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1.
Oecologia ; 192(3): 713-722, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32100152

RESUMO

Population decline and the threat of extinction are realities currently facing many species. Yet, in most cases, the detailed demographic data necessary to identify causes of population decline are unavailable. Using 43 years (1975-2017) of data from a box-nesting population of tree swallows (Tachycineta bicolor), we identified reduced survival of offspring as a probable demographic cause of population decline. Poor fledging success was associated with increased predation and poor weather conditions during early nestling development. Low juvenile survival and subsequent recruitment was linked to poor weather conditions during the post-fledging period and may also be linked to conditions on the wintering grounds. Regional weather conditions during critical stages of breeding (early nestling and post-fledging) have become progressively worse over the 43-year study period. None of the other factors linked to offspring survival have similarly deteriorated. Overall, our results suggest tree swallows should be added to the growing list of species challenged by climate change, and that other species of aerial insect specialists may face similar impacts of climate change.


Assuntos
Andorinhas , Animais , Cruzamento , Mudança Climática , Árvores , Tempo (Meteorologia)
2.
Ann Oncol ; 30(5): 804-814, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30838379

RESUMO

BACKGROUND: The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma. PATIENTS AND METHODS: Somatic mutations were identified in 99/133 (74%) patients through tumor tissue sequencing. Personalized droplet digital PCR (ddPCR) assays were used to detect known mutations in 315 prospectively collected plasma samples from mutation-positive patients. External validation was performed in a prospective independent cohort (n = 29). RESULTS: ctDNA was detected in 37 of 99 (37%) individuals. In 81 patients who did not receive adjuvant therapy, 90% of patients with ctDNA detected at baseline and 100% of patients with ctDNA detected at the postoperative timepoint relapsed at a median follow up of 20 months. ctDNA detection predicted patients at high risk of relapse at baseline [relapse-free survival (RFS) hazard ratio (HR) 2.9; 95% confidence interval (CI) 1.5-5.6; P = 0.002] and postoperatively (HR 10; 95% CI 4.3-24; P < 0.001). ctDNA detection at baseline [HR 2.9; 95% CI 1.3-5.7; P = 0.003 and postoperatively (HR 11; 95% CI 4.3-27; P < 0.001] was also associated with inferior distant metastasis-free survival (DMFS). These findings were validated in the independent cohort. ctDNA detection remained an independent predictor of RFS and DMFS in multivariate analyses after adjustment for disease stage and BRAF mutation status. CONCLUSION: Baseline and postoperative ctDNA detection in two independent prospective cohorts identified stage III melanoma patients at highest risk of relapse and has potential to inform adjuvant therapy decisions.


Assuntos
DNA Tumoral Circulante/sangue , Melanoma/sangue , Recidiva Local de Neoplasia/sangue , Neoplasias Cutâneas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Adulto Jovem , Melanoma Maligno Cutâneo
3.
Proc Biol Sci ; 286(1898): 20190018, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30862285

RESUMO

As species shift their ranges and phenology to cope with climate change, many are left without a ready supply of their preferred food source during critical life stages. Food shortages are often assumed to be driven by reduced total food abundance, but here we propose that climate change may cause short-term food shortages for foraging specialists without affecting overall food availability. We frame this hypothesis around the special case of birds that forage on flying insects for whom effects mediated by their shared food resource have been proposed to cause avian aerial insectivores' decline worldwide. Flying insects are inactive during cold, wet or windy conditions, effectively reducing food availability to zero even if insect abundance remains otherwise unchanged. Using long-term monitoring data from a declining population of tree swallows ( Tachycineta bicolor), we show that nestlings' body mass declined substantially from 1977 to 2017. In 2017, nestlings had lower body mass if it rained during the preceding 3 days, though females increased provisioning rates, potentially in an attempt to compensate. Adult body mass, particularly that of the males, has also declined over the long-term study. Mean rainfall during the nestling period has increased by 9.3 ± 0.3 mm decade-1, potentially explaining declining nestling body mass and population declines. Therefore, we suggest that reduced food availability, distinct from food abundance, may be an important and previously overlooked consequence of climate change, which could be affecting populations of species that specialize on foraging on flying insects.


