RESUMO
During C. elegans development, animals must choose between reproductive growth or dauer diapause in response to sensory cues. Insulin/IGF-I and TGF-beta signaling converge on the orphan nuclear receptor daf-12 to mediate this choice. Here we show that daf-9 acts downstream of these inputs but upstream of daf-12. daf-9 and daf-12 mutants have similar larval defects and modulate insulin/IGF-I and gonadal signals that regulate adult life span. daf-9 encodes a cytochrome P450 related to vertebrate steroidogenic hydroxylases, suggesting that it could metabolize a DAF-12 ligand. Sterols may be the daf-9 substrate and daf-12 ligand because cholesterol deprivation phenocopies mutant defects. Sensory neurons, hypodermis, and somatic gonadal cells expressing daf-9 identify potential endocrine tissues. Evidently, lipophilic hormones influence nematode metabolism, diapause, and life span.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Larva/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Tecido Adiposo/metabolismo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/classificação , Proteínas de Caenorhabditis elegans/genética , Colesterol/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Epistasia Genética , Genes Reporter , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Larva/anatomia & histologia , Longevidade , Modelos Biológicos , Fenótipo , Filogenia , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Reprodução/fisiologia , Distribuição Tecidual , Fator de Crescimento Transformador beta/metabolismoRESUMO
Compensatory hepatic regeneration after partial hepatectomy (PH) is dependent upon the extent of resection. This study analyzes the regulation of the AP-1 transcription factor c-Jun during hepatic regeneration. There is a progressive increase in c-jun mRNA levels after sham operation, one-third PH, and two-thirds PH. A concomitant increase in AP-1 binding activity is also observed. The c-Jun protein is a major constituent of the AP-1 complex in quiescent and early regenerating liver. The activity of c-Jun nuclear kinase (JNK), which phosphorylates the activation domain of the c-Jun protein, is markedly stimulated after one-third PH. JNK1 or an immunologically related kinase is a constituent of this stimulated JNK activity after PH. When primary cultures of adult rat hepatocytes are incubated with epidermal growth factor or transforming growth factor-alpha, AP-1 transcriptional activity is increased and the activation domain of the c-Jun protein is further potentiated. Phosphopeptide mapping of the endogenous c-Jun protein in proliferating cultured hepatocytes demonstrates phosphorylation of the c-Jun activation domain. Combining the results of these in vivo and culture studies, we conclude that the minimal stimulation of one-third PH activates JNK, which phosphorylates the c-Jun activation domain in hepatocytes, resulting in enhanced transcription of AP-1-dependent genes.
Assuntos
Expressão Gênica , Regeneração Hepática , Fígado/fisiologia , Proteínas Quinases/biossíntese , Proteínas Proto-Oncogênicas c-jun/biossíntese , Animais , Sequência de Bases , Núcleo Celular/metabolismo , Colagenases/genética , Sequência Consenso , Ativação Enzimática , Indução Enzimática , Genes fos , Genes jun , Hepatectomia , Humanos , Cinética , Fígado/metabolismo , Masculino , Dados de Sequência Molecular , Sondas de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos , Ratos Sprague-Dawley , Albumina Sérica/biossíntese , Fatores de TempoRESUMO
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.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Fluoruracila/uso terapêutico , Pró-Fármacos/uso terapêutico , Adenocarcinoma/secundário , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina , Neoplasias Colorretais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Estudos Prospectivos , Análise de SobrevidaRESUMO
Standard therapy for advanced or metastatic colorectal cancer consists of 5-fluorouracil plus leucovorin (5-FU/LV) administered intravenously (i.v.). Capecitabine (Xeloda), an oral fluoropyrimidine carbamate which is preferentially activated by thymidine phosphorylase in tumour cells, mimics continuous 5-FU and is a recently developed alternative to i.v. 5-FU/LV. The choice of oral rather than intravenous treatment may affect medical resource use because the two regimens do not require the same intensity of medical intervention for drug administration, and have different toxicity profiles. Here we examine medical resource use in the first-line treatment of colorectal cancer patients with capecitabine compared with those receiving the Mayo Clinic regimen of 5-FU/LV. In a prospective, randomised phase III clinical trial, 602 patients with advanced or metastatic colorectal cancer recruited from 59 centres worldwide were randomised to treatment with either capecitabine or the Mayo regimen of 5-FU/LV. In addition to clinical efficacy and safety endpoints, data were collected on hospital visits required for drug administration, hospital admissions, and drugs and unscheduled consultations with physicians required for the treatment of adverse events. Capecitabine treatment in comparison to 5-FU/LV in advanced colorectal carcinoma resulted in superior response rates (26.6% versus 17.9%, P=0.013) and improved safety including less stomatitis and myelosuppression. Capecitabine patients required substantially fewer hospital visits for drug administration than 5-FU/LV patients. Medical resource use analysis showed that patients treated with capecitabine spent fewer days in hospital for the management of