Asunto(s)
Biomarcadores de Tumor/sangre , Antígeno Ki-1/sangre , Linfoma no Hodgkin/sangre , Receptores de IgE/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Estudios de Seguimiento , Humanos , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/etiología , Masculino , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND: Some patients diagnosed with early-stage lung cancer and treated according to standard care survive for only a short period of time, while others survive for years for reasons that are not well understood. Associations between markers of inflammation and survival from lung cancer have been observed. MATERIALS AND METHODS: Here, we investigate whether circulating levels of 77 inflammatory markers are associated with long versus short survival in stage I and II lung cancer. Patients who had survived either <79 weeks (~1.5 years) (short survivors, SS) or >156 weeks (3 years) (long survivors, LS) were selected from a retrospective population-based study. Logistic regression was used to calculate adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The false discovery rate was calculated to adjust for multiple testing. RESULTS: A total of 157 LS and 84 SS were included in this analysis. Thirteen markers had adjusted OR on the order of 2- to 5-fold when comparing the upper and lower quartiles with regard to the odds of short survival versus long. Chemokine CCL15 [chemokine (C-C motif) ligand 15] was the most significant marker associated with increased odds of short survival (ORs = 4.93; 95% CI 1.90-12.8; q-value: 0.042). Smoking and chronic obstructive pulmonary disease were not associated with marker levels. CONCLUSIONS: Our results provide some evidence that deregulation of inflammatory responses may play a role in the survival of early-stage lung cancer. These findings will require confirmation in future studies.
Asunto(s)
Biomarcadores de Tumor/sangre , Inflamación/sangre , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/mortalidad , Adulto , Anciano , Citocinas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sobrevida , Resultado del TratamientoRESUMEN
The physical demands of rapid and economical running differ from the demands of fighting in ways that may prevent the simultaneous evolution of optimal performance in these two behaviors. Here, we test an hypothesis of functional trade-off in limb bones by measuring mechanical properties of limb bones in two breeds of domestic dog (Canis lupus familiaris L.) that have undergone intense artificial selection for running (greyhound) and fighting (pit bull) performance. The bones were loaded to fracture in three-point static bending. To correct for the effect of shear, we estimated the shear stress in the cross section and added energy due to shear stress to the tensile energy. The proximal limb bones of the pit bulls differed from those of the greyhounds in having relatively larger second moments of area of mid-diaphyseal cross sections and in having more circular cross-sectional shape. The pit bulls exhibited lower stresses at yield, had lower elastic moduli and failed at much higher levels of work. The stiffness of the tissue of the humerus, radius, femur and tibia was 1.5-2.4-fold greater in the greyhounds than in the pit bulls. These bones from the pit bulls absorbed 1.9-2.6-fold more energy before failure than did those of the greyhounds. These differences between breeds were not observed in the long bones of the feet, metacarpals and metatarsals. Nevertheless, the results of this analysis suggest that selection for high-speed running is associated with the evolution of relatively stiff, brittle limb bones, whereas selection for fighting performance leads to the evolution of limb bones with relatively high resistance to failure.
Asunto(s)
Adaptación Biológica/fisiología , Conducta Agonística/fisiología , Perros/anatomía & histología , Perros/fisiología , Extremidades/fisiología , Locomoción/fisiología , Animales , Fenómenos Biomecánicos , Extremidades/anatomía & histología , Fémur/anatomía & histología , Fémur/fisiología , Húmero/anatomía & histología , Húmero/fisiología , Huesos del Metacarpo/anatomía & histología , Huesos del Metacarpo/fisiología , Huesos Metatarsianos/anatomía & histología , Huesos Metatarsianos/fisiología , Radio (Anatomía)/anatomía & histología , Radio (Anatomía)/fisiología , Tibia/anatomía & histología , Tibia/fisiologíaRESUMEN
A great deal of enthusiasm is being generated for TRAIL (TNF-related apoptosis-inducing ligand)/Apo-2L as a tumor therapeutic agent because it is cytotoxic to a variety of tumor cell types but not normal cells. Moreover, it is well documented that TRAIL/Apo-2L-induced tumor cell death is a caspase-dependent apoptotic process. Through the use of a transfected cell line expressing murine TRAIL/Apo-2L and a recombinant adenovirus encoding the murine TRAIL/Apo-2L cDNA (Ad5-mTRAIL) against two murine tumor cell lines [TRAMP-C2 (prostate adenocarcinoma) and Renca (renal adenocarcinoma)], we found that mTRAIL/Apo-2L also can kill tumor cells by inducing necrosis. Specifically, we observed the default method of mTRAIL/Apo-2L-induced death in TRAMP-C2 cells was via a necrotic process, characterized by the complete lack of an annexin V(+)/PI(-) population, SAPK/JNK phosphorylation, caspase activation, Bid cleavage, or cytochrome c release. Moreover, the inclusion of zVAD-fmk, an inhibitor of caspase activation, markedly enhanced mTRAIL/Apo-2L-mediated killing of TRAMP-C2. In contrast, apoptosis was induced in TRAMP-C2 using TNF, as measured by the criteria listed above, as was Renca by mTRAIL/Apo-2L. These results demonstrate the natural occurrence of both TRAIL/Apo-2L-induced apoptotic and necrotic signaling mechanisms within tumor cells.