Assuntos
Reprodução , Andorinhas/fisiologia , Tempo (Meteorologia) , Animais , Feminino , Masculino , Ontário , Dinâmica Populacional , Chuva , Estações do Ano , Andorinhas/crescimento & desenvolvimento
4.
Proc Biol Sci ; 280(1752): 20122434, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23235706

RESUMO

Sperm competition represents an important component of post-copulatory sexual selection. It has been argued that the level of sperm competition declines in birds towards the equator. However, to date, sperm competition estimates have been available mainly for avian species inhabiting the northern temperate zone. Here we apply a novel approach, using the coefficient of between-male variation (CV(bm)) in sperm size as an index for sperm competition risk, in a comparative analysis of 31 Afrotropical and 99 northern temperate zone passerine species. We found no difference in sperm competition risk between the two groups, nor any relationship with migration distance. However, a multivariate model indicated that sperm competition risk was highest in species with a combination of low body mass and few eggs per clutch. The effect of clutch size was most pronounced in tropical species, which indicates that sperm competition risk in tropical and temperate species is differently associated with particular life-history traits. Although tropical species had lower sperm competition risk than temperate zone species for overlapping clutch sizes, the idea of a generally reduced risk of sperm competition in tropical birds was not supported by our analysis.


Assuntos
Ecossistema , Passeriformes/fisiologia , Comportamento Sexual Animal , Espermatozoides/fisiologia , Migração Animal , Animais , Tamanho Corporal , Tamanho da Ninhada , Feminino , Masculino , Análise Multivariada , Estações do Ano
5.
Behav Ecol Sociobiol ; 76(5): 61, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35535127

RESUMO

Abstract: In birds with extrapair mating, older males usually have higher fertilization success than younger males. Two hypotheses can potentially explain this pattern: 1) females prefer older, and often more ornamented males, or 2) older males invest more in reproduction and fertility than younger males. Here we studied factors associated with age-related male fertilization success in a population of barn swallows Hirundo rustica in Canada. We document that male fertilization success increased gradually up to a minimum age of four-year old. The age effect was especially strong for the number of extrapair offspring obtained and the occurrence of a second brood. The higher fertilization success of older males was also associated with an early start of breeding in spring. The length of the elongated outermost tail feathers, a postulated male ornament preferred by females, also increased with age (in both sexes), but it was not a significant predictor of male fertilization success within age classes. Male fertility traits, especially testis size, but also sperm motility and sperm velocity, increased significantly across age groups. Our results suggest that the higher fertilization success by older males is due to their higher reproductive investments and that their longer tails are an adaptation to early arrival on the breeding grounds. Significance statement: The barn swallow is a socially monogamous passerine with extensive extrapair mating. We found that males become more successful in siring both withinpair and extrapair offspring as they become older. Their increased fertilization success was associated with a higher reproductive effort as indicated by larger testes, more motile sperm, and an earlier start of breeding in spring. The length of the outer tail feathers increased with age in both sexes, but long tails did not enhance male fertilization success among males of the same age. Long tails are probably an adaptation to rapid migration and earlier arrival on the breeding grounds. Our findings suggest that the commonly observed age-related increase in male fertilization success in passerine birds is better explained by life history theory than by sexual selection theory. Supplementary Information: The online version contains supplementary material available at 10.1007/s00265-022-03170-0.

