RESUMO
Early-life adversity, even when transient, can have lasting effects on individual phenotypes and reduce lifespan across species. If these effects can be mitigated by a high-quality later-life environment, then differences in future resources may explain variable resilience to early-life adversity. Using data from over 1000 wild North American red squirrels, we tested the hypothesis that the costs of early-life adversity for adult lifespan could be offset by later-life food abundance. We identified six adversities that reduced juvenile survival in the first year of life, though only one-birth date-had continued independent effects on adult lifespan. We then built a weighted early-life adversity (wELA) index integrating the sum of adversities and their effect sizes. Greater weighted early-life adversity predicted shorter adult lifespans in males and females, but a naturally occurring food boom in the second year of life ameliorated this effect. Experimental food supplementation did not replicate this pattern, despite increasing lifespan, indicating that the buffering effect of a future food boom may hinge on more than an increase in available calories. Our results suggest a non-deterministic role of early-life conditions for later-life phenotype, highlighting the importance of evaluating the consequences of early-life adversity in the context of an animal's entire life course.
Assuntos
Longevidade , Sciuridae , Animais , Masculino , Feminino , Sciuridae/fisiologiaRESUMO
Colonization of urban areas by synanthropic wildlife introduces novel and complex alterations to established ecological processes, including the emergence and spread of infectious diseases. Aggregation at urban resources can increase disease transfer, with wide-ranging species potentially infecting outlying populations. The garrison at the National Training Center, Fort Irwin, California, USA, was recently colonized by mange-infected coyotes (Canis latrans) that also use the surrounding Mojave Desert. This situation provided an ideal opportunity to examine the effects of urban resources on disease dynamics. We evaluated seasonal space use and determined the influence of anthropogenic subsidies, water sources, and prey density on urban resource selection. We found no difference in home range size between healthy and infected individuals, but infected residents had considerably more spatial overlap with one another than healthy residents. All coyotes selected for anthropogenic subsidies during all seasons, while infected coyotes seasonally selected for urban water sources, and healthy coyotes seasonally selected for urban areas with greater densities of natural prey. These results suggest that while all coyotes were selecting for anthropogenic subsidies, infected resident coyotes demonstrated a greater tolerance for other conspecifics, which could be facilitating the horizontal transfer of sarcoptic mange to non-resident coyotes. Conversely, healthy coyotes also selected for natural prey and healthy residents exhibited a lack of spatial overlap with other coyotes suggesting they were not reliant on anthropogenic subsidies and were maintaining territories. Understanding the association between urban wildlife, zoonotic diseases, and urban resources can be critical in determining effective responses for mitigating future epizootics.
Assuntos
Coiotes , Infestações por Ácaros , Humanos , Animais , Coiotes/fisiologia , Comportamento de Retorno ao Território Vital/fisiologia , Estações do Ano , ÁguaRESUMO
Evolutionary endocrinology aims to understand how natural selection shapes endocrine systems and the degree to which endocrine systems themselves can induce phenotypic responses to environmental changes. Such responses may be specialized in that they reflect past selection for responsiveness only to those ecological factors that ultimately influence natural selection. Alternatively, endocrine responses may be broad and generalized, allowing organisms to cope with a variety of environmental changes simultaneously. Here, we empirically tested whether the endocrine response of female North American red squirrels (Tamiasciurus hudsonicus) was specialized or generalized. We first quantified the direction and magnitude of natural selection acting on three female life history traits (parturition date, litter size, offspring postnatal growth rate) during 32 years of fluctuations in four potential ecological agents of selection (food availability, conspecific density, predator abundance, and temperature). Only three of the four variables (food, density, and predators) affected patterns of natural selection on female life history traits. We then quantified fecal glucocorticoid metabolites (FGMs) across 7 years and found that all four environmental variables, regardless of their effects on patterns of selection, were associated with glucocorticoid production. Our results provide support for a generalized, rather than specific, glucocorticoid response to environmental change that can integrate across multiple co-occurring environmental stressors.
