-Emesis were assessed as exploratory end points. RESULTS: The fosaprepitant regimen improved CR significantly in the delayed (78.9% versus 68.5%; P < 0.001) and overall (77.1% versus 66.9%; P < 0.001) phases, but not in the acute phase (93.2% versus 91.0%; P = 0.184), versus control. In the overall phase, the proportion of subjects with no vomiting (82.7% versus 72.9%; P < 0.001) and no significant nausea (83.2% versus 77.9%; P = 0.030) was also significantly improved with the fosaprepitant regimen. The fosaprepitant regimen was generally well tolerated. CONCLUSION: Single-dose fosaprepitant added to a 5-HT3 RA and dexamethasone was well tolerated and demonstrated superior control of CINV (primary end point achieved) associated with non-AC MEC. This is the first study to evaluate NK1 RA therapy as an i.v. formulation in a well-defined non-AC MEC population. CLINICALTRIALSGOV: NCT01594749 (https://clinicaltrials.gov/ct2/show/NCT01594749).
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Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Morfolinas/uso terapéutico , Náusea/prevención & control , Vómitos/prevención & control , Antineoplásicos/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
NOD.H2(k) and NOD.H2(h4) mice carry the major histocompatibility complex (MHC) class II molecule I-A(k) associated with susceptibility to experimentally induced thyroiditis. Dietary iodine-enhanced spontaneous thyroid autoimmunity, well known in NOD.H2(h4) mice, has not been investigated in NOD.H2(k) mice. We compared NOD.H2(h4) and NOD.H2(k) strains for thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) without or with dietary sodium iodide (NaI) for up to 32 weeks. TgAb levels were significantly higher in NOD.H2(h4) compared with NOD.H2(k) mice on NaI, and TPOAb developed in NOD.H2(h4) mice but not in NOD.H2(k) mice. DNA exome analysis revealed, in addition to the differences in the chromosome (Chr) 17 MHC regions, that NOD.H2(k) mice, and particularly NOD.H2(h4) mice, have substantial non-MHC parental DNA. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis highlighted thyroid autoimmunity and immune-response genes on Chr 17 but not on Chr 7, and 15 parental B10.A4R DNA. Studies of parental strains provided no evidence for non-MHC gene contributions. The exon 10 Tg haplotype, associated with experimentally induced thyroiditis, is absent in NOD.H2(h4) and NOD.H2(k) mice and is not a marker for spontaneous murine thyroid autoimmunity. In conclusion, the absence of I-E is a likely explanation for the difference between NOD.H2(h4) and NOD.H2(k) mice in TgAb levels and, as in humans, autoantibody spreading to TPO.
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Autoanticuerpos/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Tiroglobulina/metabolismo , Glándula Tiroides/inmunología , Animales , Autoanticuerpos/metabolismo , Autoinmunidad/inmunología , Exoma , Haplotipos , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Yoduro Peroxidasa/inmunología , Masculino , Ratones Endogámicos NOD/genética , Ratones Endogámicos NOD/inmunología , Yoduro de Sodio/efectos adversos , Tiroglobulina/genética , Tiroglobulina/inmunología , Tiroiditis/genética , Tiroiditis/inmunología , Tiroiditis Autoinmune/inducido químicamente , Tiroiditis Autoinmune/genética , Tiroiditis Autoinmune/inmunologíaRESUMEN
PURPOSE: Emerging biomarkers of cancer cachexia and their roles in sarcopenia and prognosis are poorly understood. Baseline assessments of anthropometrics, sarcopenia, cachexia status and biomarkers of cachexia were measured in patients with advanced cancer and healthy controls. Thereafter, relationships of the biomarkers with cachexia and sarcopenia were explored. METHODS: A prospective case-control design was used, including 40 patients with advanced cancer and 40 gender, age-matched controls. Bioelectrical impedance [skeletal muscle index (SMI)] and hand dynamometry [hand grip strength (HGS)] assessed sarcopenia and a validated tool classified cancer cachexia. Albumin, lymphocyte and platelet counts, haemoglobin, C-reactive protein (CRP), pro-inflammatory cytokines/chemokines and citrullinated histone H3 (H3Cit) were measured. RESULTS: Patients had significantly lower SMI (6.67 kg/m2 versus 7.67 kg/m2, p = < 0.01) and HGS (24.42 kg versus 29.62 kg) compared to controls, with 43% being