6.
Ecology ; 92(2): 450-61, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21618924

RESUMO

In seasonal environments, vertebrates are generally thought to time their reproduction so offspring are raised during the peak of food abundance. The mismatch hypothesis predicts that reproductive success is maximized when animals synchronize their reproduction with the food supply. Understanding the mechanisms influencing the timing of reproduction has taken on new urgency as climate change is altering environmental conditions during reproduction, and there is concern that species will not be able to synchronize their reproduction with changing food supplies. Using data from five sites over 24 years (37 site-years), we tested the assumptions of the mismatch hypothesis in the Tree Swallow (Tachycineta bicolor), a widespread aerial insectivore, whose timing of egg-laying has shifted earlier by nine days since the 1950s. Contrary to the mismatch hypothesis, the start of egg-laying was strongly related to food abundance (flying insect biomass) during the laying period and not to timing of the seasonal peak in food supply. In fact, food abundance generally continued to increase throughout the breeding season, and there was no evidence of selection based on the mistiming of laying with the seasonal peak of food abundance. In contrast, there was selection for laying earlier, because birds that lay earlier generally have larger clutches and fledge more young. Overall, initial reproductive decisions in this insectivore appear to be based on the food supply during egg formation and not the nestling period. Thus, the mismatch hypothesis may not apply in environments with relatively constant or abundant food throughout the breeding season. Although climate change is often associated with earlier reproduction, our results caution that it is not necessarily driven by selection for synchronized reproduction.


Assuntos
Ecossistema , Insetos/fisiologia , Comportamento Predatório/fisiologia , Andorinhas/fisiologia , Animais , Comportamento de Nidação , Estações do Ano , Fatores de Tempo
7.
Biol Lett ; 7(6): 944-6, 2011 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-21632615

RESUMO

Variation in baseline glucocorticoid (cort) levels can be attributed, at least in part, to differences in energetic demands confronting individuals. Elevated baseline cort levels are routinely interpreted as indicating individuals in poor condition, with low relative fitness. However, when greater reproductive effort increases energetic demands, individuals with high cort might paradoxically be those with the highest fitness. Here, we experimentally test the hypothesis that increased reproductive demand causes increases in baseline cort (the Cort-Adaptation hypothesis). We measured maternal baseline cort before and after experimentally enlarging and reducing brood sizes in tree swallows (Tachycineta bicolor). Females with experimentally enlarged broods had greater increases in baseline cort and fledged more offspring than females with reduced broods. Additionally, females with greater increases in baseline cort had higher offspring-provisioning rates than females with lower changes in cort. These findings demonstrate that increased reproductive demand can cause increased baseline cort. As yet, we do not know if these increases in cort cause increased allocation of resources towards reproduction, but the positive relationship between parental behaviour and cort suggests that increased cort does not always interfere with reproductive investment, and might instead facilitate it.


Assuntos
Glucocorticoides/sangue , Reprodução , Andorinhas/fisiologia , Adaptação Fisiológica , Animais , Feminino , Masculino , Comportamento Materno , Ontário , Comportamento Paterno , Andorinhas/sangue
8.
Mutat Res ; 708(1-2): 37-43, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21291898

RESUMO

Microsatellites mutate frequently by replication slippage. Empirical evidence shows that the probability of such slippage mutations may increase with the length of the repeat region as well as exposure to environmental mutagens, but the mutation rate can also differ between the male and female germline. It has been hypothesized that more intense sexual selection or sperm competition can also lead to elevated mutation rates, but the empirical evidence is inconclusive. Here, we analyzed the occurrence of germline slippage mutations in the hypervariable pentanucleotide microsatellite locus HrU10 across six species of swallow (Aves: Hirundinidae). These species exhibit marked differences in the length range of the microsatellite, as well as differences in the intensity of sperm competition. We found a strong effect of microsatellite length on the probability of mutation, but no residual effect of species or their level of sperm competition when the length effect was accounted for. Neither could we detect any difference in mutation rate between tree swallows (Tachycineta bicolor) breeding in Hamilton Harbour, Ontario, an industrial site with previous documentation of elevated mutation rates for minisatellite DNA, and a rural reference population. However, our cross-species analysis revealed two significant patterns of sex differences in HrU10 germline mutations: (1) mutations in longer alleles occurred typically in the male germline, those in shorter alleles in the female germline, and (2) male germline mutations were more often expansions than contractions, whereas no directional bias was evident in the female germline. These results indicate some fundamental differences in male and female gametogenesis affecting the probability of slippage mutations. Our study also reflects the value of a comparative, multi-species approach for locus-specific mutation analyses, through which a wider range of influential factors can be assessed than in single-species studies.