Asunto(s)
Apoptosis/fisiología , Glicoproteínas de Membrana/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis , Glicoproteínas de Membrana/genética , Ratones , Microscopía Electrónica , Ligando Inductor de Apoptosis Relacionado con TNF , Transfección , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The cobalt(II) urease model complex [Co(2)(mu-OAc)(3)(urea)(tmen)(2)][OTf] (2) prepared from the cobalt model hydrolase [Co(2)(mu-H(2)O)(mu-OAc)(2)(OAc)(2)(tmen)(2)] (1) undergoes facile reaction with acetohydroxamic acid (AHA) to give the monobridged hydroxamate complex [Co(2)(mu-OAc)(2)(mu-AA)(urea)(tmen)(2)][OTf]( )()(3) while 1 gives the dibridged hydroxamate complex [Co(2)(mu-OAc)(mu-AA)(2)(tmen)(2)][OTf] (4). The structures and Co-Co distances of the hydroxamate derivatives of 1 and 2 are very close to those of their nickel analogues and suggest that hydroxamic acids can also inhibit cobalt-based hydrolases as well as inhibiting urease. 1 also reacts with glutarodihydroxamic acid (gluH(2)A(2)) to eliminate hydroxylamine with formation of [Co(2)(mu-OAc)(2)[mu-O(N) (OC)(2)(CH(2))(3)](tmen)(2)][OTf] (5), the structure of which is very close to that of its nickel analogue. Both 1 and 3 show weak antiferromagnetic coupling. Oxidation of 1 with H(2)O(2) gives three dicobalt(III) hydroxy complexes (7-9), the first of which [Co(2)(mu-OAc)(2)(OAc)(2)(mu-OH)(tmen)(2)][OTf] (7) contains a bridging hydroxyl and the second [Co(2)(mu-OAc)(2)(OAc)(mu-OH)(OH)(tmen)(2)][OTf] (8) containing both a bridging and terminal hydroxyl, while the third [Co(2)(mu-OAc) (OAc)(2)(mu-OH)(2)(tmen)(2)][OTf] (9) contains two bridging OH groups with mixed-valence Co(II)/(Co(III) intermediates.
Asunto(s)
Cobalto/química , Hidrolasas/química , Ácidos Hidroxámicos/química , Compuestos Organometálicos/química , Algoritmos , Fenómenos Químicos , Química Física , Cristalografía por Rayos X , Peróxido de Hidrógeno/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Oxidación-Reducción , Espectrofotometría Ultravioleta , Temperatura , Ureasa/químicaRESUMEN
Skeletal muscle is able to respond to a range of stimuli, including stretch and increased load, by increasing in diameter and length in the absence of myofiber division. This type of cellular growth (hypertrophy) is a highly complex process involving division of muscle precursor cells (myoblasts) and their fusion to existing muscle fibers as well as increased protein synthesis and decreased protein degradation. Underlying the alterations in protein levels are increases in a range of specific mRNAs including those coding for structural proteins and proteins that regulate the hypertrophic process. Seven days of passive stretch in vivo of tibialis anterior (TA) muscle has been shown to elicit muscle hypertrophy. We have identified a cDNA corresponding to an mRNA that exhibits increased expression in response to 7 days of passive stretch imposed on TA muscles in vivo. This 944-bp novel murine transcript is expressed primarily in cardiac and skeletal muscle and to a lesser extent in brain. Translation of the transcript revealed an open reading frame of 85 amino acids encoding a nuclear localization signal and two overlapping casein kinase II phosphorylation sites. This gene has been called "small muscle protein (X chromosome)" (Smpx; HGMW-approved human gene symbol SMPX) and we hypothesize that it plays a role in skeletal muscle hypertrophy.