Assuntos
Glucocorticoides , Seleção Genética , Animais , Gravidez , Feminino , Sciuridae/fisiologia , Evolução Biológica , Tamanho da Ninhada de Vivíparos/fisiologiaRESUMO
The composition of founding populations plays an important role in colonisation dynamics and can influence population growth during early stages of biological invasion. Specifically, founding populations with small propagules (i.e. low number of founders) are vulnerable to the Allee effect and have reduced likelihood of establishment compared to those with large propagules. The founding sex ratio can also impact establishment via its influence on mating success and offspring production. Our goal was to test the effects of propagule size and sex ratio on offspring production and annual population growth following introductions of a non-native lizard species (Anolis sagrei). We manipulated propagule composition on nine small islands, then examined offspring production, population growth and survival rate of founders and their descendants encompassing three generations. By the third reproductive season, per capita offspring production was higher on islands seeded with a relatively large propagule size, but population growth was not associated with propagule size. Propagule sex ratio did not affect offspring production, but populations with a female-biased propagule had positive growth, whereas those with a male-biased propagule had negative growth in the first year. Populations were not affected by propagule sex ratio in subsequent years, possibly due to rapid shifts towards balanced (or slightly female biased) population sex ratios. Overall, we show that different components of population fitness have different responses to propagule size and sex ratio in ways that could affect early stages of biological invasion. Despite these effects, the short life span and high fecundity of A. sagrei likely helped small populations to overcome Allee effects and enabled all populations to successfully establish. Our rare experimental manipulation of propagule size and sex ratio can inform predictions of colonisation dynamics in response to different compositions of founding populations, which is critical in the context of population ecology and invasion dynamics.
Assuntos
Lagartos , Razão de Masculinidade , Animais , Feminino , Masculino , Dinâmica Populacional , Estações do AnoRESUMO
AbstractLife-history theory predicts that investment in reproduction should increase as future reproductive potential (i.e., residual reproductive value [RRV]) decreases. Researchers have thus intuitively used age as a proxy for RRV and assume that RRV decreases with age when interpreting age-specific investment. Yet age is an imperfect proxy for RRV and may even be a poor correlate in some systems. We used a 31-year study of the nesting ecology of painted turtles (Chrysemys picta) to assess how age and RRV compare in explaining variation in a risky investment behavior. We predicted that RRV would be a better predictor of risky investment than age because RRV accounts for variation in future reproductive potential across life. We found that RRV was high in early life, slowly decreased until midlife, and then steadily decreased to terminal reproduction. However, age predicted risky behavior better than RRV. This finding suggests that stronger correlates of age (e.g., size) may be more responsible for this behavior in turtles. This study highlights that researchers should not assume that age-specific investment is driven by RRV and that future work should quantify RRV to more directly test this key element of life-history theory.
Assuntos
Envelhecimento/fisiologia , Tamanho da Ninhada , Comportamento de Nidação , Reprodução , Tartarugas/fisiologia , Animais , FemininoRESUMO
Increasing urbanization and use of urban areas by synanthropic wildlife has increased human and domestic animal exposure to zoonotic diseases and exacerbated epizootics within wildlife populations. Consequently, there is a need to improve wildlife disease surveillance programs to rapidly detect outbreaks and refine inferences regarding spatiotemporal disease dynamics. Multistate occupancy models can address potential shortcomings in surveillance programs by accounting for imperfect detection and the misclassification of disease states. We used these models to explore the relationship between urbanization, slope, and the spatial distribution of sarcoptic mange in coyotes (Canis latrans) inhabiting Fort Irwin, California, USA. We deployed remote cameras across 180 sites within the desert surrounding the populated garrison and classified sites by mange presence or absence depending on whether a symptomatic or asymptomatic coyote was photographed. Coyotes selected flatter sites closer to the urban area with a high probability of use (0.845, 95% credible interval (CRI): 0.728, 0.944); site use decreased as the distance to urban areas increased (standardized [Formula: see text] = - 1.354, 95% CRI - 2.423, - 0.619). The probability of correctly classifying mange presence at a site also decreased further from the urban area and was probably related to the severity of mange infection. Severely infected coyotes, which were more readily identified as symptomatic, resided closer to the urban area and were most likely dependent on urban resources for survival; urban resources probably contributed to sustaining the disease. Multistate occupancy models represent a flexible framework for estimating the occurrence and spatial extent of observable infectious diseases, which can improve wildlife disease surveillance programs.
