RESUMO
Early social interactions shape the development of social behavior, although the critical periods or the underlying neurodevelopmental processes are not completely understood. Here, we studied the developmental changes in neural pathways underlying visual social engagement in the translational rhesus monkey model. Changes in functional connectivity (FC) along the ventral object and motion pathways and the dorsal attention/visuo-spatial pathways were studied longitudinally using resting-state functional MRI in infant rhesus monkeys, from birth through early weaning (3 months), given the socioemotional changes experienced during this period. Our results revealed that (1) maturation along the visual pathways proceeds in a caudo-rostral progression with primary visual areas (V1-V3) showing strong FC as early as 2 weeks of age, whereas higher-order visual and attentional areas (e.g., MT-AST, LIP-FEF) show weak FC; (2) functional changes were pathway-specific (e.g., robust FC increases detected in the most anterior aspect of the object pathway (TE-AMY), but FC remained weak in the other pathways (e.g., AST-AMY)); (3) FC matures similarly in both right and left hemispheres. Our findings suggest that visual pathways in infant macaques undergo selective remodeling during the first 3 months of life, likely regulated by early social interactions and supporting the transition to independence from the mother.
Assuntos
Atenção , Encéfalo/diagnóstico por imagem , Plasticidade Neuronal , Comportamento Social , Vias Visuais/diagnóstico por imagem , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Encéfalo/crescimento & desenvolvimento , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/crescimento & desenvolvimento , Neuroimagem Funcional , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , Vias Neurais , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/crescimento & desenvolvimento , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/crescimento & desenvolvimento , Córtex Visual/diagnóstico por imagem , Córtex Visual/crescimento & desenvolvimento , Vias Visuais/crescimento & desenvolvimentoRESUMO
BACKGROUND: Takotsubo cardiomyopathy (TC) is increasingly recognised in patients presenting with features of acute coronary syndrome. We present a single centre experience of TC with medium term follow up. METHODS: Fifty-two consecutive patients presenting with a diagnosis of TC were included. The clinical presentation, complications, baseline and follow-up echocardiograms and cardiac magnetic resonance imaging were analysed. RESULTS: Fifty-one patients were female. A stressful event preceded presentation in 37 (71%) patients. Chest pain was the most common symptom (83%). Two patients presented with an out-of-hospital cardiac arrest. ST segment elevation (40%) and global T wave inversion (44%) were the most frequent electrocardiogram changes. Left ventricular assessment demonstrated typical apical ballooning in 41 patients and 11 patients demonstrated the mid-wall variant. In-hospital complications occurred in 11 patients (21%) and included acute pulmonary oedema (n = 2), cardiogenic shock (n = 5); two of whom had a significant left ventricular outflow gradient, atrial fibrillation (n = 1), left ventricular thrombus (n = 2) and a cerebrovascular event (n = 2). Left ventricular function at presentation and follow up was compared in 40 patients. The mean ejection fraction in this group at presentation was 47% (20-70%) compared with that at follow up of 63% (44-76%). There were no significant complications or recurrences at follow up. CONCLUSIONS: While TC is a reversible condition with low rates of complications and recurrence at follow up it is, as demonstrated in our cohort, associated with significant in-hospital morbidity in a proportion of patients.