Asunto(s)
Proteínas Musculares , Músculo Esquelético/metabolismo , Porinas/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Western Blotting , Diferenciación Celular/genética , Mapeo Cromosómico , ADN Complementario/química , ADN Complementario/genética , Embrión de Mamíferos/metabolismo , Exones , Regulación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Humanos , Inmunohistoquímica , Intrones , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Músculo Esquelético/citología , Porinas/metabolismo , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Alineación de Secuencia , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Organismos Libres de Patógenos Específicos , Estrés Mecánico , Distribución Tisular , Cromosoma X/genéticaRESUMEN
In response to extended periods of stretch, skeletal muscle typically exhibits cell hypertrophy associated with sustained increases in mRNA and protein synthesis. Several soluble hypertrophic agonists have been identified, yet relatively little is known as to how mechanical load is converted into intracellular signals regulating gene expression or how increased cell size is maintained. In skeletal muscle, hypertrophy is generally regarded as a beneficial adaptive response to increased workload. In some cases, however, hypertrophy can be detrimental as seen in long-term cardiac hypertrophy. Skeletal muscle wasting (atrophy) is a feature of both inherited and acquired muscle disease and normal aging. Elucidating the molecular regulation of cell size is a fundamental step toward comprehending the complex molecular systems underlying muscle hypertrophy and atrophy. Subtractive hybridization between passively stretched and control murine skeletal muscle tissue identified an mRNA that undergoes increased expression in response to passive stretch. Encoded within the mRNA is an open reading frame of 311 amino acids containing a highly conserved type 1 peroxisomal targeting signal and a serine lipase active center. The sequence shows identity to a family of serine hydrolases and thus is named serine hydrolase-like (Serhl). The predicted three-dimensional structure displays a core alpha/beta-hydrolase fold and catalytic triad characteristic of several hydrolytic enzymes. Endogenous Serhl protein immunolocalizes to perinuclear vesicles as does Serhl-FLAG fusion protein transiently expressed in muscle cells in vitro. Overexpression of Serhl-FLAG has no effect on muscle cell phenotype in vitro. Serhl's expression patterns and its response to passive stretch suggest that it may play a role in normal peroxisome function and skeletal muscle growth in response to mechanical stimuli.
Asunto(s)
Proteínas Musculares/genética , Músculo Esquelético/enzimología , Serina Endopeptidasas/análisis , Serina Endopeptidasas/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Técnicas de Cultivo de Célula , Clonación Molecular , ADN , Inducción Enzimática , Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Contracción Muscular , Proteínas Musculares/biosíntesis , Proteínas Musculares/metabolismo , Músculo Esquelético/citología , ARN Mensajero/biosíntesis , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Serina Endopeptidasas/biosíntesis , Serina Endopeptidasas/metabolismoRESUMEN
Mechanically induced hypertrophy of skeletal muscles involves shifts in gene expression leading to increases in the synthesis of specific proteins. Full characterization of the regulation of muscle hypertrophy is a prerequisite for the development of novel therapies aimed at treating muscle wasting (atrophy) in human aging and disease. Using suppression subtractive hybridization, cDNAs corresponding to mRNAs that increase in relative abundance in response to mechanical stretch of mouse skeletal muscles in vivo were identified. A novel 1100-bp transcript was detected exclusively in skeletal muscle. This exhibited a fourfold increase in expression after 7 days of stretch. The transcript had an open reading frame of 328 amino acids encoding an ATP/GTP binding domain, a nuclear localization signal, two PEST protein-destabilization motifs, and a 132-amino-acid ankyrin-repeat region. We have named this gene ankyrin-repeat domain 2 (stretch-responsive muscle) (Ankrd2). We hypothesize that Ankrd2 plays an important role in skeletal muscle hypertrophy.
