Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

Background: During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods: Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results: We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion: Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia.

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods: Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results: We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion: Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia

Intensity correlation functions of dye lasers: Comparison of colored-gain-noise and colored-loss-noise models

The intensity correlation functions C(t) for the colored-gain-noise model of dye lasers are analyzed and compared with those for the loss-noise model. For correlation times ¿ larger than the deterministic relaxation time td, we show with the use of the adiabatic approximation that C(t) values coincide for both models. For small correlation times we use a method that provides explicit expressions of non-Markovian correlation functions, approximating simultaneously short- and long-time behaviors. Comparison with numerical simulations shows excellent results simultaneously for short- and long-time regimes. It is found that, when the correlation time of the noise increases, differences between the gain- and loss-noise models tend to disappear. The decay of C(t) for both models can be described by a time scale that approaches the deterministic relaxation time. However, in contrast with the loss-noise model, a secondary time scale remains for large times for the gain-noise model, which could allow one to distinguish between both models.

Integrin-Specific Mechanoresponses to Compression and Extension Probed by Cylindrical Flat-Ended AFM Tips in Lung Cells

Cells from lung and other tissues are subjected to forces of opposing directions that are largely transmitted through integrin-mediated adhesions. How cells respond to force bidirectionality remains ill defined. To address this question, we nanofabricated flat-ended cylindrical Atomic Force Microscopy (AFM) tips with ~1 µm2 cross-section area. Tips were uncoated or coated with either integrin-specific (RGD) or non-specific (RGE/BSA) molecules, brought into contact with lung epithelial cells or fibroblasts for 30 s to form focal adhesion precursors, and used to probe cell resistance to deformation in compression and extension. We found that cell resistance to compression was globally higher than to extension regardless of the tip coating. In contrast, both tip-cell adhesion strength and resistance to compression and extension were the highest when probed at integrin-specific adhesions. These integrin-specific mechanoresponses required an intact actin cytoskeleton, and were dependent on tyrosine phosphatases and Ca2+ signaling. Cell asymmetric mechanoresponse to compression and extension remained after 5 minutes of tip-cell adhesion, revealing that asymmetric resistance to force directionality is an intrinsic property of lung cells, as in most soft tissues. Our findings provide new insights on how lung cells probe the mechanochemical properties of the microenvironment, an important process for migration, repair and tissue homeostasis.

Can genetic algorithms explain experimental anomalies? An application to common property resources

It is common to find in experimental data persistent oscillations in the aggregate outcomes and high levels of heterogeneity in individual behavior. Furthermore, it is not unusual to find significant deviations from aggregate Nash equilibrium predictions. In this paper, we employ an evolutionary model with boundedly rational agents to explain these findings. We use data from common property resource experiments (Casari and Plott, 2003). Instead of positing individual-specific utility functions, we model decision makers as selfish and identical. Agent interaction is simulated using an individual learning genetic algorithm, where agents have constraints in their working memory, a limited ability to maximize, and experiment with new strategies. We show that the model replicates most of the patterns that can be found in common property resource experiments.

Relaxation of selective constraints causes independent selenoprotein extinction in insect genomes

BACKGROUND: Selenoproteins are a diverse family of proteins notable for the presence of the 21st amino acid, selenocysteine. Until very recently, all metazoan genomes investigated encoded selenoproteins, and these proteins had therefore been believed to be essential for animal life. Challenging this assumption, recent comparative analyses of insect genomes have revealed that some insect genomes appear to have lost selenoprotein genes. METHODOLOGY/PRINCIPAL FINDINGS: In this paper we investigate in detail the fate of selenoproteins, and that of selenoprotein factors, in all available arthropod genomes. We use a variety of in silico comparative genomics approaches to look for known selenoprotein genes and factors involved in selenoprotein biosynthesis. We have found that five insect species have completely lost the ability to encode selenoproteins and that selenoprotein loss in these species, although so far confined to the Endopterygota infraclass, cannot be attributed to a single evolutionary event, but rather to multiple, independent events. Loss of selenoproteins and selenoprotein factors is usually coupled to the deletion of the entire no-longer functional genomic region, rather than to sequence degradation and consequent pseudogenisation. Such dynamics of gene extinction are consistent with the high rate of genome rearrangements observed in Drosophila. We have also found that, while many selenoprotein factors are concomitantly lost with the selenoproteins, others are present and conserved in all investigated genomes, irrespective of whether they code for selenoproteins or not, suggesting that they are involved in additional, non-selenoprotein related functions. CONCLUSIONS/SIGNIFICANCE: Selenoproteins have been independently lost in several insect species, possibly as a consequence of the relaxation in insects of the selective constraints acting across metazoans to maintain selenoproteins. The dispensability of selenoproteins in insects may be related to the fundamental differences in antioxidant defense between these animals and other metazoans.