Assuntos
Mutação em Linhagem Germinativa , Repetições de Microssatélites/genética , Andorinhas/genética , Animais , Evolução Molecular , Feminino , Marcadores Genéticos , Genética Populacional , Masculino , Ontário , População Rural
9.
Gen Comp Endocrinol ; 163(1-2): 208-13, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19135999

RESUMO

Glucocorticoid (cort) hormones are increasingly applied in studies of free-ranging animals, with elevated baseline cort levels generally assumed to indicate individuals or populations in worse condition and with lower fitness (the Cort-Fitness Hypothesis). The relationship between cort and fitness is rarely validated and studies investigating the cort-fitness relationship often find results inconsistent with the Cort-Fitness Hypothesis. The inconsistency of these studies may result in part from variation in the cort-fitness relationship across life history stages. Here we address the following questions in a two-year study in free-ranging tree swallows (Tachycineta bicolor): (1) Do baseline cort levels correlate with fitness within a life history stage? (2) Does the cort-fitness relationship vary across different life history stages? (3) Does the cort-fitness relationship vary across life history stages within an individual? (4) Does reproductive effort influence cort levels, and do cort levels influence reproductive effort? We measured baseline cort and fitness components in female birds of known breeding stages. We find correlations between baseline cort levels and fitness within some life history stages, but the relationship shifts from negative during early breeding to positive during late breeding, even within the same individuals. A positive relationship between baseline cort and fitness components during the nestling period suggests that reproductive investment may elicit higher cort levels that feedback to reallocate more effort to reproduction during critical periods of nestling provisioning. Our findings provide reason to question the Cort-Fitness Hypothesis, and have implications for the application of cort measures in monitoring the condition of populations of conservation concern.


Assuntos
Glucocorticoides/sangue , Reprodução/fisiologia , Andorinhas/sangue , Andorinhas/fisiologia , Animais , Feminino , Estresse Fisiológico/fisiologia
10.
Evolution ; 62(2): 494-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18070085

RESUMO

Spermatozoa are among the most diversified cells in the animal kingdom, but the underlying evolutionary forces affecting intraspecific variation in sperm morphology are poorly understood. It has been hypothesized that sperm competition is a potent selection pressure on sperm variation within species. Here, we examine intraspecific variation in total sperm length of 22 wild passerine bird species (21 genera, 11 families) in relation to the risk of sperm competition, as expressed by the frequency of extrapair paternity and relative testis size. We demonstrate, by using phylogenetic comparative methods, that between-male variation in sperm length within species is closely and negatively linked to the risk of sperm competition. This relationship was even stronger when only considering species in which data on sperm length and extrapair paternity originated from the same populations. Intramale variation in sperm length within species was also negatively, although nonsignificantly, related to sperm competition risk. Our findings suggest that postcopulatory sexual selection is a powerful evolutionary force reducing the intraspecific phenotypic variation in sperm-size traits, potentially driving the diversification of sperm morphology across populations and species.


Assuntos
Comportamento Competitivo , Variação Genética , Passeriformes/genética , Passeriformes/fisiologia , Comportamento Sexual Animal , Espermatozoides/fisiologia , Animais , Evolução Biológica , Evolução Molecular , Feminino , Fertilização , Masculino , Preferência de Acasalamento Animal , Seleção Genética , Especificidade da Espécie
11.
Sci Rep ; 8(1): 11158, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-30042403

RESUMO

A prospective study explored the heterogeneous nature of metastatic melanoma using Multiplex immunohistochemistry (IHC) and flow cytometry (FACS). Multiplex IHC data quantitated immune subset number present intra-tumoral (IT) vs the tumor stroma, plus distance of immune subsets from the tumor margin (TM). In addition, mIHC showed a close association between the presence of IT CD8+ T cells and PDL1 expression in melanoma, which was more prevalent on macrophages than on melanoma cells. In contrast, FACS provided more detailed information regarding the T cell subset differentiation, their activation status and expression of immune checkpoint molecules. Interestingly, mIHC detected significantly higher Treg numbers than FACS and showed preferential CD4+ T cell distribution in the tumor stroma. Based on the mIHC and FACS data, we provide a model which defines metastatic melanoma immune context into four categories using the presence or absence of PDL1+ melanoma cells and/or macrophages, and their location within the tumor or on the periphery, combined with the presence or absence of IT CD8+ T cells. This model interprets melanoma immune context as a spectrum of tumor escape from immune control, and provides a snapshot upon which interpretation of checkpoint blockade inhibitor (CBI) therapy responses can be built.