treatment related adverse events than did patients treated with 5-FU/LV. In addition, capecitabine reduced the requirement for expensive drugs, in particular antimicrobials fluconazole and 5-HT3-antagonists to manage adverse events. As anticipated with an oral home-based therapy patients receiving capecitabine needed more frequent unscheduled home, day care, office and telephone consultations with physicians. In the light of clinical results from the phase III trial demonstrating increased efficacy in terms of response rate, equivalent time to progression (TTP) and survival (OS), and a superior safety profile, the results from this medical resource assessment indicate that capecitabine treatment of colorectal cancer patients results in a substantial resource use saving relative to the Mayo Clinic regimen of 5-FU/LV. This benefit is derived principally from the avoidance of hospital visits for i.v. drug administration, less expensive drug therapy for the treatment of toxic side-effects, and fewer treatment-related hospitalisations required during the course of therapy for adverse drug reactions in comparison to patients treated with 5-FU/LV.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Capecitabina , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Hospitais/estatística & dados numéricos , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Estudos ProspectivosRESUMO
Joubert's syndrome is clinically characterized by attacks of tachypnea alternating with respiratory pauses, abnormal ocular movements, psychomotor retardation, and ataxia. Anatomic anomalies include cerebellar vermis agenesis with dilatation of the fourth ventricle. It is an autosomal recessive disorder; onset is in the neonatal period and prognosis is severe.
Assuntos
Ataxia Cerebelar/patologia , Cerebelo/anormalidades , Transtornos da Motilidade Ocular/patologia , Transtornos Respiratórios/patologia , Cerebelo/patologia , Humanos , Lactente , Deficiência Intelectual , Masculino , SíndromeRESUMO
Suicide is a deadly decision rooted in biology and expressed in behavior. Knowing how to care for a patient who survives a suicide attempt requires a thorough understanding of the pathophysiology of self-harm, who is susceptible, and how to intervene.
Assuntos
Tentativa de Suicídio/psicologia , Adulto , Depressão/diagnóstico , Depressão/enfermagem , Humanos , Masculino , Avaliação em Enfermagem , Cuidados de Enfermagem , Fatores de RiscoAssuntos
Antipsicóticos/efeitos adversos , Haloperidol/efeitos adversos , Síndrome Maligna Neuroléptica/diagnóstico , Síndrome Maligna Neuroléptica/etiologia , Avaliação em Enfermagem/métodos , Adulto , Diagnóstico Diferencial , Emergências , Humanos , Masculino , Síndrome Maligna Neuroléptica/enfermagem , Esquizofrenia Paranoide/tratamento farmacológicoRESUMO
The efficacy of standardized follow-up examinations after surgery for colorectal carcinoma has been repeatedly questioned. Although many studies have assessed the value of different diagnostic tools none of these procedures proved to have a predictive value high enough to accurately predict the recurrence of disease and to justify its regular use in these patients. Even a combined diagnostic approach provided a benefit only for a minority of these patients (3.5 to 4.5%). Considering the physical and psychological strain imposed by this approach risk-adapted follow-up schemes are urgently needed. Prognostic parameters indicating the individual risk for disease recurrence can be deduced from increasing CEA values as well as from classification and grading of the primary tumor. Colonoscopy is an effective procedure for early detection of intraluminal relapse or metachronous tumors with potential impact on survival of the patient. An abdominal ultrasound study appears to be the method of choice for detection of metastasis of the liver due to its high sensitivity and low invasiveness. Other imaging procedures are not indicated in routine follow-up for colorectal carcinoma. It remains to be demonstrated whether molecular biology or new scintigraphic techniques will be helpful in follow-up examinations of patients with colorectal carcinomas.
Assuntos
Assistência ao Convalescente/métodos , Neoplasias Colorretais/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Humanos , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Tumor necrosis factor alpha (TNF alpha) has multiple biological functions including the prolonged activation of the collagenase and c-jun genes, which are regulated via their AP-1 binding sites. We show that incubating human fibroblasts with TNF alpha induces prolonged activation of JNK, the c-Jun kinase, which phosphorylates the transactivation domain of c-Jun. Furthermore, an immune complex kinase assay specifically demonstrates that TNF alpha stimulates the activity of JNK1, the recently described predominant form of JNK. TNF alpha also produces a small and transient increase in extracellular signal-regulated kinase (ERK) activity and no measured increase in Raf-1 kinase activity. On the other hand, epidermal growth factor causes a prolonged activation of Raf-1 kinase and ERK activity and a smaller, more transient activation of JNK, whereas the phorbol ester phorbol 12-myristate 13-acetate causes a small stimulation of Raf-1 kinase and a pronounced stimulation of ERK activity. The activation of JNK by TNF alpha does not correlate with Raf-1 or ERK activity. The kinetics of Raf-1, ERK, and JNK induction by epidermal growth factor, phorbol 12-myristate 13-acetate, or TNF alpha indicate distinct mechanisms of activation in human fibroblasts.