sarcopenic. Significant differences were found for albumin, lymphocyte and platelet counts, haemoglobin, CRP, and tumour necrosis factor α (TNFα), (p < 0.01). Interleukin (IL)-6 (p < 0.04), IL-8 (p = 0.02), neutrophil/lymphocyte ratio (NLR), p = 0.02, platelet/lymphocyte (PLR) ratio, p < 0.01 and systemic immune inflammatory index (SII), p < 0.01 differed significantly. No difference was observed for CXC motif chemokine ligand 5 [CXCL5 or epithelial neutrophil-activating peptide 78 (ENA78)] or H3Cit. Albumin and haemoglobin correlated negatively with total protein, skeletal muscle mass and SMI (all p < 0.01). The presence of sarcopenia associated significantly with albumin, haemoglobin and CRP. CONCLUSION: Significant relationships and differences of haemoglobin, CRP and albumin supports future use of these biomarkers in cancer cachexia. CXCL5 and H3Cit as valuable biomarkers in cancer cachexia remains to be defined.
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Neoplasias , Sarcopenia , Humanos , Sarcopenia/diagnóstico , Sarcopenia/etiología , Caquexia/diagnóstico , Caquexia/etiología , Fuerza de la Mano , Neoplasias/patología , Biomarcadores , Músculo Esquelético/patología , Proteína C-Reactiva/análisis , HemoglobinasRESUMEN
The soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) is a useful marker of infection in patients with sepsis, but has not been adequately evaluated in patients with chemotherapy-associated febrile neutropenia (FN). The value of sTREM-1 in this setting has been tested in a retrospective, pilot study using stored serum from 48 cancer patients with documented FN. On presentation, patients were categorized according to the Talcott risk-index clinical score. Circulating soluble sTREM-1 was measured using an ELISA procedure, while procalcitonin (PCT) or interleukins 6 (IL-6) and 8 (IL-8), included for comparison, were measured using an immunoluminescence-based assay and Bio-Plex® suspension bead array system, respectively. Circulating concentrations of both sTREM-1 and PCT were significantly (P < 0.05) elevated in patients at high risk for complications or death, as predicted by the Talcott score and were significantly lower in patients who responded to empiric antimicrobial agents. Neither IL-6 nor IL-8 accurately predicted serious complications in patients with FN. These observations, albeit from a pilot study, demonstrate that sTREM-1 is indeed elevated in high-risk patients with FN and is potentially useful to predict their clinical course, either together with, or as an alternative to PCT.
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Antiinfecciosos/uso terapéutico , Biomarcadores/sangre , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Glicoproteínas de Membrana/sangre , Neutropenia/sangre , Neutropenia/inducido químicamente , Neutropenia/tratamiento farmacológico , Receptores Inmunológicos/sangre , Área Bajo la Curva , Calcitonina/sangre , Péptido Relacionado con Gen de Calcitonina , Femenino , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Neutropenia/fisiopatología , Proyectos Piloto , Precursores de Proteínas/sangre , Curva ROC , Estudios Retrospectivos , Receptor Activador Expresado en Células Mieloides 1RESUMEN
Somatic mutations of the TSH receptor (TSHR) gene are the main cause of autonomously functioning thyroid nodules. Except for mutations in ectodomain residue S281, all of the numerous reported activating mutations are in the TSHR membrane-spanning region. Here, we describe a patient with a toxic adenoma with a novel heterozygous somatic mutation caused by deletion of ectodomain residue Asp403 (Del-D403). Subsequent in vitro functional studies of the Del-D403 TSHR mutation demonstrated greatly increased ligand-independent constitutive activity, 8-fold above that of the wild-type TSHR. TSH stimulation had little further effect, indicating that the mutation produced near maximal activation of the receptor. In summary, we report only the second TSHR ectodomain activating mutation (and the first ectodomain deletion mutation) responsible for development of a thyroid toxic adenoma. Because Del-D403 causes near maximal activation, our finding provides novel insight into TSHR structure and function; residue D403 is more likely to be involved in the ligand-mediated activating pathway than in the ectodomain inverse agonist property.