Asunto(s)
Repetición de Anquirina/genética , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Secuencias de Aminoácidos , Animales , Secuencia de Bases , Diferenciación Celular , Células Cultivadas , Clonación Molecular , ADN Complementario/genética , Exones , Expresión Génica , Biblioteca Genómica , Humanos , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Proteínas Musculares/biosíntesis , Proteínas Musculares/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/embriología , Proteínas Nucleares , Especificidad de Órganos/genética , Regiones Promotoras Genéticas , ARN Mensajero/biosíntesis , Proteínas Represoras , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Aminoácido , Estrés MecánicoRESUMEN
BACKGROUND AND OBJECTIVES: This study provides a unique method for identifying individuals carrying the Rh haplotype cDe, and supports a model for the evolution of Rh haplotypes in which cDe is the progenitor. MATERIALS AND METHODS: DNA from 212 unrelated donors of known Rh serological phenotype was PCR amplified. The resulting products were analysed by denaturing polyacrylamide gel electrophoresis, denaturing gradient gel electrophoresis and DNA sequencing. RESULTS: Two adjacent microsatellite repeat elements of the form (AC)n (GCAC)n were found within the human Rh blood group genes. These display copy number variation which was non-randomly distributed with respect to Rh serological phenotype, and was restricted to alleles of RHCE expressing the c antigen. CONCLUSION: The predominantly Black African allele cDe displayed a unique set of microsatellite alleles, providing a method of identifying individuals carrying this haplotype.
Asunto(s)
Glicoproteínas/sangre , Glicoproteínas/genética , Repeticiones de Microsatélite/inmunología , Proteínas Recombinantes de Fusión , África/etnología , Alelos , Inglaterra/epidemiología , Europa (Continente)/etnología , Salud de la Familia , Haplotipos , Humanos , Intrones , Japón/etnología , Proteínas de Fusión Oncogénica/sangre , Polimorfismo Genético , Sistema del Grupo Sanguíneo Rh-Hr , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido NucleicoRESUMEN
We conducted a prevalence case-control study to investigate the relation between family composition, infection, and development of asthma at age 7-9 years. Potential cases (399) and controls (398) were selected from the Wellington, NZ, arm of the International Study of Asthma and Allergies in Childhood, a population-based prevalence study. Further screening questions restricted cases to children with a diagnosis of asthma and current medication use (N = 233) and restricted controls to children without a history of wheezing and no diagnosis of asthma (N = 241). After controlling for confounders (including infections, atopy, and socioeconomic status), family size was strongly related to asthma. Having no siblings [prevalence odds ratio (POR) = 2.51; 95% confidence interval (CI) = 1.05-6.01] or one sibling (POR = 1.86; 95% CI = 1.14-3.03) was associated with an increased risk of asthma compared with having more than one sibling. Parent-reported rubeola infection (and possibly other similar viral exanthems) was independently associated with a decreased risk of asthma (POR = 0.48; 95% CI = 0.27-0.83), but reported pertussis infection (POR = 1.57; 95% CI = 0.58-4.24) and day care attendance in the first year of life (POR = 1.81; 95% CI = 0.93-3.51) were not strongly associated with increased risks of asthma.
Asunto(s)
Asma/epidemiología , Enfermedades Transmisibles/epidemiología , Composición Familiar , Estudios de Casos y Controles , Niño , Humanos , Nueva Zelanda/epidemiología , Prevalencia , Factores de Riesgo , Pruebas Cutáneas , Factores SocioeconómicosRESUMEN
Almost exactly 50 years ago, R. A. Fisher and R. Race proposed a model for the evolution of the RH (rhesus) genes in which the less common haplotypes were derived from the commoner ones by recombination, and in which the gene order was D-C-E. No direct-evidence bearing on this model was available then, and has not been until now. Here we present evidence for non-reciprocal intergenic exchange (gene conversion) occurring once in human history to generate the common RHCE allele, Ce. We have also used new polymorphisms to construct haplotypes which suggest that intragenic recombination played a major role in the generation of the less common haplotypes, but only if RHD lies 3' of RHCE, i.e. the order is C-E-D. We provide both genetic and physical evidence supporting this arrangement.
