RESUMO
PURPOSE: The aim of the present review was to determine effects of strength exercise on secondary lymphedema in breast cancer patients. METHODS: Research was conducted by using the databases PubMed/Medline and Embase. Randomized controlled trials published from January 1966 to May 2015 investigating the effects of resistance exercise on breast cancer patients with or at risk of secondary lymphedema in accordance with the American College of Sports Medicine exercise guidelines for cancer survivors were included in the present study. RESULTS: Nine original articles with a total of 957 patients met the inclusion criteria. None of the included articles showed adverse effects of a resistance exercise intervention on lymphedema status. In all included studies, resistance exercise intensity was described as moderate to high. CONCLUSIONS: Strength exercise seems not to have negative effects on lymphedema status or might not increase risk of development of lymphedema in breast cancer patients. Further research is needed in order to investigate the effects of resistance exercise for patients suffering from lymphedema.
Assuntos
Neoplasias da Mama/complicações , Linfedema/etiologia , Idoso , Neoplasias da Mama/mortalidade , Exercício Físico , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco , SobreviventesRESUMO
Haldane's rule predicts that particularly high fitness reduction should affect the heterogametic sex of interspecific hybrids. Despite the fact that hybridization is widespread in birds, survival of hybrid individuals is rarely addressed in studies of avian hybrid zones, possibly because of methodological constraints. Here, having applied capture-mark-recapture models to an extensive, 19-year-long data set on individually marked birds, we estimate annual survival rates of hybrid individuals in the hybrid zone between herring (Larus argentatus) and Caspian (Larus cachinnans) gulls. In both parental species, males have a slightly higher survival rate than females (model-weighted mean ± SE: herring gull males 0.88 ± 0.01, females 0.87 ± 0.01, Caspian gull males 0.88 ± 0.01, females 0.87 ± 0.01). Hybrid males do not survive for a shorter time than nonhybrid ones (0.88 ± 0.01), whereas hybrid females have the lowest survival rate among all groups of individuals (0.83 ± 0.03). This translates to a shorter adult (reproductive) lifespan (on average by 1.7-1.8 years, i.e. ca 25%) compared with nonhybrid females. We conclude that, in line with Haldane's rule, the lower survival rate of female hybrids may contribute to selection against hybrids in this hybrid zone.
Assuntos
Charadriiformes/fisiologia , Vigor Híbrido , Hibridização Genética , Longevidade/genética , Animais , Charadriiformes/genética , Feminino , Masculino , Fatores SexuaisRESUMO
BACKGROUND: Concurrent chemoradiation with etoposide and cisplatin (EP/XRT) is standard treatment for inoperable stage III locally advanced non-small-cell lung cancer (LA-NSCLC). Consolidation docetaxel (D; Taxotere) after EP/XRT resulted in increased toxicity but no improvement in survival compared with observation (O). We report updated survival for the entire study population and include an analysis of efficacy and tolerability of EP/XRT with or without D in patients aged ≥ 70 years. PATIENTS AND METHODS: Hoosier Oncology Group LUN 01-24 enrolled 243 patients with LA-NSCLC and randomized 166 after EP/XRT to three cycles of D versus O. the trial was terminated after an analysis of the first 203 patients demonstrated futility of D. RESULTS: Median survival time (MST) for the overall study population was 21.5 months, and 3-, 4-, and 5-year survival rates were 30.7%, 18.0%, and 13.9%, respectively. No differences in MST or 3-year survival were noted between D and O arms. Older patients had similar MST (17.1 versus 22.8 months for younger patients, P = 0.15) but higher rates of grade 3/4 toxicity and hospitalization during induction. CONCLUSIONS: Consolidation docetaxel after EP/XRT does not improve survival in LA-NSCLC. Fit older adults with LA-NSCLC benefit from concurrent chemoradiation similarly as younger patients but experience higher rates of hospitalization and toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Cisplatino/administração & dosagem , Quimioterapia de Consolidação , Intervalo Livre de Doença , Docetaxel , Término Precoce de Ensaios Clínicos , Etoposídeo/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
Antibody-blocking studies have demonstrated the role of CD6 in thymocyte-thymic epithelial (TE) cell adhesion. Here we report that CD6 expressed by COS cells mediates adhesion to TE cells and that this interaction is specifically blocked with an anti-CD6 monoclonal antibody (mAb) or with a mAb (J4-81) that recognized a TE cell antigen. We isolated and expressed a cDNA clone encoding this antigen and show that COS cells transfected with this cDNA bind a CD6 immunoglobulin fusion protein (CD6-Rg). This antigen, which we named ALCAM (activated leukocyte-cell adhesion molecule) because of its expression on activated leukocytes, appears to be the human homologue of the chicken neural adhesion molecule BEN/SC-1/DM-GRASP. The gene was mapped to human chromosome 3q13.1-q13.2 by fluorescence in situ hybridization of cDNA probes to metaphase chromosomes. We prepared an ALCAM-Rg fusion protein and showed that it binds to COS cell transfectants expressing CD6, demonstrating that ALCAM is a CD6 ligand. The observations that ALCAM is also expressed by activated leukocytes and that both ALCAM and CD6 are expressed in the brain suggest that ALCAM-CD6 interactions may play a role in the binding of T and B cells to activated leukocytes, as well as in interactions between cells of the nervous system.
Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Cromossomos Humanos Par 3 , Glicoproteínas/biossíntese , Molécula de Adesão de Leucócito Ativado , Sequência de Aminoácidos , Animais , Adesão Celular , Moléculas de Adesão Celular/biossíntese , Linhagem Celular , Chlorocebus aethiops , Bandeamento Cromossômico , Mapeamento Cromossômico , Sequência Consenso , Células Epiteliais , Epitélio/fisiologia , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Cariotipagem , Ligantes , Dados de Sequência Molecular , Proteínas Recombinantes de Fusão/biossíntese , Homologia de Sequência de Aminoácidos , Linfócitos T/citologia , Linfócitos T/imunologia , Timo/citologia , Timo/fisiologia , Transfecção , Células Tumorais CultivadasRESUMO
We investigated the role of selection in generating and maintaining species distinctness in spite of ongoing gene flow, using two zones of secondary contact between large gull species in Europe (Larus argentatus and Larus cachinnans) and North America (Larus glaucescens and Larus occidentalis). We used the pattern of neutral genetic differentiation at nine microsatellite loci (F(ST)) as an indicator of expected changes under neutral processes and compared it with phenotypic differentiation (P(ST)) for a large number of traits (size, plumage melanism and coloration of bare parts). Even assuming very low heritability, interspecific divergence between L. glaucescens and L. occidentalis in plumage melanism and orbital ring colour clearly exceeded neutral differentiation. Similarly, melanism of the central primaries was highly divergent between L. argentatus and L. cachinnans. Such divergence is unlikely to have arisen randomly and is therefore attributed to spatially varying selection. Variation in plumage melanism in both transects agrees with Gloger's rule, which suggests that latitude (and associated sun and humidity gradients) could be the selective pressure shaping differentiation in plumage melanism. We suggest that strong species differentiation in orbital ring colour results from sexual selection. We conclude that these large gull species, along with other recently diverged species that hybridize after coming into secondary contact, may differ only in restricted regions of the genome that are undergoing strong disruptive selection because of their phenotypic effects.
Assuntos
Charadriiformes/genética , Fluxo Gênico , Especiação Genética , Seleção Genética , Grupos de População Animal/genética , Animais , Charadriiformes/fisiologia , Cor , Europa (Continente) , Variação Genética , Genótipo , Repetições de Microssatélites , América do Norte , FenótipoRESUMO
Oncostatin M is a polypeptide cytokine, produced by normal and malignant hematopoietic cells, that has several in vitro activities, including the ability to inhibit growth of cultured carcinoma cells. Here we present a structural and functional comparison of two oncostatin M-related proteins (Mr 36,000 and 32,000) secreted by COS cells transfected with oncostatin M cDNA. The smaller of these forms lacked a hydrophilic C-terminal domain comprising predominantly basic amino acids. This domain was also absent from native oncostatin M produced by U937 cells. The 32,000-Mr form of oncostatin M was not produced by cells transfected with plasmids (G195 and G196) in which a potential trypsinlike cleavage site within the hydrophilic C-terminal domain was altered by site-directed mutagenesis. A 32,000-Mr fragment was produced by trypsin treatment of the 36,000-Mr form of oncostatin M. These observations suggest that the 32,000-Mr form of oncostatin M was derived from the 227-amino-acid propeptide by proteolytic cleavage at or near the paired basic residues at positions 195 and 196. Pro-oncostatin M was equally active in radioreceptor assays as the processed form but was 5- to 60-fold less active in growth inhibition assays. Likewise, nonprocessed mutant protein encoded by plasmid G196 was equally active in the radioreceptor assays as the processed form but was five- to ninefold less active in growth inhibition assays. Thus, the highly charged C-terminal domain of pro-oncostatin M is not required for receptor binding or growth-inhibitory activity but may alter the functional properties of the molecule. Propeptide processing of oncostatin M may be important for regulating in vivo activities of this cytokine.