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Adenoma/genética , Receptores de Tirotropina/genética , Receptores de Tirotropina/metabolismo , Eliminación de Secuencia/genética , Neoplasias de la Tiroides/genética , Nódulo Tiroideo/metabolismo , Adenoma/metabolismo , Adenoma/patología , Animales , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Mutagénesis Sitio-Dirigida , Pruebas de Función de la Tiroides , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Tirotropina/metabolismoRESUMEN
Cancer care has been profoundly impacted by the global pandemic of severe acute respiratory syndrome coronavirus 2 disease (coronavirus disease 2019, COVID-19), resulting in unprecedented challenges. Supportive care is an essential component of cancer treatment, seeking to prevent and manage chemotherapy complications such as febrile neutropenia, anaemia, thrombocytopenia/bleeding, thromboembolic events and nausea/vomiting, all of which are common causes of hospitalisation. These adverse events are an essential consideration under routine patient management, but particularly so during a pandemic, a setting in which clinicians aim to minimise patients' risk of infection and need for hospital visits. Professional medical oncology societies have been providing updated guidelines to support health care professionals with the management, treatment and supportive care needs of their patients with cancer under the threat of COVID-19. This paper aims to review the recommendations made by the most prominent medical oncology societies for devising and modifying supportive care strategies during the pandemic.
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COVID-19/prevención & control , Personal de Salud/estadística & datos numéricos , Oncología Médica/métodos , Neoplasias/terapia , SARS-CoV-2/aislamiento & purificación , COVID-19/epidemiología , COVID-19/virología , Guías como Asunto , Personal de Salud/psicología , Humanos , Oncología Médica/estadística & datos numéricos , Neoplasias/diagnóstico , Pandemias , SARS-CoV-2/fisiología , Apoyo Social , Sociedades Médicas/organización & administraciónRESUMEN
Graves' hyperthyroidism is an autoimmune disease occurring spontaneously in humans and caused by autoantibodies that stimulate the thyrotropin receptor. In mice, inducing Graves'-like hyperthyroidism requires in vivo expression of the thyrotropin receptor using plasmid or adenovirus vectors. However, mice with different genetic backgrounds vary markedly in their susceptibility to induced hyperthyroidism. Further, in some strains major disparities exist between the induction of hyperthyroidism and detection of thyroid-stimulating antibodies. To break tolerance, virtually all Graves' mouse models involve immunization with human thyrotropin-receptor DNA and the standard thyroid-stimulating antibody bioassay uses cells expressing the human thyrotropin receptor. We hypothesized, and now report, that disparities between hyperthyroidism and thyroid-stimulating antibody bioactivity are explained, at least in part, by differential antibody recognition of the human vs the mouse thyrotropin receptor. The genetic basis for these species differences was explored using genotyped, recombinant-inbred mouse strains. We report that loci in the immunoglobulin heavy chain variable region as well as in the major histocompatibility complex region contribute in a strain-specific manner to the development of antibodies specific for the human or the mouse thyrotropin receptor. The novel finding of a role for immunoglobulin heavy chain variable region gene involvement in thyroid-stimulating antibody epitopic specificity provides potential insight into genetic susceptibility in human Graves' disease.