A singular function and its relation with the number systems involved in its definition

Minkowski's ?(x) function can be seen as the confrontation of two number systems: regular continued fractions and the alternated dyadic system. This way of looking at it permits us to prove that its derivative, as it also happens for many other non-decreasing singular functions from [0,1] to [0,1], when it exists can only attain two values: zero and infinity. It is also proved that if the average of the partial quotients in the continued fraction expansion of x is greater than k* =5.31972, and ?'(x) exists then ?'(x)=0. In the same way, if the same average is less than k**=2 log2(F), where F is the golden ratio, then ?'(x)=infinity. Finally some results are presented concerning metric properties of continued fraction and alternated dyadic expansions.

Psychometric characteristics of the Spanish version of instruments to measure neck pain disability

Background: The NDI, COM and NPQ are evaluation instruments for disability due to NP. There was no Spanish version of NDI or COM for which psychometric characteristics were known. The objectives of this study were to translate and culturally adapt the Spanish version of the Neck Disability Index Questionnaire (NDI), and the Core Outcome Measure (COM), to validate its use in Spanish speaking patients with non-specific neck pain (NP), and to compare their psychometric characteristics with those of the Spanish version of the Northwick Pain Questionnaire (NPQ).Methods: Translation/re-translation of the English versions of the NDI and the COM was done blindly and independently by a multidisciplinary team. The study was done in 9 primary care Centers and 12 specialty services from 9 regions in Spain, with 221 acute, subacute and chronic patients who visited their physician for NP: 54 in the pilot phase and 167 in the validation phase. Neck pain (VAS), referred pain (VAS), disability (NDI, COM and NPQ), catastrophizing (CSQ) and quality of life (SF-12) were measured on their first visit and 14 days later. Patients' self-assessment was used as the external criterion for pain and disability. In the pilot phase, patients' understanding of each item in the NDI and COM was assessed, and on day 1 test-retest reliability was estimated by giving a second NDI and COM in which the name of the questionnaires and the order of the items had been changed.Results: Comprehensibility of NDI and COM were good. Minutes needed to fill out the questionnaires [median, (P25, P75)]: NDI. 4 (2.2, 10.0), COM: 2.1 (1.0, 4.9). Reliability: [ICC, (95%CI)]: NDI: 0.88 (0.80, 0.93). COM: 0.85 (0.75,0.91). Sensitivity to change: Effect size for patients having worsened, not changed and improved between days 1 and 15, according to the external criterion for disability: NDI: -0.24, 0.15, 0.66; NPQ: -0.14, 0.06, 0.67; COM: 0.05, 0.19, 0.92. Validity: Results of NDI, NPQ and COM were consistent with the external criterion for disability, whereas only those from NDI were consistent with the one for pain. Correlations with VAS, CSQ and SF-12 were similar for NDI and NPQ (absolute values between 0.36 and 0.50 on day 1, between 0.38 and 0.70 on day 15), and slightly lower for COM (between 0.36 and 0.48 on day 1, and between 0.33 and 0.61 on day 15). Correlation between NDI and NPQ: r = 0.84 on day 1, r = 0.91 on day 15. Correlation between COM and NPQ: r = 0.63 on day 1, r = 0.71 on day 15.Conclusion: Although most psychometric characteristics of NDI, NPQ and COM are similar, those from the latter one are worse and its use may lead to patients' evolution seeming more positive than it actually is. NDI seems to be the best instrument for measuring NP-related disability, since its results are the most consistent with patient's assessment of their own clinical status and evolution. It takes two more minutes to answer the NDI than to answer the COM, but it can be reliably filled out by the patient without assistance.