Assuntos
Dor no Peito/etiologia , Cardiomiopatia de Takotsubo/epidemiologia , Síndrome Coronariana Aguda/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Cateterismo Cardíaco , Fármacos Cardiovasculares/uso terapêutico , Diagnóstico Diferencial , Eletrocardiografia , Feminino , Seguimentos , Parada Cardíaca/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Edema Pulmonar/epidemiologia , Edema Pulmonar/etiologia , Queensland/epidemiologia , Choque Cardiogênico/epidemiologia , Choque Cardiogênico/etiologia , Choque Cardiogênico/terapia , Estresse Psicológico/complicações , Volume Sistólico , Cardiomiopatia de Takotsubo/complicações , Cardiomiopatia de Takotsubo/diagnóstico , Cardiomiopatia de Takotsubo/diagnóstico por imagem , Cardiomiopatia de Takotsubo/tratamento farmacológico , Cardiomiopatia de Takotsubo/fisiopatologia , Ultrassonografia , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/etiologiaRESUMO
In addition to allergy and parasitic infections, immunoglobulin E (IgE) has been shown recently to possess anti-viral and anti-cancer effects. We investigated serum levels of IgE, its low-affinity receptor, soluble CD23 (sCD23) in patients with pancreatic cancer and the effect of IgE against pancreatic cancer cells. Twelve patients were evaluated for pancreatic cancer by imaging and confirmed by biopsy. Fifteen healthy volunteers served as controls. Serum Igs (IgG, IgM, IgA, IgE) and sCD23 levels were determined (enzyme-linked immunosorbent assay, nephelometry) and the presence of cancer-specific IgE was assessed (fluorescence microscopy, Western blot). IgE anti-cancer activity was determined by antibody-dependent cell-mediated cytotoxicity (ADCC). Serum levels of IgE and sCD23 were elevated significantly in patients with pancreatic cancer versus controls, whereas no differences were observed in other Ig isotypes (IgG, IgM, IgA). Flow cytometry and immunofluorescence microscopy demonstrated similar presence of IgG and IgE pancreatic cancer Igs. However, Western blot analysis indicated differences in IgG and IgE antigen-specific antibodies; IgE antibody recognized a 50 kD protein. ADCC studies demonstrated that serum and purified IgE-mediated cytotoxicity against pancreatic cancer cells, effects which were reversed with anti-IgE neutralizing antibody and IgE depletion (immunoaffinity); greater cytotoxicity was observed in patient serum when compared with healthy controls. These data suggest that IgE and sCD23 may serve as useful biomarkers for patients with pancreatic cancer and may be important in the immune response to this disease in that IgE-directed therapy may help to direct treatment.
Assuntos
Adenocarcinoma/sangue , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Imunoglobulina E/sangue , Neoplasias Pancreáticas/sangue , Receptores de IgE/sangue , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Nefelometria e Turbidimetria , Neoplasias Pancreáticas/imunologia , Receptores de IgE/imunologiaRESUMO
The p53 tumor suppressor protein plays a key role in the regulation of stress-mediated growth arrest and apoptosis. Stress-induced phosphorylation of p53 tightly regulates its stability and transcriptional activities. Mass spectrometry analysis of p53 phosphorylated in 293T cells by active Jun NH2-terminal kinase (JNK) identified T81 as the JNK phosphorylation site. JNK phosphorylated p53 at T81 in response to DNA damage and stress-inducing agents, as determined by phospho-specific antibodies to T81. Unlike wild-type p53, in response to JNK stimuli p53 mutated on T81 (T81A) did not exhibit increased expression or concomitant activation of transcriptional activity, growth inhibition, and apoptosis. Forced expression of MKP5, a JNK phosphatase, in JNK kinase-expressing cells decreased T81 phosphorylation while reducing p53 transcriptional activity and p53-mediated apoptosis. Similarly transfection of antisense JNK 1 and -2 decreased T81 phosphorylation in response to UV irradiation. More than 180 human tumors have been reported to contain p53 with mutations within the region that encompasses T81 and the JNK binding site (amino acids 81 to 116). Our studies identify an additional mechanism for the regulation of p53 stability and functional activities in response to stress.
