RESUMO
Melatonin is a small lipophile molecule, essentially secreted by pineal gland. The synthesis of this hormone shows a circadian pattern with a peak around 2-3 hours am. Many melatonin receptors are found in the body, which explains its multiple functions as biological rhythms resynchronisation, sleep induction, vasoregulation and even immunomodulation. Many experiments realised in this field have permit to discover different interactions between melatonin and the immune system, and especially the link which exists between melatonin and the fight against cancer via the immune system. Phase II studies reported a decrease of thrombocytopenia, an increase of some cytokines rate and an increase of objective responses in cancer patients. In order to confirm these results and to lead further research, we propose to realise a phase II randomised study melatonin versus placebo in metastatic breast cancer patients after two lines of treatment.
Assuntos
Melatonina/uso terapêutico , Neoplasias/tratamento farmacológico , Ritmo Circadiano/fisiologia , Humanos , Melatonina/metabolismo , Glândula Pineal , Receptores de Melatonina/fisiologia , Sono/fisiologiaRESUMO
Influence of stress on immunity and pathogenesis relates to corticotropic axis: hypothalamus-hypophysis-surrenals (HHS). Its over-stimulation due to traumas during early childhood or before birth seems to generate brain abnormalities such as reduction of hippocampus volume. More typical of adult age, hypothalamus-pineal gland axis (HP), responsible for melatonin production, may be impaired because of chronic stress, mainly through sleep disturbances or addictive behaviours. Old age has been reported to produce same impairments. Circadian cycle of melatonin is closely related to immune functions and its disturbance seems to induce, among populations undergoing frequent changes of life rhythm, a significant raise of cancer incidence: night shift workers, air pilots... Stress then seems enable to increase cancer risk through its negative impact on HHS and HP axis and therefore on immunity. Immunotherapy, which was an interesting solution considering this, has not yield yet expected results. Upstream, other ways have been successfully investigated in prospective randomised trials, such as psychotherapeutic treatments, with positive effects on cellular immunity and survival. The ability to condition immune responses in animals allows thinking that hypnotherapy could also be used along with standard treatments.
Assuntos
Ritmo Circadiano/fisiologia , Melatonina/fisiologia , Neoplasias/fisiopatologia , Estresse Fisiológico/fisiopatologia , Adulto , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Neoplasias/imunologia , Glândula Pineal/metabolismo , Glândula Pineal/fisiologia , Sistema Hipófise-Suprarrenal/fisiologiaRESUMO
We have evaluated CYFRA 21-1 serum level variations as an indicator of tumor response and survival in 44 consecutive patients with locally advanced non-small cell lung cancer (NSCLC) treated with induction chemotherapy (IC). Irrespective of the initial CYFRA 21-1 serum concentration, a more than 65% decrease in the serum level after the first chemotherapy course was significantly predictive of an objective tumor response (p = 0.0022). In addition, a more than 80% decrease in this level significantly predicted a better disease-free survival (p = 0.039). In patients with initial CYFRA 21-1 serum levels > 3.3 ng/mL (n = 29), a more than 80% decrease after the first IC course was the most significant predictor of overall survival (p = 0.025) in a Cox analysis including initial staging, tumor response and surgery. We conclude that early monitoring of CYFRA 21-1 serum levels may be a useful prognostic tool for tumor response and survival in stage III NSCLC patients treated by induction chemotherapy.
Assuntos
Antígenos de Neoplasias/sangue , Antígenos de Neoplasias/genética , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Queratina-19 , Queratinas , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
We have previously demonstrated that the bZIP transcription factor CREB-2, also called ATF-4, trans-activates, in association with the viral protein Tax, the human T-cell leukemia virus type I (HTLV-I) promoter. In this study, we have examined whether CREB-2 acetylation affects transcriptional activation mediated by Tax. We present evidence that CREB-2 is acetylated in vitro and in vivo. CREB-2 is acetylated in two regions: the basic domain of the bZIP (from amino acid residue 270 to 300) and the short basic domain (from 342 to 351) located downstream from the bZIP. We also demonstrate that CREB-2 is acetylated by p300/CBP but not by p/CAF. Moreover, replacement of lysine by arginine in the basic domains decreases the trans-activating capacity of CREB-2. However, in the presence of Tax, the HTLV-I transcription remains fully activated by these CREB-2 mutants. Although we cannot totally exclude that the mutations could also affect CREB-2 structure and activity independent of acetylation, our results suggest that activation of the viral promoter in the presence of Tax is independent of the CREB-2 acetylation.
