Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner

Previous reports have implicated an induction of genes in IFN/STAT1 (Interferon/STAT1) signaling in radiation resistant and prosurvival tumor phenotypes in a number of cancer cell lines, and we have hypothesized that upregulation of these genes may be predictive of poor survival outcome and/or treatment response in Glioblastoma Multiforme (GBM) patients. We have developed a list of 8 genes related to IFN/STAT1 that we hypothesize to be predictive of poor survival in GBM patients. Our working hypothesis that over-expression of this gene signature predicts poor survival outcome in GBM patients was confirmed, and in addition, it was demonstrated that the survival model was highly subtype-dependent, with strong dependence in the Proneural subtype and no detected dependence in the Classical and Mesenchymal subtypes. We developed a specific multi-gene survival model for the Proneural subtype in the TCGA (the Cancer Genome Atlas) discovery set which we have validated in the TCGA validation set. In addition, we have performed network analysis in the form of Bayesian Network discovery and Ingenuity Pathway Analysis to further dissect the underlying biology of this gene signature in the etiology of GBM. We theorize that the strong predictive value of the IFN/STAT1 gene signature in the Proneural subtype may be due to chemotherapy and/or radiation resistance induced through prolonged constitutive signaling of these genes during the course of the illness. The results of this study have implications both for better prediction models for survival outcome in GBM and for improved understanding of the underlying subtype-specific molecular mechanisms for GBM tumor progression and treatment response.     

The critical-period concept for juvenile survival and its relevance for population regulation in young sea trout, Salmo trutta

An example of density-dependent regulation is provided by a long-term investigation (1966-present) of a population of migratory trout (estuarine and sea trout), Salmo trutta L., in a Lake District stream. Evidence for the concept of a critical period for the survival of young fish is briefly reviewed and found to be rather equivocal. The concept is, however, relevant to the trout population. Loss rates were high before but low after a critical survival time ( t_c days after fry emergence) that varied between year-classes (range 33-70 days) and was inversely density-dependent on egg density. Survivor density and loss rates were strongly density-dependent on egg density before t _c, but proportionate survival with stable loss-rates occurred after t _c. Some trout established feeding territories soon after emergence and the number of fish without territories decreased from a high initial value to a negligible value at t _c. Fish size at t_c was not constant but increased as t _c increased. The range of t _c for the different year-classes was similar to that for survival times of unfed fry in the laboratory. A new stock-recruitment model, incorporating t _c, has been developed for the trout population and shown to be related to the model (Ricker curve) used in the long-term study. The critical time can also be regarded as the critical age for survival in young trout; this concept may be relevant to other fish species.     

Prognostic factors in human primary breast cancer: comparison of c-myc and HER2/neu amplification.

Amplification of oncogenes in primary tumours may have prognostic and/or therapeutic significance for patients with breast cancer. We have studied HER2/neu and c-myc amplification together with steroid receptors in human primary breast tumours and related the outcome with (relapse-free) survival. A strong inverse correlation was found between HER2/neu amplification and the presence of oestrogen and progesterone receptors. Actuarial 5-years survival showed that breast cancer patients with c-myc amplification in their primary tumours experience a shorter relapse-free survival, especially in node-negative and in receptor-positive tumours, whereas HER2/neu amplification may be of prognostic value for overall survival in receptor-negative tumours. Overall, in our hands, c-myc amplification appeared to be a more potent prognosticator than HER2/neu amplification in human primary breast cancer.     

Achieving Better Estimates of Greater Sage-Grouse Chick Survival in Utah

Abstract: Declining sage-grouse (Centrocercus urophasianus) populations may be characterized by poor recruitment largely attributed to low chick survival. However, few published studies have explicitly examined factors that influence chick survival. We used a suture method to radiomark 1-2-day-old sage-grouse chicks (n = 150) in 2005-2006 on Parker Mountain in south-central Utah, USA, and monitored their survival to 42 days. We modeled effects of year, hatch date, chick age, brood-female age, brood-mixing, and arthropod abundance on chick survival. Our best model revealed an average survival estimate of 0.50 days to 42 days, which is the highest level ever documented for this long-lived species. Brood-mixing occurred in 21% (31/146) of chicks and 43% (18/42) of broods we studied. Moreover, yearling females had more chicks leave their broods than did adults. We found that survival may be higher among chicks that switch broods compared to those that stayed with their natal mother until fledging. Thus, brood-mixing may be an adaptive strategy leading to increased sage-grouse chick survival and higher productivity, especially among chicks born to yearling females. Our findings also indicate that arthropod abundance may be an important driver of chick survival, particularly during the early brood-rearing period and, therefore, sage-grouse populations may benefit from a management strategy that attempts to increase arthropod abundance via brood habitat management.     