Assuntos
Inibidores do Crescimento , Peptídeos/farmacologia , Sequência de Aminoácidos , Células Cultivadas , Análise Mutacional de DNA , Glicosilação , Inibidores do Crescimento/genética , Técnicas In Vitro , Dados de Sequência Molecular , Peso Molecular , Mutação , Oncostatina M , Peptídeos/genética , Processamento de Proteína Pós-Traducional , Relação Estrutura-AtividadeRESUMO
We have isolated the gene for a novel growth regulator, amphiregulin (AR), that is evolutionarily related to epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha). AR is a bifunctional growth modulator: it interacts with the EGF/TGF-alpha receptor to promote the growth of normal epithelial cells and inhibits the growth of certain aggressive carcinoma cell lines. The 84-amino-acid mature protein is embedded within a 252-amino-acid transmembrane precursor, an organization similar to that of the TGF-alpha precursor. Human placenta and ovaries were found to express significant amounts of the 1.4-kilobase AR transcript, implicating AR in the regulation of normal cell growth. In addition, the AR gene was localized to chromosomal region 4q13-4q21, a common breakpoint for acute lymphoblastic leukemia.
Assuntos
Glicoproteínas/genética , Substâncias de Crescimento/genética , Peptídeos e Proteínas de Sinalização Intercelular , Sequência de Aminoácidos , Anfirregulina , Sequência de Bases , Northern Blotting , Cromossomos Humanos Par 4 , Clonagem Molecular , DNA/genética , Família de Proteínas EGF , Fator de Crescimento Epidérmico/genética , Genes , Humanos , Dados de Sequência Molecular , Conformação Proteica , Precursores de Proteínas/genética , RNA Mensageiro/genética , Mapeamento por Restrição , Distribuição Tecidual , Fatores de Crescimento Transformadores/genéticaRESUMO
Oncostatin M is a polypeptide of Mr approximately 28,000 that acts as a growth regulator for many cultured mammalian cells. We report the cDNA and genomic cloning, sequence analysis, and functional expression in heterologous cells of oncostatin M. cDNA clones were isolated from mRNA of U937 cells that had been induced to differentiate into macrophagelike cells by treatment with phorbol 12-myristate 13-acetate, and a genomic clone was also isolated from human brain DNA. Sequence analysis of these clones established the 1,814-base-pair cDNA sequence as well as exon boundaries. This sequence predicted that oncostatin M is synthesized as a 252-amino-acid polypeptide, with a 25-residue hydrophobic sequence resembling a signal peptide at the N terminus. The predicted oncostatin M amino acid sequence shared no homology with other known proteins, but the sequence of the 3' noncoding region of the cDNA contained an A + T-rich stretch with sequence motifs found in the 3' untranslated regions of many cytokine and lymphokine cDNAs. Oncostatin M mRNA of approximately 2 kilobase pairs was detected in phorbol 12-myristate 13-acetate-treated U937 cells and in activated human T cells. Transfection of cDNA encoding the oncostatin M precursor into COS cells resulted in the secretion of proteins with the structural and functional properties of oncostatin M. The unique amino acid sequence, expression by lymphoid cells, and growth-regulatory activities of oncostatin M suggest that it is a novel cytokine.