Assuntos
Imuno-Histoquímica/métodos , Melanoma/imunologia , Melanoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Citometria de Fluxo , Humanos , Ipilimumab/imunologia , Ipilimumab/uso terapêutico , Ativação Linfocitária , Linfócitos do Interstício Tumoral , Macrófagos/metabolismo , Melanoma/tratamento farmacológico , Metastasectomia , Pessoa de Meia-Idade , Estudos Prospectivos , Estatísticas não Paramétricas , Linfócitos T Reguladores/imunologia , Evasão Tumoral
12.
J Vet Intern Med ; 31(3): 759-763, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28421625

RESUMO

BACKGROUND: Physiologic factors in dogs that might contribute to enhanced platelet yield in platelet concentrates (PCs) are largely unknown. OBJECTIVE: To determine whether individual differences in weight, age, preprocessing blood chemistry, and CBC variables predict the final platelet concentrations in PCs. Our hypotheses were (1) increased lipemic indices would be positively associated with increased platelet concentrations in PCs and (2) increased preprocessing platelet concentrations would be associated with higher platelet concentrations in the PCs. ANIMALS: All blood donation records of dogs from February 2, 2009 through April 1, 2015 at the University of California-Davis Veterinary Blood Bank were examined with 104 cases included in this study. METHODS: In this retrospective study, data were collected from medical records of canine blood donors. Records were reviewed for internal consistency and accuracy and subjects were included in the study if donor screening and donation occurred on the same day and a viable PC was obtained. Univariate and multivariable regressions were used to test the impact that each variable had on the final platelet concentration in PCs. RESULTS: Final platelet concentration in PCs was positively associated with the predonation CBC platelet values (P < .001), lipemic index (P = .01), and phosphorous levels (P = .001). Collectively these 3 variables explained 29% of the variance in platelet concentrations in PCs. CONCLUSIONS AND CLINICAL IMPORTANCE: Future prospective studies are required to determine if canine blood donations from dogs with lipemia yield PCs with higher platelet concentrations without negatively affecting other blood components.


Assuntos
Plaquetas , Cães/sangue , Transfusão de Plaquetas/veterinária , Plaquetoferese/veterinária , Animais , Análise Química do Sangue/veterinária , Doadores de Sangue , Feminino , Masculino , Linhagem , Estudos Retrospectivos
13.
Cytometry B Clin Cytom ; 70(2): 45-55, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16456867