Assuntos
Carnívoros , Escabiose , Animais , Animais Selvagens , Coiotes , Humanos , UrbanizaçãoRESUMO
The quantification of repeatability has enabled behavioural and evolutionary ecologists to assess the heritable potential of traits. For behavioural traits that vary across life, age-related variation should be accounted for to prevent biasing the microevolutionary estimate of interest. Moreover, to gain a mechanistic understanding of ontogenetic variation in behaviour, among- and within-individual variance should be quantified across life. We leveraged a 30-year study of painted turtles (Chrysemys picta) to assess how age contributes to variation in the repeatability of nesting behaviours. We found that four components of nesting behaviour were repeatable and that accounting for age increased the repeatability estimate for maternal choice of canopy cover over nests. We detected canalization (diminished within-individual variance with age) of canopy cover choice in a reduced data set despite no shift in repeatability. Additionally, random regression analysis revealed that females became more divergent from each other in their choice of canopy cover with age. Thus, properly modelling age-related variance should more precisely estimate heritable potential, and assessing among- and within-individual variance components in addition to repeatability will offer a more mechanistic understanding of behavioural variation across age.
Assuntos
Envelhecimento/psicologia , Comportamento de Nidação , Tartarugas , Animais , Ecossistema , Feminino , IllinoisRESUMO
Fisherian sex-ratio theory predicts sexual species should have a balanced primary sex ratio. However, organisms with environmental sex determination (ESD) are particularly vulnerable to experiencing skewed sex ratios when environmental conditions vary. Theoretical work has modeled sex-ratio dynamics for animals with ESD with regard to 2 traits predicted to be responsive to sex-ratio selection: 1) maternal oviposition behavior and 2) sensitivity of embryonic sex determination to environmental conditions, and much research has since focused on how these traits influence offspring sex ratios. However, relatively few studies have provided estimates of univariate quantitative genetic parameters for these 2 traits, and the existence of phenotypic or genetic covariances among these traits has not been assessed. Here, we leverage studies on 3 species of reptiles (2 turtle species and a lizard) with temperature-dependent sex determination (TSD) to assess phenotypic covariances between measures of maternal oviposition behavior and thermal sensitivity of the sex-determining pathway. These studies quantified maternal behaviors that relate to nest temperature and sex ratio of offspring incubated under controlled conditions. A positive covariance between these traits would enhance the efficiency of sex-ratio selection when primary sex ratio is unbalanced. However, we detected no such covariance between measures of these categories of traits in the 3 study species. These results suggest that maternal oviposition behavior and thermal sensitivity of sex determination in embryos might evolve independently. Such information is critical to understand how animals with TSD will respond to rapidly changing environments that induce sex-ratio selection.
Assuntos
Evolução Biológica , Desenvolvimento Embrionário , Comportamento Materno , Processos de Determinação Sexual , Razão de Masculinidade , Animais , Meio Ambiente , Feminino , Masculino , Comportamento de Nidação , Característica Quantitativa Herdável , Temperatura , TartarugasRESUMO
Approximately two thirds of migratory songbirds in eastern North America negotiate the Gulf of Mexico (GOM), where inclement weather coupled with no refueling or resting opportunities can be lethal. However, decisions made when navigating such features and their consequences remain largely unknown due to technological limitations of tracking small animals over large areas. We used automated radio telemetry to track three songbird species (Red-eyed Vireo, Swainson's Thrush, Wood Thrush) from coastal Alabama to the northern Yucatan Peninsula (YP) during fall migration. Detecting songbirds after crossing â¼1,000 km of open water allowed us to examine intrinsic (age, wing length, fat) and extrinsic (weather, date) variables shaping departure decisions, arrival at the YP, and crossing times. Large fat reserves and low humidity, indicative of beneficial synoptic weather patterns, favored southward departure across the Gulf. Individuals detected in the YP departed with large fat reserves and later in the fall with profitable winds, and flight durations (mean = 22.4 h) were positively related to wind profit. Age was not related to departure behavior, arrival, or travel time. However, vireos negotiated the GOM differently than thrushes, including different departure decisions, lower probability of detection in the YP, and longer crossing times. Defense of winter territories by thrushes but not vireos and species-specific foraging habits may explain the divergent migratory behaviors. Fat reserves appear extremely important to departure decisions and arrival in the YP. As habitat along the GOM is degraded, birds may be limited in their ability to acquire fat to cross the Gulf.