Assuntos
Clonagem Molecular , Substâncias de Crescimento/genética , Peptídeos/genética , Sequência de Aminoácidos , Composição de Bases , Sequência de Bases , Northern Blotting , Células Cultivadas , DNA/genética , Eletroforese em Gel de Poliacrilamida , Substâncias de Crescimento/biossíntese , Humanos , Dados de Sequência Molecular , Oncostatina M , Biossíntese Peptídica , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , TransfecçãoRESUMO
The dose of interleukin 2 (IL-2) which can be administered to cancer patients is limited largely by a capillary leak syndrome. Pentoxifylline (PTX) is a methylxanthine which reduces IL-2 toxicity in animals. Ciprofloxacin (Cipro) modifies the metabolism of methylxanthines and, when coadministered with PTX, increases levels of PTX and certain of its metabolites. We conducted a phase Ib trial in patients receiving IL-2 and lymphokine-activated killer cell (LAK) cell therapy for metastatic renal cell carcinoma to identify the maximum tolerated dose of PTX which could be coadministered with Cipro in this setting. Eighteen patients received IL-2 (Roche) by continuous infusion at 6 x 10(6) units/m2/day on days 1-5 and underwent leukapheresis on days 7-9. LAK cells were infused on days 12-14. IL-2 was administered at 2 x 10(6) units/m2/day on days 10-20. Cohorts of patients received PTX at 2.5 (n = 3), 3.1 (n = 6), 3.9 (n = 6), and 4.9 (n = 3) mg/kg by 30 min i.v. infusion every 4 h on days 0-5 and 10-20 and Cipro (500 mg p.o. every 12 h) on days 1-5 and 10-20. Toxicity was compared with that observed in 33 historical control patients who received 37 cycles of an identical regimen of IL-2/LAK without PTX/Cipro. PTX at 2.5-3.9 mg/kg and Cipro were well tolerated. The maximum tolerated dose of PTX was 3.9 mg/kg. Dose-limiting emesis (n = 1) and atrial fibrillation (n = 2) occurred at 4.9 mg/kg and were reversible. Two complete, one partial and one minor, responses were observed. Patients treated with 3.9 mg/kg PTX received 95.0% of the planned dose of IL-2 as compared to 72.8% in the control patients (P < 0.025), primarily due to a lower incidence of azotemia and metabolic acidosis in PTX/Cipro recipients than had been seen in the historical control patients. The results of this study demonstrate that PTX/Cipro can be administered to patients receiving IL-2/LAK without apparent loss of therapeutic efficacy. Moreover, PTX/Cipro recipients exhibited less toxicity than historical controls. Therefore, treatment with PTX/Cipro may allow delivery of higher doses of IL-2, which might induce more responses in IL-2-responsive tumors and regression of tumors unresponsive to conventional doses of IL-2.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/terapia , Imunoterapia Adotiva , Interleucina-2/uso terapêutico , Neoplasias Renais/terapia , Células Matadoras Ativadas por Linfocina/transplante , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Carcinoma de Células Renais/sangue , Ciprofloxacina/efeitos adversos , Ciprofloxacina/sangue , Ciprofloxacina/uso terapêutico , Feminino , Humanos , Interleucina-2/efeitos adversos , Neoplasias Renais/sangue , Masculino , Pessoa de Meia-Idade , Pentoxifilina/efeitos adversos , Pentoxifilina/sangue , Pentoxifilina/uso terapêuticoRESUMO
PURPOSE: This trial evaluated the efficacy, toxicity, and practicability of a new intensive chemotherapy regimen in a multicenter setting of university and community hospitals. PATIENTS AND METHODS: We tested a hybrid protocol of two non-cross-resistant regimens, cyclophosphamide, epirubicin, vincristine, and prednisolone (CEOP) and ifosfamide, etoposide (VP-16), methotrexate, and dexamethasone (IMVP-Dexa) given every fourth week, three to six times according to response, in patients with untreated intermediate- and high-grade non-Hodgkin's lymphoma. Ten Austrian centers entered 81 patients onto this multicenter trial. Eleven patients were excluded. The median age was 55 years. Twenty-six of 70 patients had stage III or IV disease. The distribution among international risk categories low, intermediate-low, intermediate-high, and high was 20%, 34%, 23%, and 23%, respectively. RESULTS: Of 70 eligible patients, 56 (80%) had a complete remission and seven (10%) a partial remission. After a median observation time of 36 months, the estimated time to relapse and overall survival rates are 67% and 72%, respectively. Age and Karnofsky index were the only independent risk factors for survival. Toxicity was primarily hematologic, with a median granulocyte nadir of 0.56 x 10(9)/L. Sixty-seven percent of patients had infections; 25.7% were severe World Health Organization (WHO) grade III or IV. There were three treatment-related deaths. CONCLUSION: CEOP-IMVP-Dexa chemotherapy is safe and feasible on a groupwide basis even when used in community hospitals. Neutropenic infections are the major complications. A 72% 3-year survival rate in patients with intermediate- and high-grade non-Hodgkin's lymphoma warrants further studies. These data are the basis for a randomized trial to compare cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with CEOP/IMVP-Dexa.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Epirubicina/administração & dosagem , Etoposídeo/administração & dosagem , Estudos de Viabilidade , Feminino , Ácido Fólico/administração & dosagem , Doenças Hematológicas/induzido quimicamente , Humanos , Ifosfamida/administração & dosagem , Avaliação de Estado de Karnofsky , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Masculino , Mesna/administração & dosagem , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prednisolona/administração & dosagem , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