RESUMO

BACKGROUND: Although tumor hypoxia has been associated with a more aggressive phenotype and lower cure rate, there is no consensus as to the method best suited for routine measurement. Binding of the chemical hypoxia marker, pimonidazole, and expression of the endogenous hypoxia markers HIF-1alpha and CAIX were compared for their ability to detect hypoxia in tumor biopsies from 67 patients with advanced carcinoma of the cervix. METHODS: Two biopsies were taken one day after administration of pimonidazole and were analyzed for pimonidazole binding using flow cytometry or immunohistochemistry. CAIX and HIF-1alpha expression and degree of colocalization were measured in sequential antibody-stained sections. Patient subsets were examined for tumor oxygen tension using an Eppendorf electrode, S phase DNA content, or change in HIF-1alpha expression over the course of treatment. RESULTS: Approximately 6% of the tumor area stained positive for pimonidazole, HIF-1alpha, or CAIX. The CAIX positive fraction correlated with the pimonidazole positive fraction (r = 0.60). Weaker but significant correlations were observed between pimonidazole and HIF-1alpha (r = 0.31) and CAIX and HIF-1alpha (r = 0.41). Taking the extent of marker colocalization into consideration increased the confidence that all markers were identifying hypoxic regions. Over 65% of stained areas showed a high degree of colocalization with the other markers. Oxygen microelectrode measurements and S phase fraction were not correlated with the hypoxic fraction measured using the three hypoxia markers. HIF-1alpha levels tended to decrease with time after the start of therapy. CONCLUSIONS: Endogenous hypoxia marker binding shows reasonable agreement, in extent and location, with binding of pimonidazole. CAIX staining pattern is a better match to the pimonidazole staining pattern than is HIF-1alpha, and high CAIX expression in the absence (or low levels) of HIF-1alpha may indicate a different biology.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Anidrases Carbônicas/metabolismo , Hipóxia Celular/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Nitroimidazóis/metabolismo , Oxigênio/metabolismo , Neoplasias do Colo do Útero/metabolismo , Biópsia , Anidrase Carbônica IX , Colo do Útero/metabolismo , Colo do Útero/patologia , DNA de Neoplasias/análise , Eletrodos , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Fase S , Fatores de Tempo , Neoplasias do Colo do Útero/patologia
14.
Cancer Res ; 58(16): 3547-50, 1998 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-9721858

RESUMO

We have used the combination of pimonidazole labeling of hypoxic cells, bromodeoxyuridine labeling of proliferating cells, and cell sorting based on Hoechst 33342 perfusion to directly study hypoxia and proliferation in human tumor xenografts and transplantable murine tumors in vivo. Hypoxia was largely confined to cells in regions with the least perfusion, although in tumors exhibiting transient blood flow, hypoxic cells were not as highly localized. Similarly, proliferation and hypoxia were mutually exclusive except in areas of a tumor subjected to transient changes in perfusion. By determining the clonogenic potential, pimonidazole labeling intensity, and radiosensitivity of sorted tumor cell subpopulations, we have provided direct evidence that pimonidazole identifies hypoxic tumor cells of therapeutic relevance in vivo. Given that pimonidazole exhibits few diffusion or delivery problems and no apparent cytotoxicity, it appears to be a versatile and useful label for hypoxic cells in solid tumors.


Assuntos
Hipóxia Celular , Neoplasias/metabolismo , Nitroimidazóis , Radiossensibilizantes , Animais , Bromodesoxiuridina , Divisão Celular , Separação Celular , Citometria de Fluxo , Humanos , Camundongos , Camundongos SCID , Neoplasias/patologia , Transplante Heterólogo , Células Tumorais Cultivadas
15.
Cancer Res ; 61(24): 8924-9, 2001 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-11751418

RESUMO

The presence of radiation-resistant hypoxic cells in some solid tumors is known to predict for relapse after radiotherapy. Use of an endogenous marker of hypoxia would be a convenient alternative to current methods that measure tumor oxygenation, provided the marker could be shown to reliably identify viable, radiation-resistant, hypoxic cells. Carbonic anhydrase 9 (CA9) is a transmembrane protein overexpressed in a wide variety of tumor types and induced by hypoxia. Using a monoclonal antibody and cell sorting, CA9-positive cells in SiHa cervical carcinoma xenografts growing in immunodeficient mice were found to be clonogenic, resistant to killing by ionizing radiation, and preferentially able to bind the hypoxia marker pimonidazole. CA9 and pimonidazole immunostaining were compared in formalin-fixed sections from tumors of 18 patients undergoing treatment for cancer of the cervix. Excellent colocalization was observed, although the area of the tumor section that bound anti-CA9 antibodies represented double the number of cells that bound anti-pimonidazole antibodies. Occasional regions staining with pimonidazole but not CA9 could be indicative of transient changes in tumor perfusion. Results support the hypothesis that CA9 is a useful endogenous marker of tumor hypoxia.