Assuntos
Produtos do Gene tax/fisiologia , Vírus Linfotrópico T Tipo 1 Humano/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional , Acetilação , Fator 4 Ativador da Transcrição , Sequência de Aminoácidos , Humanos , Dados de Sequência Molecular , Proteínas Nucleares/fisiologia , Transativadores/fisiologia , Fatores de Transcrição/químicaRESUMO
cAMP response element binding protein-2 (CREB-2) is a basic leucine zipper (bZIP) factor that was originally described as a repressor of CRE-dependent transcription but that can also act as a transcriptional activator. Moreover, CREB-2 is able to function in association with the viral Tax protein as an activator of the human T-cell leukemia virus type I (HTLV-I) promoter. Here we show that CREB-2 is able to interact with C/EBP-homologous protein (CHOP), a bZIP transcription factor known to inhibit CAAT/enhancer-dependent transcription. Cotransfection of CHOP with CREB-2 results in decreased activation driven by the cellular CRE motif or the HTLV-I proximal Tax-responsive element, confirming that CREB-2 and CHOP can interact with each other in vivo.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Zíper de Leucina , Fatores de Transcrição/metabolismo , Fator 4 Ativador da Transcrição , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Células COS , Linhagem Celular , Núcleo Celular/metabolismo , Chlorocebus aethiops , Regulação Viral da Expressão Gênica , Produtos do Gene tat/metabolismo , HIV-1/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Regiões Promotoras Genéticas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Saccharomyces cerevisiae , Fator de Transcrição CHOP , Fatores de Transcrição/genética , Transcrição Gênica , Técnicas do Sistema de Duplo-Híbrido , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates viral transcription through three 21-bp repeats located in the U3 region of the HTLV-1 long terminal repeat and called Tax-responsive elements (TxREs). Each TxRE contains nucleotide sequences corresponding to imperfect cyclic AMP response elements (CRE). In this study, we demonstrate that the bZIP transcriptional factor CREB-2 is able to bind in vitro to the TxREs and that CREB-2 binding to each of the 21-bp motifs is enhanced by Tax. We also demonstrate that Tax can weakly interact with CREB-2 bound to a cellular palindromic CRE motif such as that found in the somatostatin promoter. Mutagenesis of Tax and CREB-2 demonstrates that both N- and C-terminal domains of Tax and the C-terminal region of CREB-2 are required for direct interaction between the two proteins. In addition, the Tax mutant M47, defective for HTLV-1 activation, is unable to form in vitro a ternary complex with CREB-2 and TxRE. In agreement with recent results suggesting that Tax can recruit the coactivator CREB-binding protein (CBP) on the HTLV-1 promoter, we provide evidence that Tax, CREB-2, and CBP are capable of cooperating to stimulate viral transcription. Taken together, our data highlight the major role played by CREB-2 in Tax-mediated transactivation.
Assuntos
Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , Regiões Promotoras Genéticas , Proteínas de Saccharomyces cerevisiae , Fatores de Transcrição/metabolismo , Ativação Transcricional , Fator 2 Ativador da Transcrição , Fator 4 Ativador da Transcrição , Sítios de Ligação , Proteína de Ligação a CREB , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Ligação a DNA , Proteínas Fúngicas , Produtos do Gene tax/genética , Zíper de Leucina , Mutagênese , Proteínas Nucleares/metabolismo , Ligação Proteica , Elementos de Resposta , Linfócitos T , Sequências Repetidas Terminais , Transativadores/metabolismo , Fatores de Transcrição/genéticaRESUMO
Regulation of viral genome expression is the result of complex cooperation between viral proteins and host cell factors. We report here the characterization of a novel cellular factor sharing homology with the specific cysteine-rich C-terminal domain of the basic helix-loop-helix repressor protein I-mfa. The synthesis of this new factor, called HIC for Human I-mfa domain-Containing protein, is controlled at the translational level by two different codons, an ATG and an upstream non-ATG translational initiator, allowing the production of two protein isoforms, p32 and p40, respectively. We show that the HIC protein isoforms present different subcellular localizations, p32 being mainly distributed throughout the cytoplasm, whereas p40 is targeted to the nucleolus. Moreover, in trying to understand the function of HIC, we have found that both isoforms stimulate in T-cells the expression of a luciferase reporter gene driven by the human T-cell leukemia virus type I-long terminal repeat in the presence of the viral transactivator Tax. We demonstrate by mutagenesis that the I-mfa-like domain of HIC is involved in this regulation. Finally, we also show that HIC is able to down-regulate the luciferase expression from the human immunodeficiency virus type 1-long terminal repeat induced by the viral transactivator Tat. From these results, we propose that HIC and I-mfa represent two members of a new family of proteins regulating gene expression and characterized by a particular cysteine-rich C-terminal domain.
