RESUMO
Carbon therapy is a promising treatment option for cancer. The physical and biological properties of carbon ions can theoretically allow for the delivery of curative doses to the tumor, while simultaneously limiting risks of toxicity to adjacent healthy structures. The treatment effectiveness can be further improved by decreasing the uncertainties stemming from several sources, including the modeling of tissue heterogeneity. Current treatment plans employ density-based conversion methods to translate patient-specific anatomy into a water system, where dose distribution is calculated. This approach neglects differences in nuclear interactions stemming from the elemental composition of each tissue. In this work, we investigated the interaction of therapeutic carbon ions with bone-like materials. The study concentrated on nuclear interactions and included attenuation curves of 200 and 400 AMeV beams in different types of bones, as well as kinetic energy spectra of all charged fragments produced up to 29 degrees from the beam direction. The comparison between measurements and calculations of the treatment planning system TRiP98 indicated that bone tissue causes less fragmentation of carbon ions than water. Overall, hydrogen and helium particles were found to be the most abundant species, while heavier fragments were mostly detected within 5 degrees from the beam direction. We also investigated how the presence of a soft tissue-bone interface could affect the depth-dose profile. The results revealed a dose spike in the transition region, that extended from the entry channel to the target volume. The findings of this work indicated that the tissue-to-water conversion method based only on density considerations can result in dose inaccuracies. Tissue heterogeneity regions containing bones can potentially produce dose spikes, whose magnitude will depend on the patient anatomy. Dose uncertainties can be decreased by modeling nuclear interactions directly in bones, without applying the tissue-to-water conversion.
Assuntos
Radiometria , Planejamento da Radioterapia Assistida por Computador , Osso e Ossos , Hélio , Humanos , ÍonsRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. METHODS: Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 microg m(-2) once every 3 weeks. The primary aim of the study was progression-free survival (PFS). RESULTS: No grade 3-4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months. CONCLUSION: NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Fator de Necrose Tumoral alfa/uso terapêutico , Adulto , Idoso , Carcinoma Hepatocelular/irrigação sanguínea , Feminino , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/efeitos adversos , Fator de Necrose Tumoral alfa/efeitos adversosRESUMO
Churg-Strauss syndrome (CSS) is a disseminated small vessel vasculitis characterized by late-onset asthma, upper airways disease, eosinophilia and late neurological manifestations such as peripheral neuropathy. Recently, several cases of CSS have been reported in patients treated with leukotriene antagonists after weaning corticosteroids. We describe a case of CSS developed while the patient was receiving montelukast for asthma treatment, after corticosteroids withdrawal. A causal relationship between montelukast therapy and CSS is hypothesized.
Assuntos
Acetatos/efeitos adversos , Síndrome de Churg-Strauss/induzido quimicamente , Antagonistas de Leucotrienos/efeitos adversos , Quinolinas/efeitos adversos , Idoso , Asma/tratamento farmacológico , Síndrome de Churg-Strauss/fisiopatologia , Ciclopropanos , Eletrofisiologia , Feminino , Humanos , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , SulfetosAssuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Hemorragia/etiologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Trombocitopenia/etiologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Antineoplásicos/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/patologia , Infiltração Leucêmica , Pessoa de Meia-Idade , Rituximab , EsplenomegaliaRESUMO
Mouse AIDS (MAIDS) induced in C57BL/6 mice by infection with a replication-defective retrovirus (Du5H) combines extensive lymphoproliferation and profound immunodeficiency. Although B cells are the main target of viral infection, recent research has focused on CD4(+) T cells, the activation of which is a key event in MAIDS induction and progression. A preliminary observation of increased expression of B7 molecules on B cells in MAIDS prompted us to address the possible involvement of the CD28/B7 costimulatory pathway in MAIDS. Mice infected with the MAIDS-inducing viral preparation were treated with murine fusion protein CTLA4Ig (3 x 50 microg/week given intraperitoneally), a competitive inhibitor of physiological CD28-B7 interactions. In CTLA4Ig-treated animals, the onset of the disease was delayed, lymphoproliferation progressed at a much slower rate than in untreated mice, and the loss of in vitro responsiveness to mitogens was reduced. Relative expression of Du5H did not differ between treated and untreated animals. These results suggest that the CD28/B7 costimulatory pathway contributes to MAIDS development.