Mathematical models of bacterial growth,inhibition and death under combined stress conditions

Summary In this report we review the history of growth theories. We show how classical growth models may be derived as special cases of a generic growth rate equation. We show how growth models may be modified to represent survival data. We use linear combinations of growth and survival models to represent complex growth/survival curves and give practical examples utilizing nonlinear regression analysis. We show that traditional methods of estimating D values are inappropriate for complex, multiphasic growth/survival data. We show how such data may be modeled mathematically and illustrate methods for estimating true D values from such data.     

CCL2/CCR2 Chemokine Signaling Coordinates Survival and Motility of Breast Cancer Cells through Smad3 Protein- and p42/44 Mitogen-activated Protein Kinase (MAPK)-dependent Mechanisms

Increased cell motility and survival are important hallmarks of metastatic tumor cells. However, the mechanisms that regulate the interplay between these cellular processes remain poorly understood. In these studies, we demonstrate that CCL2, a chemokine well known for regulating immune cell migration, plays an important role in signaling to breast cancer cells. We report that in a panel of mouse and human breast cancer cell lines CCL2 enhanced cell migration and survival associated with increased phosphorylation of Smad3 and p42/44MAPK proteins. The G protein-coupled receptor CCR2 was found to be elevated in breast cancers, correlating with CCL2 expression. RNA interference of CCR2 expression in breast cancer cells significantly inhibited CCL2-induced migration, survival, and phosphorylation of Smad3 and p42/44MAPK proteins. Disruption of Smad3 expression in mammary carcinoma cells blocked CCL2-induced cell survival and migration and partially reduced p42/44MAPK phosphorylation. Ablation of MAPK phosphorylation in Smad3-deficient cells with the MEK inhibitor U0126 further reduced cell survival but not migration. These data indicate that Smad3 signaling through MEK-p42/44MAPK regulates CCL2-induced cell motility and survival, whereas CCL2 induction of MEK-p42/44MAPK signaling independent of Smad3 functions as an alternative mechanism for cell survival. Furthermore, we show that CCL2-induced Smad3 signaling through MEK-p42/44MAPK regulates expression and activity of Rho GTPase to mediate CCL2-induced breast cancer cell motility and survival. With these studies, we characterize an important role for CCL2/CCR2 chemokine signaling in regulating the intrinsic relationships between breast cancer cell motility and survival with implications on the metastatic process.     

Differential survival in adult Eurasian oystercatchers Haematopus ostralegus

I explored the fitness implications of individual and sex differences in foraging strategy in the Eurasian oystercatcher Haematopus ostralegus by monitoring the survival of individually colour-ringed birds of known sex and known feeding specialisation. Over the period of this study, adult female annual and overwinter survival was significantly lower than adult male survival. However, contrary to previous findings, no differences in survival were found between birds of different feeding specialisations. Lower female survival was not due to sex differences in feeding specialisation. Possible mechanisms for sex differences in survival and the survival implications of different feeding specialisations are discussed. I conclude that sex differences in survival may be due to differences in social status. I also suggest that worm/clam feeders and mussel-stabbers, feeding specialisations previously associated with lower survival rates, may have benefited more than mussel-hammerers from milder winter temperatures in recent years.     

Survival of AIDS according to injecting drug use among Puerto Rican AIDS patients.