The transforming growth factor-beta 1 (TGF beta 1) and -beta 2 (414) precursors both contain three predicted sites of N-linked glycosylation within their pro regions. These are located at amino acid residues 72, 140, and 241 for the TGF beta 2 (414) precursor and at residues 82, 136, and 176 for the TGF beta 1 precursor; both proteins contain mannose-6-phosphate (M-6-P) residues. The major sites of M-6-P addition are at Asn (82) and Asn (136), the first two sites of glycosylation, for the TGF beta 1 precursor. We now show that the major site of M-6-P addition within the TGF beta 2 (414) precursor is at Asn241, the third glycosylation site. To determine the importance of N-linked glycosylation to the secretion of TGF beta 1 and -beta 2, site-directed mutagenesis was used to change the Asn residues to Ser residues; the resulting DNAs were transfected into COS cells, and their supernatants were assayed for TGF beta activity. Substitution of Asn (241) of the TGF beta 2 (414) precursor resulted in an 82% decrease in secreted TGF beta 2 bioactivity. Mutation at Asn72 resulted in a 44% decrease, while mutation at Asn140 was without effect. Elimination of all three glycosylation sites resulted in undetectable levels of TGF beta 2. These results were compared with similar mutations made in the cDNA encoding the TGF beta 1 precursor. Mutagenesis of the two M-6-P-containing sites (Asn82 and Asn136) resulted in an 83% decrease in secreted TGF beta 1; replacement of Asn82 and Asn136 with Ser individually resulted in 85% and 42% decreases in activity, respectively. Substitution of Asn176 with Ser was without effect, while substitution of all three sites of glycosylation resulted in undetectable levels of TGF beta 1 activity, similar to the results obtained with TGF beta 2. The nine Cys residues within the mature region of TGF beta 1 were mutated to serine, and their effects on TGF beta 1 secretion were evaluated. Mutation of most Cys residues resulted in undetectable levels of TGF beta 1 protein or activity in conditioned medium. Mutation of Cys (355) led to the secretion of inactive TGF beta 1 monomers, suggesting that this residue is either directly involved in dimer formation or required for correct interchain disulfide bond formation.
Assuntos
Cisteína , Mutagênese Sítio-Dirigida , Precursores de Proteínas/genética , Proteínas Recombinantes/biossíntese , Fator de Crescimento Transformador beta/genética , Sequência de Aminoácidos , Animais , Células CHO , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Cricetinae , Glicosilação , Manosefosfatos/análise , Proteínas Recombinantes/farmacologia , Mapeamento por Restrição , Transfecção , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/farmacologiaRESUMO
The lymphocyte antigen CD6 has been extensively studied in humans, but has not been reported in mouse. Here we describe the isolation and characterization of a cDNA clone encoding the murine homologue of the human lymphocyte antigen CD6. Comparison of the predicted amino acid sequence of human and murine CD6 shows that the cytoplasmic domain of murine CD6 is 160 residues longer than that of the human protein. Inspection of the 3' untranslated sequence of the human CD6 clone and the genomic organization of the murine CD6 gene suggests the expression of differentially spliced CD6 polypeptides in both species.
Assuntos
Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Clonagem Molecular , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA Complementar/química , Humanos , Camundongos , Dados de Sequência Molecular , Homologia de Sequência de AminoácidosRESUMO
In this study, we describe the identification of a novel Drosophila melanogaster (Dm) gene, l(2)dtl, characterized by elevated expression under heat-shock (HS) conditions. It encodes a protein of 83 kDa with no homology to known members of the HSP90 family and other proteins. Gene l(2)dtl is located on the right arm of the second chromosome at locus 59F5, close to the tumor suppressor gene l(2)tid, a homolog of the dnaJ encoding a chaperone strongly conserved in evolution. In the following, we present the sequence of l(2)dtl, the putative protein it encodes, and its molecular localization in a closely interspaced gene cluster consisting of at least four nested genes spanning an approximately 10-kb genomic interval. Furthermore, we present the temporal expression of l(2)dtl in the wild type under normal and HS conditions, and describe the isolation and the phenotype of eight embryonic lethal l(2)dtl mutants.