Assuntos
Antígenos de Diferenciação/administração & dosagem , Linfócitos B/imunologia , Antígeno B7-1/imunologia , Antígenos CD28/imunologia , Linfócitos T CD4-Positivos/imunologia , Imunidade Celular , Imunoconjugados , Imunossupressores/administração & dosagem , Síndrome de Imunodeficiência Adquirida Murina/imunologia , Abatacepte , Animais , Antígenos CD , Antígenos de Diferenciação/imunologia , Antígeno CTLA-4 , Camundongos , Síndrome de Imunodeficiência Adquirida Murina/prevenção & controleRESUMO
RadLV-Rs infection induces a murine immunodeficiency syndrome associated with a dramatic enlargement of spleen and lymph nodes. Surprisingly, the lymphoproliferation excludes thymus and Peyer's patches (PP). To understand the cellular interactions underlying lymphoproliferation further, the authors investigated the fate of PP in RadLV-Rs infected mice. The atrophy of PP was mostly due to the depletion of B cells, while the proportion of CD4+ and CD8+ T cells was increased. Nevertheless, B cell phenotype was modified with the emergence of lymphocytes with a low expression of B220 in infected PP. T cells characterized by a memory/activated phenotype in control PP did not undergo phenotypical changes after viral infection (i.e. regarding Thy-1 and CD44 expression). Despite the absence of lymphoproliferation, PP T and B cells displayed altered responses to mitogens in vitro. Finally, alterations of the expression of adhesion molecules and vascular addressins could not explain the atrophy of PP by a reduced homing to this lymphoid site. B cells and T cells from normal PP are clearly different from lymph nodes (LN) lymphocytes. The authors propose that the particular functional state which characterizes PP lymphocytes influences the B cell/T cell crosstalk necessary for RadLV-Rs-induced lymphoproliferation.
Assuntos
Linfócitos B/imunologia , Tolerância Imunológica , Ativação Linfocitária , Síndrome de Imunodeficiência Adquirida Murina/imunologia , Nódulos Linfáticos Agregados/imunologia , Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular , Citometria de Fluxo , Receptores de Hialuronatos/biossíntese , Imunoglobulinas/biossíntese , Imuno-Histoquímica , Integrinas/biossíntese , Selectina L/biossíntese , Antígenos Comuns de Leucócito/biossíntese , Linfonodos/imunologia , Contagem de Linfócitos , Antígeno-1 Associado à Função Linfocitária/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucoproteínas/biossíntese , Provírus/genética , Antígenos Thy-1/biossínteseRESUMO
Infection of susceptible strains of mice with the Duplan strain of murine leukemia viruses induces a syndrome called MAIDS (murine acquired immunodeficiency syndrome) characterized by immunodeficiency and lymphoproliferation. In addition to a complete refractoriness of most subsets of lymphocytes to mitogen stimulation, the development of phenotypic abnormalities occurs such as the appearance of an abnormal CD4+ T cell subset lacking membranes Thy-1. This study was performed to compare the calcium responses during the early stages of MAIDS (week 9 or earlier) between T cells and B cells and between CD4+Thy-1- and CD4+Thy-1+ T cells. B cells were strikingly less affected than T cells: their baseline [Ca2+]i did not significantly increase, and their calcium response to anti-IgM antibody and concanavalin A (Con A) was partially maintained. In contrast, the response to Con A was completely abolished in T cells. Interestingly, calcium mobilization in response to membrane receptor-independent stimuli such as ionophores and thapsigargin was strongly inhibited in T cells, while no such inhibition was found in B cells. In comparison with their CD4+Thy-1+ counterparts, CD4+Thy-1- T cells had blunted calcium responses in controls, as well as in infected mice. However, CD4+Thy-1+ T cells were also strikingly altered, suggesting that the loss of membrane Thy-1 could be associated with, but not directly responsible for abnormalities of calcium responses in CD4+ T cells from RadLV-Rs-infected mice.