This paper aims to: 1/ describe IDU's and non-IDU's according to age, gender, AIDS criteria and antiretroviral therapy; and 2/ assess survival differences between IDU's and non-IDU's according to age, gender, AIDS diagnosis criteria and antiretroviral therapy. This study is a survival study of a longitudinal cohort. The sample was composed of 1,258 AIDS patients of a cohort of HIV-infected adults who sought medical care at either the Immunology clinic of Bayamon or the Ramon Ruiz Arnau University Hospital between 1992 and 1999. The variables studied were: survival time of AIDS, intravenous drug use, age, gender, AIDS defining criteria and antiretroviral therapy (yes/no). The results have been that IDU's had lower survival than non-IDU's. Significant differences in the survival functions (IDU's vs non-IDU's) were found among male patients, older patients, patients with immunological criteria and patients with antiretroviral therapy. The survival among these variables was lower in IDU's than non-IDU's. This study suggested that decreased survival of IDU's may be related to later diagnosis and decreased access to drug therapy. Clinical endeavors should take into consideration the variables related to IDU's survival to develop health programs in order to enhance the quality of life and the survival of the AIDS patients.     

Evolution of delayed reproduction in uncertain environments: a life-history perspective

Environmental uncertainty alone can select for delayed reproduction; however, its relative role in the evolution of delayed reproduction across life histories is not known. Along a life-history spectrum from low-survival/high-fertility species to high-survival/low-fertility species, we show that the latter are more likely to evolve delayed reproduction if fertility varies over time. By contrast, if survival varies over time, low-survival life histories are more likely to evolve delays. If there is variation in both survival and fertility, and if this variation is positively associated, the evolutionarily stable reproductive delay is decreased (relative to independent variation in survival and fertility). Conversely, if variation in survival and fertility is negatively associated, the evolutionarily stable reproductive delay is increased. We further show that environmental uncertainty can drive the evolution of delayed reproduction in an iteroparous organism but only in the special case where juvenile survival is greater than adult survival. For common iteroparous life histories (adult survival > juvenile survival), environmental uncertainty does not select for delayed reproduction. Thus, any benefits that delayed reproduction might have on reproduction or survival could be especially important in explaining the common observation of delayed reproduction in many vertebrates and perennial plants.     

Estimates of Apparent Survival Rates for Forest Birds in Eastern Ecuador

Knowledge of survival rates of Neotropical landbirds remains limited, with estimates of apparent survival available from relatively few sites and species. We used capture–mark–recapture models to estimate apparent survival of 31 species from eastern Ecuador based on data collected from 2001 to 2006. Models assuming constant survival had highest support for 27 species; models incorporating effects of transients were highest for four. Average apparent survival across 30 species of passerines was 0.58 (± 0.02 SE); apparent survival was lower during the first interval after initial capture (φ₁: mean = 0.49 ± 0.03) than during subsequent intervals (φ₂: mean = 0.60 ± 0.02). Apparent survival was similar among three families represented by at least four species (Thamnophilidae: 0.57 ± 0.03, N = 10; Furnariidae: 0.59 ± 0.03, N = 5; Pipridae: 0.56 ± 0.02, N = 4). There was no indication that species that occur in flocks had higher survival than nonflocking species (obligate flock members: 0.57 ± 0.03, N = 10; facultative flock members: 0.56 ± 0.04, N = 5; nonflocking: 0.59 ± 0.03, N = 15). Comparisons of published estimates of apparent survival of tropical species demonstrated substantial differences among species and, in some cases, within species across different sites in the Neotropics. Our results support previous studies that concluded that early estimates of high (> 85%) survival in tropical birds may not be representative of all tropical species. Future studies should focus on understanding factors ( e.g. , life-history traits) that promote differences in survival among species within tropical forests.     

Colony specific variation in the use of a moulting site in the migratory little tern Sterna albifrons

Individual-based data on little terns Sterna albifrons at a post-breeding moulting area were used to investigate the spatial extent at which this site attract birds. Combining information collected on young terns, ringed at the natal colonies, with that on birds captured a few months later at the moulting site, we estimated a survival/movement parameter for each age-by-colony combination. This parameter is the product between the survival probability and the probability to visit the moulting site. The distance between the natal colony and the moulting site negatively influenced the probability of reaching the site in yearlings. Having corrected for the distance from the moulting area, colony characteristics explained only about 10% of the spatial variation in the survival/movement parameter of juveniles. In older birds that had visited the site at least once in their life, neither the colony nor the distance affected the survival/movement parameter significantly. The average annual adult survival/movement probability was 0.90. Juvenile survival between June and September was 0.60. Overall results suggest that the moulting area could act as a 'population funnel' within a system of moult migration that involves birds breeding up to 500 km away. However, other unknown moulting site must exist within this area that could be important for the conservation of the species.     