Assuntos
Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , Divisão Celular , Linhagem Celular , Primers do DNA/genética , Estabilidade de Medicamentos , Fosfatases de Especificidade Dupla , Genes p53 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Quinases JNK Ativadas por Mitógeno , MAP Quinase Quinase 4 , Espectrometria de Massas , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosfatases da Proteína Quinase Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Fosforilação , Proteínas Tirosina Fosfatases/metabolismo , Estresse Fisiológico/genética , Estresse Fisiológico/metabolismo , Treonina/química , Transcrição Gênica , Proteína Supressora de Tumor p53/genética , Raios UltravioletaRESUMO
A general model is developed for the binding of ligands to multiple receptor sites in which steric blockage of sites is taken into account. Analytical expressions for extent of ligand binding as a function of ligand concentration are derived employing a stochastic matrix approach. Using simple numerical techniques to evaluate these expressions it is possible to obtain the inherent affinity of each site for a ligand, the number of sites available and the number of sites excluded when a ligand binds to any site. The expressions derived here are contrasted with other expressions based on simple equilibrium considerations in which there are no interactions between sites and no interactions between ligands in different sites. It is shown that the expressions derived here predict significant departures from linearity in Scatchard plots and a strong negative cooperatively, especially toward the saturation limit.
Assuntos
Sítios de Ligação , Ligantes , Matemática , Modelos Biológicos , Conformação Molecular , Polímeros , Relação Estrutura-AtividadeRESUMO
Platelet-type von Willebrand disease (PT-vWD) is an autosomal dominant bleeding disorder in which patient platelets exhibit an abnormally increased binding of circulating von Willebrand factor (vWF). We have recently shown that this abnormality is associated with a point mutation resulting in substitution of Val for Gly 233 in platelet membrane glycoprotein Ib alpha (GPIb alpha), a major component of the platelet GPIb/IX receptor for vWF. To investigate the effect of this substitution on the three-dimensional structure of this region of the protein, we have generated the allowed (low energy) conformations of the region of the GPI alpha protein containing residues 228-238 (with 5 residues on either side of the critical residue 233) with Gly 233 (wild type) and Val 233 (PT-vWD) using the computer program ECEPP (Empirical Conformational Energies of Peptides Program). The wild-type sequence is Tyr-Val-Trp-Lys-Gln-Gly-Val-Asp-Val-Lys-Ala. We find that the Gly 233-containing peptide can exist in two low energy conformers. The lowest energy conformer is a structure containing a beta-turn at Gln 232-Gly 233 while the alternative conformation is an amphipathic helical structure. Only the amphipathic helical structure is allowed for the Val 233-containing peptide which contains a hydrophobic 'face' consisting of Val 229, Val 233 and Val 236 and another hydrophilic surface composed of such residues as Lys 231 and Asp 235. No such surfaces exist for the lowest energy bend conformer for the Gly 233-containing peptide, but do exist in the higher energy helical structure. The amphipathic surfaces in the 228-238 region of the Val 233-containing GPIb alpha protein may associate strongly with complementary surfaces during vWF binding to the GPIb/IX receptor complex and may help explain heightened association of vWF with this receptor in PT-vWD.
Assuntos
Plaquetas/química , Glicoproteínas da Membrana de Plaquetas/química , Doenças de von Willebrand/sangue , Sequência de Aminoácidos , Simulação por Computador , Glicina/química , Humanos , Substâncias Macromoleculares , Modelos Moleculares , Dados de Sequência Molecular , Mutação/genética , Fragmentos de Peptídeos/química , Agregação Plaquetária/fisiologia , Glicoproteínas da Membrana de Plaquetas/genética , Conformação Proteica , Valina/química , Doenças de von Willebrand/genéticaRESUMO
The protein products of oncogenes and tumor suppressor genes play critical roles in the development of many cancers. The expression of a number of these proteins can be detected in extracellular fluids such as blood. This article reviews the literature on the application of methods for the detection of the proteins of oncogenes and tumor suppressor genes in the blood of humans with cancer or at risk for the development of cancer. The detection of these proteins in blood may be useful molecular markers of carcinogenesis that could play an important part in cancer diagnosis, prognosis, and prevention.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias/diagnóstico , Anticorpos/sangue , Substâncias de Crescimento/sangue , Humanos , Neoplasias/prevenção & controle , Proteína Oncogênica p21(ras)/sangue , Proteína Oncogênica p21(ras)/imunologia , Prognóstico , Proteínas Proto-Oncogênicas c-myc/sangue , Proteínas Proto-Oncogênicas c-myc/imunologia , Receptores de Fatores de Crescimento/sangue , Transdução de Sinais , Proteína Supressora de Tumor p53/sangue , Proteína Supressora de Tumor p53/imunologiaRESUMO