Assuntos
Regulação Viral da Expressão Gênica/genética , HIV-1/genética , Vírus Linfotrópico T Tipo 1 Humano/genética , Fatores de Regulação Miogênica/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Células COS , Clonagem Molecular , DNA Complementar , Repetição Terminal Longa de HIV , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
The Tax protein of the human T-cell leukemia virus type 1 (HTLV-1) has been implicated in human T-cell immortalization. The primary function of Tax is to transcriptionally activate the HTLV-1 promoter, but Tax is also known to stimulate expression of cellular genes. It has been reported to associate with several transcription factors, as well as proteins not involved in transcription. To better characterize potential cellular targets of Tax present in infected cells, a Saccharomyces cerevisiae two-hybrid screening was performed with a cDNA library constructed from the HTLV-1-infected MT2 cell line. From this study, we found 158 positive clones representing seven different cDNAs. We focused our attention on the cDNA encoding the transcription factor CREB-2. CREB-2 is an unconventional member of the ATF/CREB family in that it lacks a protein kinase A (PKA) phosphorylation site and has been reported to negatively regulate transcription from the cyclic AMP response element of the human enkephalin promoter. In this study, we demonstrate that CREB-2 cooperates with Tax to enhance viral transcription and that its basic-leucine zipper C-terminal domain is required for both in vitro and in vivo interactions with Tax. Our results confirm that the activation of the HTLV-1 promoter through Tax and factors of the ATF/CREB family is PKA independent.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Produtos do Gene tax/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/genética , Regiões Promotoras Genéticas , Proteínas Repressoras/metabolismo , Sequência de Aminoácidos , Animais , Células COS , DNA Complementar , HumanosRESUMO
The disposition and metabolism of two 14C-labeled species of Mitozolomide (Mz) were studied in healthy and in B16 melanoma-bearing mice after po administration of a 40 mg/kg dose. Urine was the main elimination route of the radioactivity derived from [14C]chloroethyl Mz whereas a major part of the radiocarbon was recovered as 14CO2 in the expired air of mice given C]tetrazin Mz, indicating an extensive metabolism of the drug. Subsequent studies conducted only with the [14C]chloroethyl species, showed that total radioactivity and Mz were rapidly distributed to plasma and tissues but that Mz levels decreased more rapidly than those of total radioactivity, thus indicating an early metabolism of the drug. It is noteworthy that B16 melanoma concentrated Mz and/or metabolites to the same extent as normal tissues except the brain. Elimination of Mz from all tissues including the tumor was first order with a t 1/2 ranging from 1.52 to 2.03 hr. In the part of the study related to disposition, pharmacokinetic parameters did not significantly differ between control and B16-bearing mice. In the other part related to metabolic fate, we showed that among the urinary excretion products, unchanged Mz represented about one third of the eliminated radioactivity. Eight metabolites were separated by HPLC and five identified as degradation products of alkylated glutathione, namely thiodiacetic acid and its sulfoxide, S-carboxymethylcysteine and N-acetyl derivatives of S-carboxymethylcysteine and S-hydroxyethylcysteine.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antineoplásicos/farmacocinética , Compostos de Mostarda Nitrogenada/farmacocinética , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Radioisótopos de Carbono , Masculino , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Compostos de Mostarda Nitrogenada/administração & dosagem , Compostos de Mostarda Nitrogenada/metabolismo , Radiometria , Distribuição TecidualRESUMO
A multicenter and retrospective study of the diagnosis value of SCC-TA4 in squamous cell carcinomas of 4 localisations was made with the 2 thresholds of 2 and 2.5 ng/ml. However, 3.1% of controls have a SCC value above 2.5 ng/ml. Sixteen benign gynecologic pathologies had no positive level. The benign digestive (N = 73), bronchial (N = 345) pathologies and no squamous cell carcinomas (N = 93, N = 220 respectively), had SCC-TA4 mean levels significantly lower than corresponding squamous cell carcinomas (N = 153, N = 128 respectively). Sensitivity of the test varied from 40% in the squamous cell carcinomas of the lung, to 72% in the squamous cell carcinomas of the uterine cervix. Specificity was always very high and varied from 91% in the SCC of lung, to 100% in the SCC of uterine cervix. For the SCC of uterine cervix, oesophagus and head and neck, the mean values and incidence of positive levels increased significantly with increasing tumor size and advancing disease stage. For the SCC of uterine cervix, mean SCC-TA4 levels and percentages of positive levels above 2 ng/ml were significantly higher for the patients with recurrence (22.5 +/- 4.6 ng/ml; 76%) or with metastasis appearance (23.6 +/- 5.4 ng/ml; 77%) than for the patients in remission (less than 1.5 ng/ml; 0%). In the SCC of oesophagus, we report levels before treatment that are significantly higher for the patients with metastasis at the first attempt (4.2 +/- 5.1 ng/ml; 59%), and an elevated SCC level at the diagnosis evoked a SCC of lung already disseminated (8.8 +/- 12.1 ng/ml; 50%) that will fail to respond to treatment (4.0 +/- 4.2 ng/ml; 48%).