Quantifying the Effects of Green Crab Damage to Eelgrass Transplants

Mesocosm experiments were conducted in the summer of 1996 to quantify the effect of bioturbation by Carcinus maenas (the introduced European green crab) on survival of transplanted Zostera marina (eelgrass). The research grew out of a successful 2.52 ha eelgrass transplant project in the Great Bay Estuary of New Hampshire. At several subtidal sites, green crabs were found to damage transplanted eelgrass by cutting the shoots to the extent that some sites demonstrated poor survival. In three separate experiments, eight replicate mesocosm tanks were transplanted with 36 shoots of eelgrass, and different crab densities were introduced into the tanks. The number of shoots damaged by crabs was significantly higher in tanks with moderate (4.0 crabs/m²), high (7.0 crabs/m²), or very high (15.0 crabs/m²) crab densities than in tanks with low (1.0 crabs/m²) crab densities. Up to 39% of viable shoots were lost within one week of exposure to green crab activities. The mesocosm results demonstrated that green crabs were not directly attracted to eelgrass but that they significantly decreased transplant survival through their activity. Field densities of green crabs were found to exceed the density at which most damage occurred in the experiments, suggesting that this introduced species can be a major determinant of eelgrass transplant survival. The results underscore the major influence that biological components of transplant sites can have on transplant survival, and the need for their consideration in the site selection process.     

African trypanosomes: inheritance of factors involved in resistance

The C3HeB/FeJ mouse strain has a shorter survival time and is therefore more susceptible to a Trypanosoma brucei rhodesiense infection than the B10.BR/SgSnJ strain. The work reported here demonstrated that survival time is inherited as a recessive trait, whereas the ability to produce antibody to the first variant antigen population is inherited as a dominant trait. It was therefore not possible to correlate survival time with the ability to produce antibody in the F-1 and F-2 offspring. Both characteristics appeared to be multigenic. In addition, it was not possible to link the ability of an animal to control its early parasitemia, or its change in hematocrit, with either antibody production or survival time. The work strongly suggests that the increased survival time of the B10.BR/SgSnJ mouse is due at least partially to nonspecific but unidentified factors which do not segregate with VSG-specific immune responses. These nonspecific factors could include differences in susceptibility to toxic trypanosome catabolites.     

Individual quality, survival variation and patterns of phenotypic selection on body condition and timing of nesting in birds

Questions about individual variation in quality and fitness are of great interest to evolutionary and population ecologists. Such variation can be investigated using either a random effects approach or an approach that relies on identifying observable traits that are themselves correlated with fitness components. We used the latter approach with data from 1,925 individual females of three species of ducks (tufted duck, Aythya fuligula; common pochard, Aythya ferina; northern shoveler, Anas clypeata) sampled on their breeding grounds at Engure Marsh, Latvia, for over 15 years. Based on associations with reproductive output, we selected two traits, one morphological (relative body condition) and one behavioral (relative time of nesting), that can be used to characterize individual females over their lifetimes. We then asked whether these traits were related to annual survival probabilities of nesting females. We hypothesized quadratic, rather than monotonic, relationships based loosely on ideas about the likely action of stabilizing selection on these two traits. Parameters of these relationships were estimated directly using ultrastructural models embedded within capture-recapture-band-recovery models. Results provided evidence that both traits were related to survival in the hypothesized manner. For all three species, females that tended to nest earlier than the norm exhibited the highest survival rates, but very early nesters experienced reduced survival and late nesters showed even lower survival. For shovelers, females in average body condition showed the highest survival, with lower survival rates exhibited by both heavy and light birds. For common pochard and tufted duck, the highest survival rates were associated with birds of slightly above-average condition, with somewhat lower survival for very heavy birds and much lower survival for birds in relatively poor condition. Based on results from this study and previous work on reproduction, we conclude that nest initiation date and body condition covary with both reproductive and survival components of fitness. These associations lead to a positive covariance of these two fitness components within individuals and to the conclusion that these two traits are indeed correlates of individual quality.     