Assuntos
Tecido Adiposo , Migração Animal/fisiologia , Aves Canoras/fisiologia , Tempo (Meteorologia) , Animais , Golfo do MéxicoRESUMO
The impact of host immunity on outcome in nonsmall cell lung cancer (NSCLC) is controversial. We examined the relationship between lymphoid infiltration patterns in NSCLC and prognosis.Tumour- and stroma-infiltrating CD3(+), CD8(+) and forkhead box P3 (Foxp3)(+) T-lymphocytes were identified using immunohistochemistry and a novel image analysis algorithm to assess total, cytotoxic and regulatory T-lymphocyte counts, respectively, in 196 NSCLC cases. The median cell count was selected as a cut-point to define patient subgroups and the ratio of the corresponding tumour islet:stroma (TI/S) counts was determined.There was a positive association between overall survival and increased CD8(+) TI/S ratio (hazard ratio (HR) for death 0.44, p<0.001) but an inverse relationship between Foxp3(+) TI/S ratio and overall survival (HR 4.86, p<0.001). Patients with high CD8(+) islet (HR 0.48, p<0.001) and Foxp3(+) stromal (HR 0.23, p<0.001) counts had better survival, whereas high CD3(+) and CD8(+) stromal counts and high Foxp3(+) islet infiltration conferred a worse survival (HR 1.55, 2.19 and 3.14, respectively). By multivariate analysis, a high CD8(+) TI/S ratio conferred an improved survival (HR 0.48, p=0.002) but a high Foxp3(+) TI/S ratio was associated with worse survival (HR 3.91, p<0.001).Microlocalisation of infiltrating T-lymphocytes is a powerful predictor of outcome in resected NSCLC.
Assuntos
Adenocarcinoma/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Grandes/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos T Reguladores/imunologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/patologia , Carcinoma de Células Grandes/cirurgia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Estudos de Coortes , Receptores ErbB/genética , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasia Residual , Pneumonectomia , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos , Linfócitos T Reguladores/metabolismo , Carga TumoralRESUMO
Understanding the relationships between environmental variables and wildlife activity is an important part of effective management. The desert tortoise (Gopherus agassizii), an imperiled species of arid environments in the southwest US, may have increasingly restricted windows for activity due to current warming trends. In summer 2013, we deployed 48 motion sensor cameras at the entrances of tortoise burrows to investigate the effects of temperature, sex, and day of the year on the activity of desert tortoises. Using generalized estimating equations, we found that the relative probability of activity was associated with temperature (linear and quadratic), sex, and day of the year. Sex effects showed that male tortoises are generally more active than female tortoises. Temperature had a quadratic effect, indicating that tortoise activity was heightened at a range of temperatures. In addition, we found significant support for interactions between sex and day of the year, and sex and temperature as predictors of the probability of activity. Using our models, we were able to estimate air temperatures and times (days and hours) that were associated with maximum activity during the study. Because tortoise activity is constrained by environmental conditions such as temperature, it is increasingly vital to conduct studies on how tortoises vary their activity throughout the Sonoran Desert to better understand the effects of a changing climate.
Assuntos
Comportamento Animal , Clima Desértico , Tartarugas/fisiologia , Animais , Feminino , Masculino , Atividade Motora , Estações do Ano , TemperaturaRESUMO
With the recent increase in utility-scale wind energy development, researchers have become increasingly concerned how this activity will affect wildlife and their habitat. To understand the potential impacts of wind energy facilities (WEF) post-construction (i.e., operation and maintenance) on wildlife, we compared differences in activity centers and survivorship of Agassiz's desert tortoises (Gopherus agassizii) inside or near a WEF to neighboring tortoises living near a wilderness area (NWA) and farther from the WEF. We found that the size of tortoise activity centers varied, but not significantly so, between the WEF (6.25 ± 2.13 ha) and adjacent NWA (4.13 ± 1.23 ha). However, apparent survival did differ significantly between the habitat types: over the 18-year study period apparent annual survival estimates were 0.96 ± 0.01 for WEF tortoises and 0.92 ± 0.02 for tortoises in the NWA. High annual survival suggests that operation and maintenance of the WEF has not caused considerable declines in the adult population over the past two decades. Low traffic volume, enhanced resource availability, and decreased predator populations may influence annual survivorship at this WEF. Further research on these proximate mechanisms and population recruitment would be useful for mitigating and managing post-development impacts of utility-scale wind energy on long-lived terrestrial vertebrates.