Intraspinal hemorrhage is a rare but dangerous complication of anticoagulant therapy. It must be suspected in any patient taking anticoagulant agents who complains of local or referred spinal pain associated with limb weakness, sensory deficits, or urinary retention. We describe a patient with hematomyelia, review the literature on hematomyelia and other intraspinal hemorrhage syndromes, and summarize intraspinal hemorrhage associated with oral anticoagulant therapy. The patient (a 62-year-old man) resembled previously described patients with hematomyelia in age and sex. However, he was unusual in having cervical rather than thoracic localization. As with intracranial bleeding, the incidence of intraspinal hemorrhage associated with anticoagulant therapy might be minimized by close monitoring and tight control of the intensity of anticoagulation. However, it is noteworthy that many of the reported cases were anticoagulated in the therapeutic range. If intraspinal hemorrhage is suspected, anticoagulation must be reversed immediately. Emergency laminectomy and decompression of the spinal cord appear mandatory if permanent neurologic sequelae are to be minimized. A high index of suspicion, prompt recognition, and immediate intervention are essential to prevent major morbidity and mortality from intraspinal hemorrhage.
Assuntos
Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Doenças Vasculares da Medula Espinal/induzido quimicamente , Varfarina/efeitos adversos , Administração Oral , Anticoagulantes/administração & dosagem , Diagnóstico Diferencial , Hematoma Epidural Craniano/induzido quimicamente , Hematoma Epidural Craniano/diagnóstico , Hematoma Epidural Craniano/cirurgia , Hematoma Subdural/induzido quimicamente , Hematoma Subdural/diagnóstico , Hematoma Subdural/cirurgia , Hemorragia/diagnóstico , Hemorragia/cirurgia , Humanos , Laminectomia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Vasculares da Medula Espinal/diagnóstico , Doenças Vasculares da Medula Espinal/cirurgia , Tromboembolia/tratamento farmacológico , Varfarina/administração & dosagemRESUMO
Widely disseminated cryptococcosis was found on autopsy in a 50-year-old alcoholic man. The spleen, lungs, CNS, liver, kidney, and lymph nodes were all involved. In his clinical course, the patient showed no signs of immunologic anergy. His terminal hospital course resulted directly from end-stage liver disease and renal failure. The cryptococcal infection was of the nongranulomatous, diffuse type with little or no inflammatory response, which probably explains the lack of symptoms.
Assuntos
Criptococose/diagnóstico , Cirrose Hepática Alcoólica/complicações , Antígenos de Fungos/análise , Autopsia , Criptococose/imunologia , Criptococose/patologia , Humanos , Cirrose Hepática Alcoólica/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Based on the concept that hydrophobic interactions cause a polypeptide chain to adopt a compact structure, a method is proposed to predict the structure of a protein. The procedure is carried out in four stages: (1) use of a virtual-bond united-residue approximation with the side chains represented by spheres to search conformational space extensively using specially designed interactions to lead to a collapsed structure, (2) conversion of the lowest-energy virtual-bond united-residue chain to one with a real polypeptide backbone, with optimization of the hydrogen-bond network among the backbone groups, (3) perturbation of the latter structure by the electrostatically driven Monte Carlo (EDMC) procedure, and (4) conversion of the spherical representation of the side chains to real groups and perturbation of the whole molecule by the EDMC procedure using the empirical conformational energy program for peptides (ECEPP/2) energy function plus hydration. Application of this procedure to the 36-residue avian pancreatic polypeptide led to a structure that resembled the one determined by X-ray crystallography; it had an alpha-helix starting at residue 13, with the N-terminal portion of the chain in an extended conformation packed against the alpha-helix. Similar structures with slightly higher energies, but looser packing, were also obtained.