Assuntos
Proteínas de Drosophila , Drosophila melanogaster/genética , Proteínas de Choque Térmico/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Drosophila melanogaster/embriologia , Embrião não Mamífero/patologia , Genes Letais , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/química , Resposta ao Choque Térmico , Dados de Sequência Molecular , Mutação , Análise de Sequência de DNARESUMO
2-Chlorodeoxyadenosine (Cladribine) is a new purine analogue with high activity in pretreated low grade non-Hodgkin's lymphoma (NHL). To evaluate the efficacy of this drug in untreated patients with advanced NHL, we performed a prospective multicentre trial. Cladribine (0.12 mg/kg) was administered intravenously daily for 5 consecutive days in an out-patient setting. The treatment was repeated every 28 days for four cycles. Included were patients with a histological diagnosis of low grade NHL according to the Kiel classification and stage III or IV disease. Stage II patients were included when radiotherapy had failed. 55 patients were entered into the study. 50 patients were evaluable. The remission rate was 44/50 (88%; 95% confidence interval 82-100%), including complete remissions (CR) in 14 (28%) patients. Only 2 patients showed progression while on Cladribine treatment. The estimated overall survival, and time to treatment failure (TTF) were 85% and 51%, respectively, after a median observation time of 92 weeks. 11 (22%) patients showed grade 3 or 4 toxicity according to the WHO grading. Haematological toxicity was responsible for 86% of the overall toxicity and 100% of grade 3 and 4 toxicity. 7 patients (14%) had an infection, two of which were opportunistic. 12 (24%) patients did not experience any toxicity during the treatment. The results of this study clearly demonstrate the safety and considerable activity of this regimen. Cladribine is very effective even at lower doses than have been used so far.
Assuntos
Antineoplásicos/administração & dosagem , Cladribina/administração & dosagem , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Cladribina/efeitos adversos , Progressão da Doença , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida , Falha de TratamentoRESUMO
Immunotherapy with interleukin-2 (IL-2) early after peripheral blood stem cell transplantation (PBSCT) is being considered as a potential way to eradicate minimal residual disease. The aim of this study was to determine whether lymphocytes which can acquire lymphokine-activated killer (LAK) cell activity are present in PBSC and in the blood of patients after PBSCT. Fresh and cryopreserved G-CSF-mobilized PBSC from eight patients were incubated with IL-2 (1000 U/ml) for 3-6 days and then tested for LAK activity as measured by lysis of the Daudi cell line. LAK activity was present in both fresh and cryopreserved PBSC, with mean lysis of 32% and 36%, respectively, at an effector:target (E:T) ratio of 50:1. To assess the reconstitution of LAK precursor activity after PBSCT, peripheral blood (PB) obtained from eight other patients 15-60 days after PBSCT was similarly tested. LAK activity was detected in PB from every patient (mean lysis of 38% at an E:T ratio of 12.5:1). PB from patients after PBSCT contained a higher percentage of CD8+ cells and CD56+ cells than did PB from 9 normal controls (47.2% vs. 21.4% CD8+ cells, P < 0.005 and 28.6% vs. 8.6% CD56+ cells, P < 0.0005). Moreover, PB from 4 of 5 patients tested after PBSCT exhibited a high percentage of cells expressing p75, the intermediate affinity IL-2R. Thus, precursor cells capable of acquiring IL-2-inducible LAK activity are present in PBSC and are rapidly reconstituted after PBSCT. The findings provide a rationale for testing IL-2 as a way of decreasing relapses after PBSCT.