Assuntos
Animais Selvagens/fisiologia , Ecossistema , Arquitetura de Instituições de Saúde , Tartarugas/fisiologia , Vento , Animais , Animais Selvagens/crescimento & desenvolvimento , Clima Desértico , Monitoramento Ambiental , Dinâmica Populacional , Energia Renovável , Sudoeste dos Estados Unidos , Taxa de SobrevidaRESUMO
BACKGROUND & AIMS: With the increasing prevalence of liver disease worldwide, there is an urgent clinical need for reliable methods to diagnose and stage liver pathology. Liver biopsy, the current gold standard, is invasive and limited by sampling and observer dependent variability. In this study, we aimed to assess the diagnostic accuracy of a novel magnetic resonance protocol for liver tissue characterisation. METHODS: We conducted a prospective study comparing our magnetic resonance technique against liver biopsy. The individual components of the scanning protocol were T1 mapping, proton spectroscopy and T2* mapping, which quantified liver fibrosis, steatosis and haemosiderosis, respectively. Unselected adult patients referred for liver biopsy as part of their routine care were recruited. Scans performed prior to liver biopsy were analysed by physicians blinded to the histology results. The associations between magnetic resonance and histology variables were assessed. Receiver-operating characteristic analyses were also carried out. RESULTS: Paired magnetic resonance and biopsy data were obtained in 79 patients. Magnetic resonance measures correlated strongly with histology (r(s)=0.68 p<0.0001 for fibrosis; r(s)=0.89 p<0.001 for steatosis; r(s)=-0.69 p<0.0001 for haemosiderosis). The area under the receiver operating characteristic curve was 0.94, 0.93, and 0.94 for the diagnosis of any degree of fibrosis, steatosis and haemosiderosis respectively. CONCLUSION: The novel scanning method described here provides high diagnostic accuracy for the assessment of liver fibrosis, steatosis and haemosiderosis and could potentially replace liver biopsy for many indications. This is the first demonstration of a non-invasive test to differentiate early stages of fibrosis from normal liver.
Assuntos
Hepatopatias/diagnóstico , Espectroscopia de Ressonância Magnética/métodos , Adolescente , Adulto , Idoso , Biópsia , Fígado Gorduroso/diagnóstico , Feminino , Humanos , Ferro/análise , Fígado/patologia , Cirrose Hepática/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
PURPOSE: To review the reliability of MR imaging features for the purpose of distinguishing lipoma and atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL). MATERIALS AND METHODS: A retrospective review of 87 patients with histologically proven lipomatous tumors was performed. All underwent MR imaging, assessing lipomatous content, septation, and nodules. The associations between these features and tumor diagnosis based on morphology and the presence or absence of MDM2 amplification were explored. The age of the patient and the size and location of the lesion were also recorded for statistical analysis. RESULTS: Of the 87 patients, 54 were classified as lipomas and 33 as ALT/WDL. MR identified ALT/WDL with a sensitivity of 90.9 % (CI 74.5-97.6) and a specificity of 37.0 % (CI 24.6-51.3). The positive and negative predictive values were 46.9 % (CI 34.5-59.7) and 86.9 % (CI 65.3-96.6), respectively. The mean age of patients with ALT/WDL was greater (60 years [range 40-83 years]) than those with lipoma (52 years [range 10-79 years]) (p = 0.025). The mean size of ALT/WDL (18.7 cm [range 5-36 cm]) was significantly greater than lipoma (13.9 cm [range 3-32 cm]) (p = 0.003). Features that increased the likelihood of ALT/WDL included: patient age over 60 years, maximal lesion dimension over 10 cm, location in lower limb, and presence of non-fatty areas, by a factor of 2.61-6.25 times. CONCLUSIONS: ALT/WDL and lipoma have overlapping MR imaging characteristics. The most reliable imaging discriminators of ALT/WDL were size of lesion and lipomatous content, but due to the overlap in the MRI appearances of lipoma and ALT/WDL, discrimination should be based on molecular pathology rather than imaging.