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Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Región Variable de Inmunoglobulina/genética , Inmunoglobulinas Estimulantes de la Tiroides/inmunología , Animales , Células CHO , Mapeo Cromosómico , Cricetinae , Cricetulus , Estudio de Asociación del Genoma Completo , Enfermedad de Graves/genética , Enfermedad de Graves/inmunología , Humanos , Hipertiroidismo/genética , Hipertiroidismo/inmunología , Inmunización/métodos , Inmunoglobulinas Estimulantes de la Tiroides/sangre , Inmunoglobulinas Estimulantes de la Tiroides/genética , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos , Receptores de Tirotropina/genética , Receptores de Tirotropina/inmunología , Recombinación GenéticaRESUMEN
Thyrotropin (TSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) are structurally related glycoprotein hormones, which bind to receptors that share a high degree of sequence similarity. However, comparison of the primary amino acid sequences of the TSH and LH-CG receptors reveals two unique insertions of 8 and 50 amino acids in the extracellular domain of the TSH receptor. The functional significance of these insertions were determined by site-directed mutagenesis. Deletion of the 50-amino acid tract (residues 317 to 366) had no effect on TSH binding or on TSH and thyroid-stimulating immunoglobulin (TSI) biological activities. In contrast, either deletion or substitution of the eight-amino acid region (residues 38 to 45) abolished these activities. This eight-amino acid tract near the amino terminus of the TSH receptor appears to be an important site of interaction for both TSH and TSI.
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Receptores de Tirotropina/genética , Tirotropina/metabolismo , Animales , Secuencia de Bases , Sitios de Unión , Línea Celular , Deleción Cromosómica , Células Clonales , AMP Cíclico/metabolismo , Humanos , Datos de Secuencia Molecular , Mutación , Sondas de Oligonucleótidos , Receptores de Tirotropina/metabolismo , Tirotropina/farmacología , TransfecciónRESUMEN
OBJECTIVE: This phase II study assessed the activity and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin in relapsed ovarian cancer (ROC). METHOD: Forty women with platinum-sensitive and partially platinum-sensitive ROC were treated with PLD 50 mg/m2 plus carboplatin area under the curve 5 every 28 days in this South African multicenter study. All patients who completed 3 cycles of chemotherapy were evaluated for response. Primary outcome was response in the intent-to-treat population. RESULTS: Complete response was 35%, and partial response was 32.5% (overall response, 67.5%). Median time-to-progression was 11.9 months, and median survival was 30.0 months. Overall response was higher in platinum-sensitive (81%) versus partially platinum-sensitive patients (53%), as were median duration of response, median time-to-progression, and median survival. Treatment was well tolerated, with no grade 4 nonhematologic toxicities. Grade 3/4 hematologic toxicities included leukopenia (58%), neutropenia (55%), and thrombocytopenia (43%). CONCLUSION: Pegylated liposomal doxorubicin plus carboplatin is well tolerated and active in the treatment of platinum-sensitive and partially platinum-sensitive ROC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma/tratamiento farmacológico , Doxorrubicina/análogos & derivados , Neoplasias Ováricas/tratamiento farmacológico , Polietilenglicoles/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Carcinoma/mortalidad , Carcinoma/patología , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Enfermedades Hematológicas/inducido químicamente , Enfermedades Hematológicas/epidemiología , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Compuestos de Platino/efectos adversos , Compuestos de Platino/farmacología , Polietilenglicoles/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Transgenic BALB/c mice that express intrathyroidal human thyroid stimulating hormone receptor (TSHR) A-subunit, unlike wild-type (WT) littermates, develop thyroid lymphocytic infiltration and spreading to other thyroid autoantigens after T regulatory cell (T(reg)) depletion and immunization with human thyrotropin receptor (hTSHR) adenovirus. To determine if this process involves intramolecular epitope spreading, we studied antibody and T cell recognition of TSHR ectodomain peptides (A-Z). In transgenic and WT mice, regardless of T(reg) depletion, TSHR antibodies bound predominantly to N-terminal peptide A and much less to a few downstream peptides. After T(reg) depletion, splenocytes from WT mice responded to peptides C, D and J (all in the A-subunit), but transgenic splenocytes recognized only peptide D. Because CD4(+) T cells are critical for thyroid lymphocytic infiltration, amino acid sequences of these peptides were examined for in silico binding to BALB/c major histocompatibility complex class II (IA-d). High affinity subsequences (inhibitory concentration of 50% < 50 nm) are present in peptides C and D (not J) of the hTSHR and mouse TSHR equivalents. These data probably explain why transgenic splenocytes do not recognize peptide J. Mouse TSHR mRNA levels are comparable in transgenic and WT thyroids, but only transgenics have human A-subunit mRNA. Transgenic mice can present mouse TSHR and human A-subunit-derived peptides. However, WT mice can present only mouse TSHR, and two to four amino acid species differences may preclude recognition by CD4+ T cells activated by hTSHR-adenovirus. Overall, thyroid lymphocytic infiltration in the transgenic mice is unrelated to epitopic spreading but involves human A-subunit peptides for recognition by T cells activated using the hTSHR.