Assuntos
Antígenos de Neoplasias , Biomarcadores Tumorais/metabolismo , Anidrases Carbônicas , Proteínas de Neoplasias/metabolismo , Oxigênio/metabolismo , Neoplasias do Colo do Útero/enzimologia , Animais , Anidrase Carbônica IX , Hipóxia Celular , Feminino , Glioma/enzimologia , Glioma/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/biossíntese , Transplante de Neoplasias , Nitroimidazóis/metabolismo , Nitroimidazóis/farmacologia , Tolerância a Radiação , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Transplante Heterólogo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapia
16.
Cancer Res ; 58(17): 3765-8, 1998 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-9731480

RESUMO

Hypoxia in human tumors is associated with poor prognosis, but the molecular mechanisms underlying this association are poorly understood. One possibility is that hypoxia is linked to malignant progression through vascular endothelial growth factor (VEGF) induction and the associated angiogenesis and metastasis. The present clinical study measures hypoxia and VEGF expression on a cell-by-cell basis in human squamous cell carcinomas to test the hypothesis that hypoxia and VEGF protein expression are coupled in human tumors. Eighteen patients with invasive squamous cell carcinoma of the uterine cervix and head and neck have been investigated by a quantitative image analysis of immunostained sections from their tumors. The hypoxia marker pimonidazole was used to measure tumor hypoxia, and a commercially available antibody was used to measure VEGF protein expression. A quantitative immunohistochemical comparison of hypoxia and VEGF protein expression revealed no correlation between the two factors.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Hipóxia Celular , Fatores de Crescimento Endotelial/análise , Neoplasias de Cabeça e Pescoço/metabolismo , Linfocinas/análise , Nitroimidazóis/metabolismo , Neoplasias do Colo do Útero/metabolismo , Biomarcadores , Feminino , Humanos , Imuno-Histoquímica , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
17.
Clin Cancer Res ; 6(3): 855-62, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10741707

RESUMO

The objective was to discover whether the oxygen-regulated protein, metallothionein, is expressed in the hypoxic cells of squamous cell carcinomas. Twenty patients with squamous cell carcinoma of the uterine cervix or head and neck were infused with a solution of the hypoxia marker, pimonidazole hydrochloride, at a dose of 0.5 g/m2. The following day, biopsies were collected, formalin fixed, paraffin embedded, and sectioned at 4 microm. Sections from each biopsy were immunostained for pimonidazole binding, metallothioneins I and II, involucrin, and proliferating cell nuclear antigen. A total of 84 biopsies were analyzed. Sixty-four of 84 biopsy sections contained hypoxia. Of the hypoxia-containing sections, 43 of 64 or 67% showed no microregional overlap between hypoxia and metallothionein; 7 of 64 showed overlap; and 14 of 64 showed a combination of overlap and no overlap. On a tumor-by-tumor basis, 5 of 7 head and neck and 7 of 13 cervix tumors showed no overlap between metallothionein and hypoxia at the microregional level. Ranges for the percentage of the area of hypoxia in head and neck (<0.9 to 17%) and cervix (<0.1 to 14%) tumors were similar. In the hypoxia-containing sections, immunostaining for involucrin, a molecular marker for differentiation, overlapped with that for hypoxia in 82% of the cases. The majority of hypoxic cells in squamous cell carcinomas do not express metallothionein protein, although metallothionein is induced by hypoxia in human tumor cells in vitro. Hypoxic cells in human tumors tend to be in regions immunostaining for involucrin, and it seems possible that differentiation of hypoxic cells in squamous cell carcinomas might affect metallothionein I and II expression.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Hipóxia Celular , Neoplasias de Cabeça e Pescoço/metabolismo , Metalotioneína/biossíntese , Neoplasias do Colo do Útero/metabolismo , Biomarcadores/análise , Carcinoma de Células Escamosas/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Metalotioneína/análise , Estadiamento de Neoplasias , Nitroimidazóis/administração & dosagem , Nitroimidazóis/metabolismo , Antígeno Nuclear de Célula em Proliferação/análise , Precursores de Proteínas/análise , Neoplasias do Colo do Útero/patologia
18.
Diabetes Res Clin Pract ; 108(3): 466-72, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25836944