Assuntos
Lipoma/diagnóstico , Lipoma/genética , Lipossarcoma/diagnóstico , Lipossarcoma/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Amplificação de Genes , Humanos , Hibridização in Situ Fluorescente , Lipoma/patologia , Lipossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
This study assessed whether analysis of MDM2 copy number by fluorescence in situ hybridization (FISH) would help distinguish lipomas from atypical lipomatous tumors, otherwise referred to as well-differentiated liposarcomas, using a commercially available MDM2 FISH kit. 227 lipomatous and 201 non-lipomatous tumors were analyzed to assess its sensitivity and specificity. Of 178 mature lipomatous tumors, 86 were classified histologically as lipoma and 92 as atypical lipomatous tumor. Two of the lipomas harboring MDM2 amplification were reclassified as atypical lipomatous tumors. Overall, 13 atypical lipomatous tumors did not reveal MDM2 or CDK4 amplification, although this was reduced to 12 following analysis of multiple slides. Three of these cases revealed very occasional tumor cells harboring high-level MDM2 amplification, two had a dedifferentiated component, and MDM2 amplification was detected when one tumor recurred. The remaining six cases exhibited reactive/inflammatory features and were reclassified as lipomas. The findings indicate that MDM2 amplification is 93.5% sensitive for diagnosing atypical lipomatous tumor. A total of 2 of the 20 dedifferentiated liposarcomas failed to reveal MDM2 amplification. All atypical lipomatous tumors measured >10 cm, two dedifferentiated liposarcoma presented de novo at <10 cm, and ~50% of lipomas measured >10 cm. Spindle cell lipomas, lipoblastomas, hibernomas and pleomorphic liposarcomas did not reveal MDM2 amplification. Of 201 non-lipomatous tumors, eight revealed MDM2 amplification or multiple faint alphoid 12 signals and were reclassified as dedifferentiated liposarcoma. Multiple faint alphoid 12 signals were observed in nine tumors from seven patients, an observation not previously reported on paraffin sections: these included four atypical lipomatous tumors, and three dedifferentiated liposarcomas, one previously diagnosed as a myxofibrosarcoma, all of which also revealed amplification of CDK4, although two lacked MDM2 amplification. MDM2 FISH test is a useful adjunct to histology for distinguishing lipoma from atypical lipomatous tumor. The limitations of molecular genetic tests must be known before introducing them into a clinical service.
Assuntos
DNA Satélite/genética , Amplificação de Genes , Dosagem de Genes , Lipoma/genética , Lipossarcoma/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Neoplasias de Tecidos Moles/genética , Adulto , Idoso , Centrômero/genética , Feminino , Marcadores Genéticos/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Lipoma/diagnóstico , Lipoma/metabolismo , Lipossarcoma/diagnóstico , Lipossarcoma/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/metabolismoRESUMO
Pleomorphic rhabdomyosarcoma is the most common variant of this tumour in adults and has a very poor outcome. Two genes which are known to play a role in rhabdomyosarcoma development are KRas and p53. In the majority of human tumours, p53 abnormalities are point mutations that result in the expression of a mutant form of the protein. It is now hypothesized that these mutant forms of p53 may be playing an oncogenic role, over and above simple loss of the wild-type function. In this study, we use Cre-LoxP technology to develop a novel mouse model of rhabdomyosarcoma, crossing mice expressing a common KRas mutation (G12V) with mice that either lose p53 expression or express a mutant form of p53. We use this model to explore the different effects of p53 loss and mutation in the setting of an activating KRas mutation. We found that either complete loss of p53 (p53(fl/fl)) or the expression of one mutant p53 allele with concomitant loss of the second allele (p53(R172H/+)) resulted in the rapid development of rhabdomyosarcoma in 15/16 and 19/19 mice, respectively. In contrast, there was a marked difference between mice which lose a single copy of p53 (p53(fl/+)) and mice expressing a single copy of mutant p53 (p53(172H/+)). Fourteen out of 16 p53(R172H/) mice developed rhabdomyosarcoma, compared with two out of 31 p53(fl/+) mice. As a consequence of this, p53(fl/+) mice had a median lifespan nearly double that of the p53(R172H/+) mice. To underline the enhanced effect of p53 mutation in tumour progression, metastases were seen only in those mice which expressed the mutant form. These data demonstrate that mutant p53 can co-operate with activated, mutant KRas to influence tumourigenesis and metastatic potential, over and above simple loss of normal protein function.