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Receptores de Tirotropina/inmunología , Linfocitos T Reguladores/inmunología , Tiroiditis Autoinmune/inmunología , Secuencia de Aminoácidos , Animales , Autoanticuerpos/biosíntesis , Autoantígenos/inmunología , Quimiotaxis de Leucocito/inmunología , Epítopos de Linfocito T/inmunología , Humanos , Inmunización , Depleción Linfocítica/métodos , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Datos de Secuencia Molecular , ARN Mensajero/genética , Receptores de Tirotropina/genética , Bazo/inmunología , Glándula Tiroides/inmunología , Glándula Tiroides/fisiopatología , Tiroiditis Autoinmune/fisiopatologíaRESUMEN
The effect of thyrotropin (TSH) on the ADP-ribosylation of endogenous thyroid cell acceptor proteins was examined. Cells were "permeabilized" at 4 degrees C in hypotonic medium and then exposed to [(32)P]- or [(3)H-adenine]NAD(+). The net incorporation of labeled ADP-ribose was measured by trichloroacetic acid precipitation. TSH (100 mU/ml) enhanced ADP-ribosylation with a maximum effect after 30-60 min in the majority of experiments. TSH stimulation was observed even when the incubation contained 1,000-fold more exogenous NAD(+) than the amount of NAD(+) contributed by the permeabilized cells, indicating an effect on enzymatic activity rather than an alteration in NAD(+) pool size or specific activity. No incorporation of radioactivity from labeled NAD(+) was observed in cells not rendered permeable to NAD(+) by hypotonic shock. TSH did not increase the rate of disappearance of trichloroacetic-precipitable radioactivity and did not contain intrinsic NAD(+) glycohydrolase activity. Alkali and snake venom phosphodiesterase, but not ribonuclease or deoxyribonuclease digestion of trichloroacetic acid precipitable thyroid cell radioactivity, revealed primarily 5'-AMP, consistent with an effect of TSH on mono-ADP ribosylation. Nicotinamide and thymidine (50 mM) inhibited both basal and TSH-stimulated ADP-ribosylation of thyroid cell protein. Dibutyryl cyclic (c)AMP (0.1 mM) inhibited endogenous ADP-ribosylation by approximately 35% but had no effect at lower concentrations. 0.5 mM isobutylmethylxanthine inhibited this reaction by approximately 60%. We suggest that TSH enhances thyroid cell ADP-ribosylation by a mechanism independent of cAMP as a second messenger, and that ADP-ribosylation plays a role in the expression of TSH.
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Adenosina Difosfato Ribosa/metabolismo , Azúcares de Nucleósido Difosfato/metabolismo , Glándula Tiroides/metabolismo , Tirotropina/farmacología , Animales , Bucladesina/farmacología , Células Cultivadas , Perros , NAD/metabolismo , Niacinamida/farmacología , Proteínas/metabolismo , Timidina/farmacologíaRESUMEN
In hypophysectomized rats given dietary regimens either rich or deficient in iodine, the increase in thyroid cyclic AMP concentration induced acutely by a single dose of TSH was significantly less in iodine-enriched than in iodine-deficient animals. Direct assays revealed that this difference was because the thyroid adenylate cyclase response to TSH was less in the iodine-enriched animals, phosphodiesterase activity being no different in the two groups. This effect may explain the inhibitory action of dietary iodine enrichment on diverse functional and anatomical responses of the thyroid to TSH.