Asunto(s)
Evolución Molecular , Sistema del Grupo Sanguíneo Rh-Hr/genética , Secuencia de Bases , Cromosomas Artificiales de Levadura , ADN Complementario , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Haplotipos , Humanos , Intrones , Datos de Secuencia Molecular , Polimorfismo Genético , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
We have studied the arrangement of Rh (rhesus) genes in donors who are completely null for the products of one of them, RHCE. We show that five of six homozygous individuals with the so-called Rh D-- phenotype, who express no red-cell antigens of the C/c and E/e series, have rearranged RHCE genes in which internal sequences have been replaced by the corresponding sequences from RHD. Moreover, although there is heterogeneity at the 3' end, the 5' boundary of this chimerism is within the same small interval around exon 2. This interval is characterized by an exceptionally high degree of sequence homology between RHCE and RHD, a high density of dispersed repetitive elements, and the presence of an alternating purine-pyrimidine copolymer tract. We suggest that these features may explain the mechanistic basis for the origin of the rearrangement.
Asunto(s)
Donantes de Sangre , Reordenamiento Génico , Sistema del Grupo Sanguíneo Rh-Hr/genética , Alelos , Humanos , Fenotipo , Análisis de Secuencia de ADNAsunto(s)
Alérgenos/análisis , Ropa de Cama y Ropa Blanca , Polvo/análisis , Ácaros/inmunología , Animales , Asma/etiología , Plumas , Humanos , Nueva Zelanda , PoliésteresRESUMEN
A wide range of N-substituted mono- and dihydroxamic acids undergo oxygen abstraction on reaction with V(III), V(IV), and Mo(V) compounds to form hydroxamates of V(V) and Mo(VI) respectively together with the corresponding amides and diamides. The molybdenyl and vanadyl hydroxamates form metal-oxygen clusters under FABMS conditions. The X-ray crystal structures of [MoO(2){CH(3)(CH(2))(n)()C(O)N(C(6)H(5))O}(2) (1 and 2) (n = 4, 5) show monomeric structures with structural trans effects and consequent weakening of the Mo-O(ligand) bonds which may account for the tendency to form clusters in FABMS. In constrast, the electrospray MS of the vanadyl dihydroxamates, VO(OH)[PhN(O)C(O)(CH(2))(n)()C(O)N(O)Ph] (n = 3, 5) and VO(OH)[p-CH(3)C(6)H(4)N(O)C(O) (CH(2))(n)()C(O)N(O)C(6)H(4)-CH(3)) (n = 2, 4) show the presence of dimers in solution.
RESUMEN
We describe a PCR-based method of performing RHD and C/c typing in a single reaction. The method is based on an earlier observation of a polymorphism in intron 2 of both genes which, in addition to detecting the RHD deletion responsible for most known D-negative phenotypes, is also associated with C/c serological type. Using this assay, we typed 105 unrelated individuals from at least four different population groups and compared the results to those obtained using conventional serological testing of red cells. An absolute correlation, with no exceptions, was seen. We also showed that the method has potential in the antenatal determination of RH type, as it was possible to type fetal trophoblasts recovered from the endocervical canal at 9 weeks pregnancy.
Asunto(s)
Tipificación y Pruebas Cruzadas Sanguíneas/métodos , ADN/química , Reacción en Cadena de la Polimerasa/métodos , Sistema del Grupo Sanguíneo Rh-Hr/genética , Southern Blotting , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Electroforesis en Gel de Agar , Femenino , Eliminación de Gen , Humanos , Intrones , Hibridación de Ácido Nucleico , Fenotipo , Polimorfismo de Longitud del Fragmento de Restricción , EmbarazoRESUMEN
The use of nitrose compounds and nitrones as spin traps for the detection of short-lived inorganic radicals is discussed. To a certain degree nitrones and nitroso compounds are complementary. While nitroso compounds are superior with respect to spin trapping metal-centred radicals, nitrones form more persistent spin adducts with most small inorganic radicals. Erroneous results may be obtained when hydrolysis and redox reactions involving the spin adducts are ignored. Spin trapping of pseudohalide radicals (.N3, .CN, .SCN) are discussed in more detail.