Assuntos
Polipeptídeo Pancreático/química , Aminoácidos/química , Animais , Aves , Carbono/química , Fenômenos Químicos , Físico-Química , Cristalização , Dipeptídeos/química , Eletroquímica , Ligação de Hidrogênio , Conformação Proteica , TermodinâmicaRESUMO
An algorithm is proposed for the conversion of a virtual-bond polypeptide chain (connected C alpha atoms) to an all-atom backbone, based on determining the most extensive hydrogen-bond network between the peptide groups of the backbone, while maintaining all of the backbone atoms in energetically feasible conformations. Hydrogen bonding is represented by aligning the peptide-group dipoles. These peptide groups are not contiguous in the amino acid sequence. The first dipoles to be aligned are those that are both sufficiently close in space to be arranged in approximately linear arrays termed dipole paths. The criteria used in the construction of dipole paths are: to assure good alignment of the greatest possible number of dipoles that are close in space; to optimize the electrostatic interactions between the dipoles that belong to different paths close in space; and to avoid locally unfavorable amino acid residue conformations. The equations for dipole alignment are solved separately for each path, and then the remaining single dipoles are aligned optimally with the electrostatic field from the dipoles that belong to the dipole-path network. A least-squares minimizer is used to keep the geometry of the alpha-carbon trace of the resulting backbone close to that of the input virtual-bond chain. This procedure is sufficient to convert the virtual-bond chain to a real chain; in applications to real systems, however, the final structure is obtained by minimizing the total ECEPP/2 (empirical conformational energy program for peptides) energy of the system, starting from the geometry resulting from the solution of the alignment equations. When applied to model alpha-helical and beta-sheet structures, the algorithm, followed by the ECEPP/2 energy minimization, resulted in an energy and backbone geometry characteristic of these alpha-helical and beta-sheet structures. Application to the alpha-carbon trace of the backbone of the crystallographic 5PTI structure of bovine pancreatic trypsin inhibitor, followed by ECEPP/2 energy minimization with C alpha-distance constraints, led to a structure with almost as low energy and root mean square deviation as the ECEPP/2 geometry analog of 5PTI, the best agreement between the crystal and reconstructed backbone being observed for the residues involved in the dipole-path network.
Assuntos
Carbono/química , Proteínas/química , Algoritmos , Aprotinina/química , Fenômenos Químicos , Físico-Química , Cristalografia por Raios X , Eletroquímica , Ligação de Hidrogênio , Matemática , Estrutura Secundária de ProteínaRESUMO
The specificity of the interaction of cytochrome b5 with different forms of cytochrome P-450 was examined. Immunopurification of cytochromes P-450 1A1, 2B1 and 2E1 from rat liver microsomes resulted in co-purification of cytochrome b5 with cytochrome P-450 forms 2B1 and 2E1 but not 1A1. This specificity was evaluated in conjunction with multiple sequence alignment of the three cytochrome P-450s and a molecular model of the cytochrome P-450-cytochrome b5 complex [(1989) Biochemistry 28, 8201-8205]. These analyses suggest two basic residues in the arginine cluster region of P-450, which are present in P-450s 2B1 and 2E1 but are absent in P-450 1A1, as potential binding sites for cytochrome b5.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Citocromos b5/metabolismo , Sequência de Aminoácidos , Animais , Citocromo P-450 CYP1A1 , Citocromo P-450 CYP2B1 , Citocromo P-450 CYP2E1 , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/isolamento & purificação , Citocromos b5/química , Citocromos b5/isolamento & purificação , Masculino , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Dados de Sequência Molecular , Oxirredutases/química , Oxirredutases/isolamento & purificação , Oxirredutases/metabolismo , Oxirredutases N-Desmetilantes/química , Oxirredutases N-Desmetilantes/isolamento & purificação , Oxirredutases N-Desmetilantes/metabolismo , Ratos , Ratos Sprague-Dawley , Alinhamento de SequênciaRESUMO