Assuntos
Genes p53/genética , Mutação Puntual , Rabdomiossarcoma/genética , Neoplasias de Tecidos Moles/genética , Animais , Transformação Celular Neoplásica/genética , Instabilidade Cromossômica , Modelos Animais de Doenças , Perda de Heterozigosidade , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/secundário , Neoplasias de Tecidos Moles/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
False negatives, not detecting things that are actually present, are an important but understudied problem. False negatives are the result of our inability to perfectly detect species, especially those at low density such as endangered species or newly arriving introduced species. They reduce our ability to interpret presence-absence survey data and make sound management decisions (e.g., rapid response). To reduce the probability of false negatives, we need to compare the efficacy and sensitivity of different sampling approaches and quantify an unbiased estimate of the probability of detection. We conducted field experiments in the intertidal zone of New England and New York to test the sensitivity of two sampling approaches (quadrat vs. total area search, TAS), given different target characteristics (mobile vs. sessile). Using logistic regression we built detection curves for each sampling approach that related the sampling intensity and the density of targets to the probability of detection. The TAS approach reduced the probability of false negatives and detected targets faster than the quadrat approach. Mobility of targets increased the time to detection but did not affect detection success. Finally, we interpreted two years of presence-absence data on the distribution of the Asian shore crab (Hemigrapsus sanguineus) in New England and New York, using our probability model for false negatives. The type of experimental approach in this paper can help to reduce false negatives and increase our ability to detect species at low densities by refining sampling approaches, which can guide conservation strategies and management decisions in various areas of ecology such as conservation biology and invasion ecology.
Assuntos
Braquiúros , Modelos Estatísticos , Tamanho da Amostra , Animais , New England , Densidade DemográficaRESUMO
Bone and soft tissue metabolic and neoplastic diseases are increasingly characterized by their molecular signatures. This has resulted from increased knowledge of the human genome, which has contributed to the unraveling of molecular pathways in health and disease. Exploitation of this information has allowed it to be used for practical diagnostic purposes. The aim of the first part of this two-part review is to provide an up-to-date review of molecular genetic investigations that are available and routinely used by specialist musculoskeletal histopathologists in the diagnosis of neoplastic disease. Herein we focus on the benefits of employing well characterized somatic mutations in soft tissue lesions that are commonly employed in diagnostic pathology today. The second part highlights the known somatic and germline mutations implicated in osteoclast-rich lesions of bone, and the genetic changes that disturb phosphate metabolism and result in a variety of musculoskeletal phenotypes. Finally, a brief practical guide of how to use and provide a molecular pathology service is given.
Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Proteínas de Neoplasias/genética , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Biomarcadores Tumorais/análise , Humanos , Proteínas de Neoplasias/análiseRESUMO
The second part of this review, on the benefits of molecular pathology in the diagnosis disease, focuses on the genetics of bone tumors and metabolic disease. Unlike soft tissue tumors, the number of currently exploitable molecular abnormalities for diagnosing bone neoplasms is small, although the same gene rearrangements are found in primitive neuroectodermal tumor/Ewing sarcoma in both skeletal and extraskeletal sites. Compared with soft tissue tumors, genetic abnormalities, which are valuable to diagnosticians in skeletal disease, are often germline and post-zygotic aberrations rather than somatic translocations. In addition, the review highlights the range of disease entities classified as "osteoclast-rich lesions," some of which harbor germline mutations. It also addresses the importance of phosphate metabolism in skeletal disorders including phosphaturic mesenchymal tumor, vitamin D-resistant rickets, and tumoral calcinosis.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Ósseas/diagnóstico , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/metabolismo , Técnicas de Sonda Molecular , Proteínas de Neoplasias/análise , Neoplasias Ósseas/metabolismo , HumanosRESUMO
OBJECTIVE: To report on the biochemistry and clinical and genetic findings of two siblings, the younger sister presenting with recurrent bone pain of the radius and ulna, and medullary sclerosis, and the older brother with soft tissue calcific deposits (tumoral calcinosis) but who later developed bone pain. Both were found to be hyperphosphaturic. MATERIALS AND METHODS: The index family comprised four individuals (father, mother, brother, sister). The affected siblings were the offspring of a non-consanguineous Indian family of Tamil origin. Bidirectional sequencing was performed on the DNA from the index family and on 160 alleles from a population of 80 unrelated unaffected control individuals of Tamil extraction and 72 alleles from individuals of non-Tamil origin. RESULTS: Two symptomatic siblings were found to harbour previously unreported compound heterozygous missense UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3) mutations in exon 4 c.842A>G and exon 5 c.1097T>G. This sequence variation was not detected in the control DNA. This is the first report of siblings exhibiting stigmata of familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome with documented evidence of autosomal recessive missense GALNT3 mutations. CONCLUSION: The findings from this family add further evidence to the literature that familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are manifestations of the same disease and highlight the importance of appropriate metabolic and genetic investigations.