Assuntos
Subpopulações de Linfócitos B/imunologia , Cálcio/metabolismo , Síndrome de Imunodeficiência Adquirida Murina/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Subpopulações de Linfócitos B/efeitos dos fármacos , Calcimicina/farmacologia , Antígenos Comuns de Leucócito/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subpopulações de Linfócitos T/efeitos dos fármacos , Tapsigargina/farmacologia , Antígenos Thy-1/análiseAssuntos
Albuminas/análise , Ascite/diagnóstico , Líquido Ascítico/química , Colesterol/análise , Neoplasias/complicações , Albumina Sérica/análise , Idoso , Ascite/etiologia , Diagnóstico Diferencial , Reações Falso-Positivas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
The possible contribution of the thymus in the setting of acquired immunodeficiencies is still questioned. Here we report some new findings regarding a potential involvement of the thymus in mice infected with RadLV-Rs, a viral mixture inducing murine acquired immunodeficiency syndrome (MAIDS). Thymi were sequentially removed, weighted and morphologically analyzed at different time intervals post-infection. Infection with RadLV-Rs led to a decrease in thymus weight mostly apparent from the fourth week. The first changes were seen at the third week as perivascular clusters of B-cells at the cortico-medullary junction. The ensuing process of atrophy mainly involved the cortex, while a mixed population of large T- and B-cells filled the medulla. These observations are discussed with regard to the pathological changes occurring in other lymphoid and non-lymphoid organs, in the context of the lymphoproliferation and immunodeficiency characterizing the disease, and by comparison with other models of retrovirus-induced immunodeficiencies.
Assuntos
Síndrome de Imunodeficiência Adquirida Murina/patologia , Timo/patologia , Animais , Atrofia/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Retroviridae , Fatores de TempoRESUMO
Several progesterone-AH Sepharose 4B matrices were prepared as biospecific adsorbents suitable for affinity chromatography to fractionate antibodies of different affinity and specificity from a polyclonal antiserum to progesterone-11 alpha-hemisuccinate-BSA. From an affinity column of progesterone-11 alpha-hemisuccinate-AH Sepharose 4B no antibodies can be eluted, even with glycine buffer (pH 2.6) and 30% of 2-methoxyethanol. The use of biospecific adsorbents, prepared by coupling with AH Sepharose 4B progesterone derivatives [5-pregnene-3,20-dione di(ethyleneacetal)-11 alpha-ol-11 alpha-hemisuccinate; 4-pregnene-11,20 beta-diol-3-one-11 alpha-hemisuccinate 20 beta-benzoate; progesterone-3-carboxymethyloxime] having a low cross-reactivity with the antiserum, makes the elution of various antibody fractions of variable affinity and specificity possible. 2-Methoxyethanol or N,N-dimethylformamide gradients, in acetate or TRIS buffer, were equally efficient for fractionating the antiprogesterone serum, while a decreasing pH gradient was less effective and eluted antibody fractions that were further separated into various binding components by a solvent gradient. Antibodies eluted from the affinity columns by an eluent containing a high solvent concentration have affinities higher than antibodies eluted at lower solvent concentration.
Assuntos
Anticorpos/análise , Progesterona/imunologia , Absorção , Cromatografia de Afinidade , Humanos , Concentração de Íons de Hidrogênio , SolventesRESUMO
In order to obtain the beneficial effects from granulocyte-macrophage colony-stimulating factor (GM-CSF) on granulo-monocyte recovery with the minimum dose and toxicity, we compared the effect of two different GM-CSF schedules (5 micrograms/kg/day subcutaneously, days 5 to > 18 versus days 12 to > 18 on the cytopenias which follow cytostatic treatment with carboplatin (400 mg/m2 intravenous (i.v.) day 1) and etoposide (100 mg/m2 i.v. days 1 to > 3). 13 patients entered the study for a total of 36 evaluable cycles. The cytostatic treatment produced a neutropenia that persisted for up to day 22 (absolute neutrophil count (ANC) < 1000/microliters in 25% and ANC < 2000 in 50% of control cycles). Early GM-CSF administration markedly increased the leucocyte nadir and produced two waves of leucocytosis: an early one, linked to marrow reserve release and presumably of no value to the patients; and a delayed one, due to marrow precursor and progenitor cell proliferation, in which the granulomonocytosis was associated with a marked eosinophilia. The delayed GM-CSF administration markedly increased the leucocyte nadir and accelerated granulo-monocyte recovery (with an only modest eosinophilia), so that chemotherapy could be repeated every 21 days in all the patients.