This study compares the prevalence of elevated serological levels of erbB-2 and myc proteins in 36 breast cancer patients and 25 healthy, ambulatory female controls. The controls were frequency matched to the cases by age and ethnicity. Oncoprotein levels were determined blind to the "case-control status" of the individual from whom the specimen was derived. Corresponding tissue levels were examined in tumors of the 13 cases from whom sufficient tissue was available. Serum oncoproteins were elevated as follows: erbB-2 in one control (4%) compared with nine cases (25%; PFisher's exact = 0.03); myc in no control (0%) compared with seven cases (19%; PFisher's exact = 0.02). Elevated serum levels of erbB-2 or myc oncoproteins were detected in four of the seven cases (57.1%) of in situ cancer without evidence of infiltration. In all cases with elevated serum oncoproteins where tumor tissue was available, the corresponding protein was elevated in the tumor. The three cases who had elevated preoperative serum oncoprotein levels and from whom it was possible to procure postoperative specimens had normal postoperative serum oncoprotein levels. We conclude that (a) erbB-2 and myc oncoproteins are elevated in a proportion of breast cancer patients, (b) the tumor seems to be the source of the serum elevation, and (c) these proteins may be useful as part of a panel of biomarkers of early malignant disease.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Proteínas Oncogênicas Virais/análise , Proteínas Proto-Oncogênicas c-myc/análise , Adulto , Idoso , Neoplasias da Mama/sangue , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/química , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Immunoblotting , Metástase Linfática , Pessoa de Meia-Idade , Prevalência , Receptor ErbB-2RESUMO
More than 1/3 of all non-small cell lung carcinoma (NSCLC) patients present with locally advanced non-metastatic disease. Despite radiation therapy and surgery the survival of these patients remains poor. In an effort to improve upon these results 33 clinical Stage III M0 patients from April 1985 through September 1986 were entered into a Phase II study at Rush-Presbyterian-St. Luke's Medical Center. Treatment included 5-FU by continuous infusion, VP-16, cisplatin and concurrent split course radiation therapy followed by surgical resection when possible. The overall clinical response rate is 74%. Fifty-seven percent of the preoperative group of patients went to surgery with a 100% resectability rate. These patients had a 50% pathologic complete response with no tumor found in the resected specimen. All surgical margins were free of disease and there were no operative deaths. This concurrent combined modality therapy is feasible with the major toxicities being leukopenia, nausea, and vomiting. With an overall median follow-up of 15 months, 36% of the patients remain alive. Overall local control is 71%. Actuarial observed 2 yr. survival is 33% and the median survival is 15 months. Histologic complete response appears to be an early indicator of the efficacy of this treatment regime. With 83% of the resected pathologic complete responders alive without evidence of disease, this preoperative combined modality therapy offers an appealing approach.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Adenocarcinoma/cirurgia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Cisplatino/administração & dosagem , Terapia Combinada , Etoposídeo/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-IdadeRESUMO
This study presents the clinicopathologic findings 43 cases of cancer of the gallbladder. Particular attention was paid to the classification of various histologic types along with their distribution by age, sex, race, the presenting symptoms, the presence of gallstones, the occupational history, and the sites of metastases. The most common type was found to be differentiated adenocarcinoma, and the bulk of the cases occurred in elderly white females. Of note was the fact that in 79 per cent of the cases it was possible to identify underlying predisposing circumstances, either cholelithiasis or a positive occupational history. In light of the dismal prognosis associated with this malignant tumor, the identification of such predisposing factors provides an important avenue for the future investigation and prevention of this disease. In addition, in this series, a high rate of multiple primary malignant tumors of different tissues was note. This was attributable to the age and sex distribution of the cases, that is, their being primarily elderly and female. However, this subpopulation of multiple cancers was significantly different with regard to etiologic factors, and this may provide further clues for future preventive measures for this cancer.