RESUMO

UNLABELLED: Non-alcoholic fatty liver disease (NAFLD) is common in diabetes and obesity but few have clinically significant liver fibrosis. Improved risk-assessment is needed as the commonly used clinical-risk algorithm, the NAFLD fibrosis score (NFS), is often inconclusive. AIMS: To determine whether circulating fibroblast activation protein (cFAP), which is elevated in cirrhosis, has value in excluding significant fibrosis, particularly combined with NFS. METHODS: cFAP was measured in 106 with type 2 diabetes who had transient elastography (Cohort 1) and 146 with morbid obesity who had liver biopsy (Cohort 2). RESULTS: In Cohort 1, cFAP (per SD) independently associated with median liver stiffness (LSM) ≥ 10.3 kPa with OR of 2.0 (95% CI 1.2-3.4), p=0.006. There was 0.12 OR (95% CI 0.03-0.61) of LSM ≥ 10.3 kPa for those in the lowest compared with the highest FAP tertile (p=0.010). FAP levels below 730 pmol AMC/min/mL had 95% NPV for LSM ≥ 10.3 kPa and reclassified 41% of 64 subjects from NFS 'indeterminate-risk' to 'low-risk'. In Cohort 2, cFAP (per SD), associated with 1.7 fold (95% CI 1.1-2.8) increased odds of significant fibrosis (F ≥ 2), p=0.021, and low cFAP reclassified 49% of 73 subjects from 'indeterminate-risk' to 'low-risk'. CONCLUSIONS: Lower cFAP, when combined with NFS, may have clinical utility in excluding significant fibrosis in diabetes and obesity.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Gelatinases/sangue , Cirrose Hepática/etiologia , Proteínas de Membrana/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Obesidade Mórbida/complicações , Serina Endopeptidases/sangue , Adulto , Antígenos de Superfície , Biópsia , Técnicas de Imagem por Elasticidade , Endopeptidases , Feminino , Fibroblastos/patologia , Humanos , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações
19.
Front Biosci ; 4: e42-6, 1999 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-10417060

RESUMO

Alcohol treatment results in increases in the release of endotoxin from gut bacteria and membrane permeability of the gut to endotoxin, or both. Females are more sensitive to these changes. Elevated levels of endotoxin activate Kupffer cells to release substances such as eicosanoids, TNF-alpha and free radicals. Prostaglandins increase oxygen uptake and most likely are responsible for the hypermetabolic state in the liver. The increase in oxygen demand leads to hypoxia in the liver, and on reperfusion, alpha-hydroxyethyl free radicals are formed which lead to tissue damage in oxygen-poor pericentral regions of the liver lobule.


Assuntos
Etanol/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Animais , Hipóxia Celular , Endotoxinas/sangue , Etanol/metabolismo , Feminino , Radicais Livres/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/metabolismo , Células de Kupffer/patologia , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Fatores Sexuais
20.
Int J Radiat Oncol Biol Phys ; 10(8): 1337-40, 1984 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-6547938

RESUMO

Glyoxal has been identified as a product in the fragmentation of reduced 2-nitroimidazole radiosensitizers. Quantitative analysis of glyoxal as its bis (2,4-dinitrophenylhydrazone) derivative shows that it is formed in good yield (9-23%) in a variety of 2-nitroimidazoles. In addition to glyoxal a second as-yet-unidentified carbonyl compound, and a series of amines are formed when reduced 2-nitromidazoles fragment in the presence of water. One of the amines derived from misonidazole is identified as 1-amino-3-methoxypropan-2-ol, the product of extensive ring cleavage. Radiation chemical reduction of the 2-nitromidazoles proceeds with the consumption of 3 electrons for each molecule reduced. This could imply that a radical disproportionation or dimerization step is involved in the reductive degradation of 2-nitroimidazoles.


Assuntos
Nitroimidazóis/efeitos da radiação , Aminas , Glioxal , Misonidazol/efeitos da radiação , Oxirredução , Propanolaminas
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