Assuntos
Antígenos de Neoplasias/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias Esofágicas/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Otorrinolaringológicas/imunologia , Neoplasias do Colo do Útero/imunologia , Adulto , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Neoplasias Otorrinolaringológicas/patologia , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologiaRESUMO
The metabolism and disposition of letosteine, labeled either with 14C or 35S, has been investigated in Sprague-Dawley rats. In separate experiments, rats received 20 mg/kg, iv or orally, [14C]letosteine or [35S]letosteine. Radioactivity was rapidly excreted, mainly in urine, after iv and oral administration. Recovery of radioactivity from 0-72-hr excreta averaged 95% after both routes of [14C]letosteine administration, whereas only 50% was recovered when [35S]letosteine was administered. 14CO2 accounted for about 7.3% (iv) and 5.1% (po) of the dose of [14C]letosteine. Comparison of the iv and oral areas under the plasma 14C radioactivity concentration-time curves suggested that oral absorption of letosteine was complete. Analysis of the radioactivity content of urine showed that letosteine undergoes rapid and extensive metabolism. Several metabolites were identified by TLC, HPLC, and MS. The findings are consistent with a splitting of the ester group of letosteine and subsequent cleavage of the thiazolidinyl ring, yielding cysteine, hypotaurine, taurine, and inorganic sulfate. The metabolite derived from the side chain was identified in the urine as 3-(hydroxycarbonylmethylthio)propanoic acid. It undergoes further oxidation into sulfoxide and sulfone derivatives, which are also present in the urine.
Assuntos
Expectorantes/farmacocinética , Tiazóis/farmacocinética , Animais , Biotransformação , Fenômenos Químicos , Físico-Química , Expectorantes/metabolismo , Fezes/análise , Masculino , Ratos , Ratos Endogâmicos , Tiazóis/metabolismo , Tiazolidinas , Distribuição TecidualAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/metabolismo , Gonadotropina Coriônica/sangue , Pinealoma/metabolismo , Adolescente , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Gonadotropina Coriônica/líquido cefalorraquidiano , Feminino , Humanos , Pinealoma/tratamento farmacológico , Pinealoma/radioterapia , Pinealoma/cirurgiaRESUMO
HCG levels have been studied in 76 patients following laparoscopic treatment using laparotomy. This shows that early detection of treatment failure is possible of ectopic pregnancy. The decrease of HCG was the same as after conservative treatment from the third or fifth post-operative day onwards. The authors report a scheme for the post-operative follow-up after laparoscopic treatment of ectopic pregnancy based on the rate of HCG decrease.
Assuntos
Gonadotropina Coriônica/sangue , Laparoscopia , Gravidez Ectópica/terapia , Feminino , Humanos , GravidezRESUMO
Dropping hCG levels have been studied in 76 patients following laparoscopic treatment of ectopic pregnancy. The drop in hCG is the same as after conservative treatment using laparotomy. This study shows that early detection of treatment failure is possible from the third or fourth post-operative day onwards. The authors report a scheme for the post-operative follow-up after laparoscopic treatment for ectopic pregnancy relying on the hCG rate.