Assuntos
Adenocarcinoma/patologia , Neoplasias da Vesícula Biliar/patologia , Adenocarcinoma/etiologia , Adenocarcinoma Mucinoso/etiologia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Papilar/etiologia , Adenocarcinoma Papilar/patologia , Adulto , Fatores Etários , Idoso , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Colelitíase/complicações , Feminino , Neoplasias da Vesícula Biliar/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/complicações , Fatores SexuaisRESUMO
Possible biologically active (receptor-bound) conformations of peptides derived from cholecystokinin (CCK) have been deduced using conformational analysis combined with comparative studies of their biological specificities. Two peptides, the completely active carboxyl terminal heptapeptide from CCK (CCK-7), whose sequence is Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2, and the carboxyl terminal heptapeptide from cerulein (CER-7) which has the same sequence as for CCK-7 except for replacement of Met 2 with a Thr 2, both stimulate peripheral receptors in gall bladder, pancreas, and pylorus in the gastrointestinal system. In contrast, two other very similar peptides, the last four residues of CCK (CCK-4) whose sequence is Trp-Met-Asp-Phe-NH2, and the carboxyl terminal hexapeptide of little gastrin (LGA-6, Tyr-Gly-Trp-Met-Asp-Phe-NH2, i.e., residue 2 deleted relative to CCK-7 and CER-7 sequences), interact specifically with gastrin receptors and not at all or very weakly with peripheral receptors. All of these peptides react with CCK receptors in the central nervous system, especially in forebrain. The results in the GI tract suggest that the peptides active on peripheral receptors adopt structures that are significantly different from those of the peptides that interact with gastrin receptors. We have generated all of the many low energy conformations for each of these peptides. By retaining only the conformations that are the same for peptides within the same group and then rejecting those resulting conformations that are the same for the peptides in the two different groups, we can greatly reduce the possible active conformations for the peptides within each class.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Ceruletídeo/química , Colecistocinina/química , Encefalina Metionina/química , Gastrinas/química , Neuropeptídeos/química , Peptídeos/química , Sequência de Aminoácidos , Ceruletídeo/metabolismo , Colecistocinina/metabolismo , Encefalina Metionina/metabolismo , Gastrinas/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Neuropeptídeos/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos/metabolismo , Conformação Proteica , Receptores da Colecistocinina/metabolismo , Homologia de Sequência de Aminoácidos , Sincalida/metabolismo , Tetragastrina/metabolismoRESUMO
We have obtained evidence that oncogenic and activated normal ras-p21 proteins utilize overlapping but distinct signal transduction pathways. Recently, we found that ras-p21 binds to both jun and its kinase, jun kinase (JNK). We now present evidence that suggests that oncogenic but not normal activated p21 depends strongly on early activation of JNK/jun. This early activation most likely involves direct interaction between oncogenic p21 and JNK/jun because p21 peptides that blocked the binding of p21 to JNK and jun strongly inhibited oncogenic p21-induced oocyte maturation while they did not inhibit insulin-activated normal cellular p21-induced maturation. Very similar results were also obtained for a newly characterized specific inhibitor of JNK which blocked oncogenic but not normal activated p21-induced oocyte maturation. We also found that both jun and JNK strongly enhanced oncogenic p21-induced oocyte maturation while they inhibited insulin-activated normal p21-induced oocyte maturation. These results suggest that the peptides and JNK inhibitor may be useful agents in selectively blocking the effects of oncogenic but not normal p21 in cells.