Assuntos
Agranulocitose/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Adulto , Idoso , Agranulocitose/induzido quimicamente , Agranulocitose/prevenção & controle , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Fatores de TempoAssuntos
Subpopulações de Linfócitos/patologia , Síndrome de Imunodeficiência Adquirida Murina/patologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/patologia , Morte Celular , Senescência Celular , Vírus Defeituosos/patogenicidade , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Imunofenotipagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Imunodeficiência Adquirida Murina/virologia , Vírus da Leucemia Induzida por Radiação , Retroviridae/patogenicidadeRESUMO
Due to self-renewal of the peripheral pool of T-cells, adult thymectomy has normally little influence on immunocompetence. However, thymus might play a more important role in the setting of viral-induced cytopathic effects on T-cells in the periphery. Therefore, thymus weight, cell numbers, and subset distribution were sequentially analysed after infection with RadLV-Rs, a viral mixture known to induce murine retrovirus induced immunodeficiency (MAIDS). Infection induced thymic atrophy (concerning organ weight as well as total cell number) which culminated seven weeks after inoculation. The atrophic process mostly reflected the depletion of double positive CD4+ CD8+ cells since their proportion sharply decreased around week 6. Single positive T-cells were less affected by the process. The proportion of B-cells progressively increased. Surprisingly, there was a strong correlation between the extent of atrophy and the frequency of B-cells in the thymus. Finally, an abnormal CD4+ T-cell subset lacking Thy-1 and previously described in the periphery also appeared in the thymus and its frequency was strongly correlated with the expansion of B-cells in this organ.
Assuntos
Síndrome de Imunodeficiência Adquirida Murina/imunologia , Subpopulações de Linfócitos T/imunologia , Timo/patologia , Animais , Linfócitos B/imunologia , Proteínas de Transporte/biossíntese , Diferenciação Celular/imunologia , Citometria de Fluxo , Receptores de Hialuronatos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Imunodeficiência Adquirida Murina/virologia , Vírus da Leucemia Induzida por Radiação , Receptores de Superfície Celular/biossíntese , Receptores de Retorno de Linfócitos/biossíntese , Subpopulações de Linfócitos T/virologia , Antígenos Thy-1/imunologia , Timo/virologiaRESUMO
Syntheses and cross-reactivities with progesterone toward the same specific antibody are reported for a series of amides of 11 alpha-hydroxyprogesterone 11-hemisuccinate. Some hypotheses are made regarding the effects of the chemical structure of the substituents on the immunological properties of derivatives.
Assuntos
Amidas/imunologia , Afinidade de Anticorpos , Hidroxiprogesteronas/imunologia , Progesterona/análogos & derivados , Amidas/síntese química , Especificidade de Anticorpos , Fenômenos Químicos , Química , Cromatografia/métodos , Reações Cruzadas , Hidroxiprogesteronas/síntese química , Progesterona/imunologia , Radioimunoensaio , Relação Estrutura-AtividadeRESUMO
A study was conducted into the hormone profile of women with no previous history of allergy who developed bronchial asthma after menopause in order to discover any differences between these and patients of a similar age with allergic bronchial asthma. The serum levels of the following hypophyseal and gonadal hormones were therefore analysed: luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), 17 oestradiol (17BE2) in both groups of patients and in a control group of healthy postmenopausal volunteers. The results showed lower FSH and LH and higher 17B7(2) levels in the patients with bronchial asthma but no clinical history of allergy than in either the patients with allergic asthma or the healthy volunteers. When the hormone picture in some of the group 1 patients normalised, the clinical symptoms disappeared. One possible explanation is the following: excess oestrogen in the "non-allergy" patients might have caused an imbalance in the PgF/PgE ratio which is thought to contribute to the regulation of bronchomotor tone. The same phenomena might also have accelerated the release of arachidonic acid and its metabolites.
Assuntos
Asma/epidemiologia , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Hormônio Luteinizante/sangue , Prolactina/sangue , Fatores Etários , Ácidos Araquidônicos/sangue , Asma/sangue , Asma/imunologia , Feminino , Humanos , Menopausa , Pessoa de Meia-IdadeRESUMO
Synthesis, fluorometric and immunological properties of two new fluorescent derivatives of progesterone are reported. Both compounds were obtained from 11 alpha-hydroxyprogesterone 11-hemisuccinate; the fluorescent molecules were joined to the steroid by bifunctional arms. The first of these is cysteamine whose thiol group was reacted with N-(3-fluoranthenyl) maleimide, and the second is tyramine whose phenolic group was reacted with 1-nitroso-2 naphthol.