Effects of Continuous Low Dose-Rate Irradiation: Computer Simulations

Abstract. The effects of continuous low dose-rate irradiation are studied with a computer model that incorporates cell kinetics and the accumulation and repair of radiation damage. This theoretical approach independently explores the effects on survival curves of a phase block, inherited damage and proliferation by dying cells. the computer model is a Monte Carlo simulation which follows the evolution in time of the family trees of a growing cell population under continuous irradiation. the model uses as input the measured phase-specific survival curves for acute exposures and the cell kinetic parameters to generate survival curves for continous low dose-rate irradiations. Cell survival curves for Chinese hamster lung cells (V79) for dose rates ranging from 15 to 500 cGy/h have been generated using various model assumptions. the model shows that for these cells a G₂ block will maximize cell killing for an optimum dose rate near 75 cGy/h. the effect on survival curves of inherited damage, as well as that of the proliferation by dying cells, is shown to increase monotonically with decreasing dose rates, and to be quite large at low dose rates.     

Bcl-xL promotes metastasis of breast cancer cells by induction of cytokines resistance

Metastasis is a highly complex process involving the survival of tumor cells, both in the blood stream and within specific organs. Cell-death and survival are determined by a number of gene products from an expanding family of the Bcl-2 gene, either promoting or preventing apoptosis. Furthermore, the survival of tumor cells may favor the accumulation of additional genetic alterations causing further growth and invasive opportunities which may lead to metastasis. To examine whether the prevention of cell-death influences the metastatic behavior, we transfected a human breast cancer cell line MDA-MB-435 with the Bcl-xL cDNA and then studied metastatic ability of the selected clones in vivo. Our results show that Bcl-xL-clones had a decreased tumor growth latency and an increased metastatic ability. Apoptosis-resistance to cytokines was induced in 435 cells by Bcl-xL-expression with minor modifications in their proliferation rates. These cells also showed diminished adhesion to extracellular matrix proteins and a survival advantage in suspension over 435/Neo cells. Moreover, to determine survival in blood stream and in cells lodged in the lungs, we injected 435/Bcl-xL and 435/Neo cells at 1:3 proportion i.v., and animals were killed at intervals of 15' to 16 h after injection. Tumor cells were recovered from the lungs and Southern-blot analysis revealed the presence of exogenous Bcl-xL cDNA. These results showed that 435/Bcl-xL cells had a survival advantage in circulation over 435/Neo cells. This advantage in vivo was attributable to Bcl-xL expression. We conclude that Bcl-xL expression in breast cancer cells can increase metastatic activity. This advantage could be created by inducing resistance to apoptosis against cytokines, increasing cell survival in circulation, and enhancing anchorage-independent growth.     

Nitric Oxide Synthase and Breast Cancer: Role of TIMP-1 in NO-mediated Akt Activation

Prediction of therapeutic response and cancer patient survival can be improved by the identification of molecular markers including tumor Akt status. A direct correlation between NOS2 expression and elevated Akt phosphorylation status has been observed in breast tumors. Tissue inhibitor matrix metalloproteinase-1 (TIMP-1) has been proposed to exert oncogenic properties through CD63 cell surface receptor pathway initiation of pro-survival PI3k/Akt signaling. We employed immunohistochemistry to examine the influence of TIMP-1 on the functional relationship between NOS2 and phosphorylated Akt in breast tumors and found that NOS2-associated Akt phosphorylation was significantly increased in tumors expressing high TIMP-1, indicating that TIMP-1 may further enhance NO-induced Akt pathway activation. Moreover, TIMP-1 silencing by antisense technology blocked NO-induced PI3k/Akt/BAD phosphorylation in cultured MDA-MB-231 human breast cancer cells. TIMP-1 protein nitration and TIMP-1/CD63 co-immunoprecipitation was observed at NO concentrations that induced PI3k/Akt/BAD pro-survival signaling. In the survival analysis, elevated tumor TIMP-1 predicted poor patient survival. This association appears to be mainly restricted to tumors with high NOS2 protein. In contrast, TIMP-1 did not predict poor survival in patient tumors with low NOS2 expression. In summary, our findings suggest that tumors with high TIMP-1 and NOS2 behave more aggressively by mechanisms that favor Akt pathway activation.