Assuntos
Genes jun/genética , Proteínas Quinases Ativadas por Mitógeno , Proteína Oncogênica p21(ras)/genética , Proteínas Quinases/genética , Transdução de Sinais/fisiologia , Fatores de Transcrição/genética , Proteínas Virais/genética , Animais , Antineoplásicos , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Escherichia coli/genética , Expressão Gênica , Genes jun/fisiologia , Insulina/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno , Proteína Oncogênica p21(ras)/fisiologia , Oócitos/crescimento & desenvolvimento , Ligação Proteica , Fatores de Transcrição/fisiologia , Proteínas Virais/fisiologia , Xenopus laevisRESUMO
PURPOSE: We have previously found that a synthetic peptide corresponding to ras-p21 residues 96 110 (PNC2) selectively blocks oncogenic (Val 12-containing) ras-p21 protein-induced oocyte maturation. With a view to introducing this peptide into ras-transformed human cells to inhibit their proliferation, we synthesized an inducible plasmid that expressed this peptide sequence. Our purpose was to test this expression system in oocytes to determine if it was capable of causing selective inhibition of oncogenic ras-p21. METHODS: We injected this plasmid and a plasmid expressing a control peptide into oocytes either together with oncogenic p21 or in the presence of insulin (that induces maturation that is dependent on normal cellular ras-p21) in the presence and absence of the inducer isopropylthioglucose (IPTG). RESULTS: Microinjection of this plasmid into oocytes together with Val 12-p21 resulted in complete inhibition of maturation in the presence of inducer. Another plasmid encoding the sequence for the unrelated control peptide, X13, was unable to inhibit Val 12-p21-induced maturation. In contrast, PNC2 plasmid had no effect on the ability of insulin-activated normal cellular or wild-type ras-p21 to induce oocyte maturation, suggesting that it is selective for blocking the mitogenic effects of oncogenic (Val 12) ras p21. CONCLUSION: We conclude that the PNC2 plasmid selectively inhibits oncogenic ras-p21 and may therefore be highly effective in blocking proliferation of ras-induced cancer cells. Also, from the patterns of inhibition, by PNC2 and other ras- and raf-related peptides, of raf- and constitutively activated MEK-induced maturation, we conclude that PNC2 peptide inhibits oncogenic ras p21 downstream of raf.
Assuntos
MAP Quinase Quinase Quinase 1 , Proteína Oncogênica p21(ras)/antagonistas & inibidores , Oócitos/fisiologia , Fragmentos de Peptídeos/genética , Plasmídeos , Sequência de Aminoácidos , Animais , Feminino , Insulina/farmacologia , Dados de Sequência Molecular , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Xenopus laevisRESUMO
PURPOSE: We have previously found that microinjection of activated MEK (mitogen activated kinase kinase) and ERK (mitogen-activated protein; MAP kinase) fails to induce oocyte maturation, but that maturation, induced by oncogenic ras-p21 and insulin-activated cell ras-p21, is blocked by peptides from the ras-binding domain of raf. We also found that jun kinase (JNK), on the stress-activated protein (SAP) pathway, which is critical to the oncogenic ras-p21 signal transduction pathway, is a strong inducer of oocyte maturation. Our purpose in this study was to determine the role of the raf-MEK-MAP kinase pathway in oocyte maturation and how it interacts with JNK from the SAP pathway. METHODS: We microinjected raf dominant negative mutant mRNA (DN-raf) and the MEK-specific phosphatase, MKP-T4, either together with oncogenic p21 or c-raf mRNA, into oocytes or into oocytes incubated with insulin to determine the effects of these raf-MEK-MAP kinase pathway inhibitors. RESULTS: We found that oocyte maturation induced by both oncogenic and activated normal p21 is inhibited by both DN-raf and by MKP-T4. The latter more strongly blocks the oncogenic pathway. Also an mRNA encoding a constitutively activated MEK strongly induces oocyte maturation that is not inhibited by DN-raf or by MKP-T4. Surprisingly, we found that oocyte maturation induced by JNK is blocked both by DN-raf and MKP-T4. Furthermore, we discovered that c-raf induces oocyte maturation that is inhibited by glutathione-S-transferase (GST), which we have found to be a potent and selective inhibitor of JNK. CONCLUSION: We conclude that there is a strong reciprocal interaction between the SAP pathway involving JNK and the raf-MEK-MAP kinase pathway and that oncogenic ras-p21 can be preferentially inhibited by MEK inhibitors. The results imply that blockade of both MEK and JNK-oncogenic ras-p21 interactions may constitute selective synergistic combination chemotherapy against oncogenic ras-induced tumors.