Asunto(s)
Adenilil Ciclasas/metabolismo , Hipofisectomía , Yodo/farmacología , Glándula Tiroides/enzimología , Tirotropina/farmacología , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Glándulas Suprarrenales/enzimología , Animales , AMP Cíclico/metabolismo , Masculino , RatasRESUMEN
We examined the relative effects of thyrotropin (TSH) and TSH receptor autoantibodies in the sera of patients with autoimmune thyroid disease on three TSH-lutropin/chorionic gonadotropin (LH/CG) receptor extracellular domain chimeras. Each chimera binds TSH with high affinity. Only the chimera with TSH receptor extracellular domains ABC (amino acids 1-260) had a functional (cAMP) response to thyroid stimulatory IgG. The chimeras with TSH receptor domains CD (amino acids 171-360) and DE (amino acids 261-418) were unresponsive. The lack of response of the chimera with TSH receptor domains DE was anticipated because it fails to transduce a signal with TSH stimulation, unlike the other two chimeras. A different spectrum of responses occurred when the TSH-LH/CG chimeras were examined in terms of autoantibody competition for TSH binding. IgG with TSH binding-inhibitory activity when tested with the wild-type TSH receptor also inhibited TSH binding to the chimera with TSH receptor domains DE. Dramatically, however, these IgG did not inhibit TSH binding to the chimera with TSH receptor domains CD, and had weak or absent activity with the chimera with TSH receptor domains ABC. Chimeras with TSH receptor domains ABC and DE were equally effective in affinity-purifying IgG with thyroid-stimulatory and TSH binding-inhibitory activities. Nonstimulatory IgG with TSH binding-inhibitory activity inhibited the action of stimulatory IgG on the wild-type TSH receptor, but not with the chimera containing TSH receptor domains ABC. In summary, TSH receptor autoantibodies and TSH bind to regions in both domains ABC and DE of the TSH receptor extracellular region. Stimulatory and inhibitory TSH receptor autoantibodies, as well as TSH, appear to bind to different sites in domains ABC, but similar sites in domains DE, of the receptor. Alternatively, TSH and the different TSH receptor antibodies bind with differing affinities to the same site in the ABC region.
Asunto(s)
Autoanticuerpos/inmunología , Receptores de Gonadotropina/química , Receptores de HL/química , Receptores de Tirotropina/química , Sitios de Unión , Quimera , Epítopos/análisis , Humanos , Inmunoglobulina G/metabolismo , Receptores de Tirotropina/inmunología , Tiroiditis Autoinmune/inmunología , Tirotropina/metabolismoRESUMEN
We immunized rabbits with thyroid-stimulating hormone (TSH) to investigate the hypothesis that such immunization could result in production of thyroid-stimulating autoantiidiotypic antibodies to anti-TSH. Thyroid-stimulating immunoglobulin (TSI) appeared in the serum of several rabbits after immunization. At 160 d, TSI equivalent to 6-18 microU TSH/1.5 mg IgG was present in two of six human (h)TSH-, two of six hTSH beta chain-, and two of the four surviving bovine (b)TSH-immunized animals. Control (human serum albumin-immunized rabbits) serum TSI was 4.3 +/- 0.4 (mean +/- SD) at this time. Antiidiotypic antibodies that could bind to monoclonal anti-hTSH were found in the sera of the bTSH-immunized rabbits. The peak TSI activity occurred 3 mo after a TSH booster immunization and declined gradually during subsequent weeks. Evidence that antiidiotypic antibodies to anti-TSH can cause thyroid stimulation strengthens the notion that such antibodies may be the cause of Graves' hyperthyroidism.