Assuntos
Células Sanguíneas/citologia , Transfusão de Sangue Autóloga , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células Matadoras Ativadas por Linfocina/citologia , Adulto , Células Sanguíneas/imunologia , Remoção de Componentes Sanguíneos , Relação CD4-CD8 , Criopreservação , Feminino , Células-Tronco Hematopoéticas/imunologia , Humanos , Interleucina-2/farmacologia , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/imunologia , Fenótipo , Fatores de TempoRESUMO
Prolactin (PRL) and Growth Hormone (GH) secretions were studied in human serum after the oral administration of 5 mg/kg mescaline (3,4,5-trimethoxy-beta-phenylethylamine) or 2,3,4-trimethoxy-beta-phenylethylamine (2,3,4-TMPEA) respectively. Mescaline stimulated the secretion of PRL more than four-fold above base-line levels. Peak concentrations were found 90--120 min after drug intake. Five hours later serum PRL was still markedly increased. Mescaline also triggered GH secretion. There was no alteration of serum PRL and GH concentrations after intake of the non-hallucinogenic 2,3,4-TMPEA.
Assuntos
Mescalina/farmacologia , Prolactina/metabolismo , 2,5-Dimetoxi-4-Metilanfetamina/farmacologia , Adulto , Feminino , Hormônio do Crescimento/sangue , Meia-Vida , Alucinações/induzido quimicamente , Humanos , Masculino , Fenetilaminas/farmacologia , Estimulação QuímicaRESUMO
We have identified two related genes whose mRNAs are increased after treatment with transforming growth factor-beta (TGF-beta 1). Mouse AKR-2B cells were treated with TGF-beta 1 in the presence of cyclohexamide and a cDNA library was subjected to differential screening. Several TGF-beta-induced genes (beta IG) were isolated and two of these, beta IG-M1 and beta IG-M2, were characterized. beta IG-M1 and beta IG-M2 RNAs were significantly increased after TGF-beta 1 treatment and both were superinduced in the presence of cyclohexamide. cDNA sequence analysis of beta IG-M1 showed that it encoded a 379-amino-acid protein which was 81% homologous to CEF-10, a v-src and TPA-inducible gene, and identical to cyr61, a gene induced by serum in growth-arrested BALB-3T3 cells. cDNA sequence analysis of beta IG-M2 showed that it encoded a 348-amino-acid protein that was 50% homologous to beta IG-M1. Thirty-eight cysteine residues are conserved between beta IG-M1 and beta IG-M2, which are clustered at the amino and carboxy ends: The middle regions of the two proteins are cysteine free and display the highest degree of nonhomology. Both proteins contain an amino-terminal cysteine-rich motif common to insulin-like growth factor binding proteins and a carboxy-terminal domain with strong homology to a motif found near the carboxy-terminal of the malarial circumsporozoite protein which may be involved in cell adhesion. The regulation of mRNA encoding these proteins by TGF-beta 1 suggests that they may be involved in mediating some of the pleiotropic effects of this multipotent modulator of cell growth and differentiation.
Assuntos
Família Multigênica , RNA Mensageiro/análise , Fator de Crescimento Transformador beta/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Southern Blotting , Linhagem Celular , Cicloeximida/farmacologia , Regulação da Expressão Gênica , Camundongos , Dados de Sequência Molecular , Homologia de Sequência do Ácido Nucleico , Transcrição GênicaRESUMO
Transforming growth factor-beta (TGF-beta) is capable of affecting the proliferation of many cell types. To identify novel genes whose protein products may mediate cellular responses to this factor, a cDNA library was made from mRNA isolated from a human lung adenocarcinoma cell line (A549) that had been treated for 3 days with TGF-beta. The library was screened by differential hybridization and a cDNA clone, beta ig-h3, was isolated. This gene was induced up to 20-fold in A549 cells after 2 days of treatment with TGF-beta 1. It was also induced in several other cell lines, including PC-3 and H2981. DNA sequence analysis of beta ig-h3 indicated that it encoded a novel protein, beta IG-H3, of 683 amino acids, which contained an amino-terminal secretory sequence and a carboxy-terminal Arg-Gly-Asp (RGD) sequence that can serve as a ligand recognition site for several integrins. beta IG-H3 also contained short amino acid regions homologous to similar regions in Drosophila fasciclin-I and four homologous internal domains, which can be folded into a potential bivalent structure and could act as a bridge between cells expressing the appropriate ligand. beta ig-h3 RNA was detected in several cell lines and tissues. COS cells transfected with plasmids encoding beta IG-H3 secreted a major 68-kD protein that was detected by immunoblotting using antipeptide antibodies. Since beta ig-h3 is induced in several cell lines whose proliferation is affected by TGF-beta 1, it may be involved in mediating some of the signals of this multifunctional growth modulator.