Assuntos
Proteínas Quinases Ativadas por Mitógeno , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/biossíntese , Células Cultivadas , DNA/metabolismo , Ativação Enzimática , Humanos , Proteína Quinase 3 Ativada por Mitógeno , Fosforilação , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas c-raf , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
During a 6-month period approximately 20% of the 589 patients admitted to the Maryland Institute for Emergency Medical Services Systems (MIEMSS), and who did not die, stayed less than 48 hours. About two thirds of these short-stay admissions (13% of the total number of admissions during the study period) were judged inappropriate on clinical grounds. This percentage is lower than the inappropriate rate (20%) experienced at areawide trauma centers in Maryland and may approximate the lower limit of the rate of inappropriate admissions due to unavoidable errors in triage. The inappropriately admitted patients did not impose a large fiscal or service drain on MIEMSS and did not interfere with the care of patients with more serious problems.
Assuntos
Tempo de Internação , Centros de Traumatologia/estatística & dados numéricos , Revisão da Utilização de Recursos de Saúde , Humanos , Maryland , TriagemRESUMO
The underlying molecular mechanisms of the tumor-promoting activity of bile acids such as chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) and the protective effect of ursodeoxycholic acid (UDCA) remain largely unclear. Using RNA arbitrarily primed PCR (RAP-PCR) for differential display, we identified, cloned and sequenced differentially expressed transcripts after treating gastric carcinoma cells (St 23132) with the bile acids CDCA, DCA and UDCA. One of these transcripts was identified to be an estrogen-responsive RING finger protein (efp) mRNA. The differential expression of efp in gastric cancer cells was confirmed by low stringency RT-PCR. efp mRNA levels were induced 3-fold in gastric carcinoma cells after CDCA and DCA treatment, whereas no change in expression was detected after UDCA treatment. Finally, treatment of the colon carcinoma cell line HT 29 with DCA resulted in a 2- to 5-fold induction of efp mRNA levels whereas UDCA did not induce efp. As expected, efp expression was also increased after 24 h of estrogen treatment. In summary, a synergy or a common pathway of tumor enhancement of bile acids and estrogen via efp in gastrointestinal carcinogenesis can be envisioned.
Assuntos
Ácidos e Sais Biliares/farmacologia , Proteínas de Ligação a DNA/genética , Estrogênios/farmacologia , Neoplasias Gastrointestinais/metabolismo , RNA Mensageiro/análise , Fatores de Transcrição/genética , Dedos de Zinco , Ácido Quenodesoxicólico/farmacologia , Ácido Desoxicólico/farmacologia , Neoplasias Gastrointestinais/etiologia , Humanos , Proteínas com Motivo Tripartido , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases , Ácido Ursodesoxicólico/farmacologiaRESUMO
Bile acid processing in the long-term, bile duct obstructed rat liver was studied ex vivo. Twenty four and 72 h, respectively, after bile duct obstruction the isolated liver was perfused with taurodeoxycholate (16 nmol/min per g liver) the bile duct still being closed. Uptake, metabolism and regurgitation profile were traced by bolus injection of tritium-labeled bile acid; in addition, concurrent histological changes were examined by light- and electron microscopy. Ligation caused dilatation of the intrahepatic ductular branches and increased the serum bile acid concentration to 740 +/- 75 microM (controls: 16 +/- 2.12), reaching its maximum within 24 h. At 16 nmol/min per g liver uptake rate was > 96% in controls and in bile duct obstructed rats. Maximal uptake rates (assessed separately) differed between controls and bile duct obstructed rats (700 nmol/min per g liver vs. 460). Controls excreted more than 80% of labeled bile acid in bile within 10 min after bolus injection. Biliary recovery of label was virtually completed after 30 min. In bile duct obstructed rats excretion of label back to the perfusate effluent (regurgitation) started quantitatively 5 min after bolus application and peaked between 10 and 40 min; after 80 min, effluent recovery was incomplete (about 60% of bolus injected). Biliary bile acids of controls consisted of about 20% taurodeoxycholate-metabolites; bile acids in the perfusate effluent of bile duct obstructed rats of about 55%. The major metabolite in all animal groups was taurocholate; minor metabolites were tauroursocholate, tauro-3 alpha,7 = 0,12 alpha-cholanoic acid and 3-sulfo-taurodeoxycholate. Histologically, inflammation and periportal edema were present after 1 day of bile duct obstruction. After 3 days, marked proliferation of bile ductules was the dominant histological feature. It is concluded that during initial bile duct obstruction, bile acid processing is not altered, although ultrastructural alterations occur early.