Immunomodulation by conjugated linoleic acid (CLA) in early life

Conjugated linoleic acid (CLA) has been reported to exert beneficial physiological effects on body composition and the immune system. However, little information is available on the influence of CLA on immune function during early life periods. The present study evaluates the effect of feeding an 80:20 mixture of cis-9,trans-11- and trans-10,cis-12-CLA isomers duringgestation, suckling and early infancy on the systemic and mucosal immune responses of Wistar rats at three different time points: at the end of the suckling period (21-day-old rats), in early infancy (28-day-old rats), and later in life (adulthood). Cis-9,trans-11- and trans-10,cis-12-CLA isomers were detected in the milk of CLA-fed dams and in the plasma of all CLA-supplemented pups, and the highest content was achieved in those rats supplemented over the longest period. Dietary supplementation with that CLA mix enhances the systemic production of the main in vivo and ex vivo immunoglobulin (Ig) isotypes in 21- and 28-day-old rats. Moreover, CLA supplementation during suckling and early infancy also enhances the humoral immune defenses at intestinal level, by means of mucosal IgA increase, whereas down-regulates thesystemic lymphoproliferative response. Finally, we described herein how feeding a diet enriched with the same isomer mix of cis9,trans11- and trans10,cis12-CLA from gestation to adulthood improves the capacity of adult rats to achieve a specific systemic and mucosal immune responses. All these data support the immunomodulatory effects of dietary supplementation of CLA, particularly of the cis9,trans11-CLA isomer, during early stages of life on immune system development, as well as the long-term effects on the specific immune response in adult age.

Contribution of S6K1/MAPK signaling pathways in the response to oxidative stress: activation of RSK and MSK by hydrogen peroxide

Cells respond to different kind of stress through the coordinated activation of signaling pathways such as MAPK or p53. To find which molecular mechanisms are involved, we need to understand their cell adaptation. The ribosomal protein, S6 kinase 1 (S6K1), is a common downstream target of signaling by hormonal or nutritional stress. Here, we investigated the initial contribution of S6K1/MAPK signaling pathways in the cell response to oxidative stress produced by hydrogen peroxide (H2O2). To analyze S6K1 activation, we used the commercial anti-phospho-Thr389-S6K1 antibody most frequently mentioned in the bibliography. We found that this antibody detected an 80-90 kDa protein that was rapidly phosphorylated in response to H2O2 in several human cells. Unexpectedly, this phosphorylation was insensitive to both mTOR and PI3K inhibitors, and knock-down experiments showed that this protein was not S6K1. RSK and MSK proteins were candidate targets of this phosphorylation. We demonstrated that H2O2 stimulated phosphorylation of RSK and MSK kinases at residues that are homologous to Thr389 in S6K1. This phosphorylation required the activity of either p38 or ERK MAP kinases. Kinase assays showed activation of RSK and MSK by H2O2. Experiments with mouse embryonic fibroblasts from p38 animals" knockout confirmed these observations. Altogether, these findings show that the S6K1 signaling pathway is not activated under these conditions, clarify previous observations probably misinterpreted by non-specific detection of proteins RSK and MSK by the anti-phospho-Thr389-S6K1 antibody, and demonstrate the specific activation of MAPK signaling pathways through ERK/p38/RSK/MSK by H2O2.

Elastic properties and secondary structure formation of single-stranded DNA at monovalent and divalent salt conditions

Single-stranded DNA (ssDNA) plays a major role in several biological processes. It is therefore of fundamental interest to understand how the elastic response and the formation of secondary structures are modulated by the interplay between base pairing and electrostatic interactions. Here we measure force-extension curves (FECs) of ssDNA molecules in optical tweezers set up over two orders of magnitude of monovalent and divalent salt conditions, and obtain its elastic parameters by fitting the FECs to semiflexible models of polymers. For both monovalent and divalent salts, we find that the electrostatic contribution to the persistence length is proportional to the Debye screening length, varying as the inverse of the square root of cation concentration. The intrinsic persistence length is equal to 0.7 nm for both types of salts, and the effectivity of divalent cations in screening electrostatic interactions appears to be 100-fold as compared with monovalent salt, in line with what has been recently reported for single-stranded RNA. Finally, we propose an analysis of the FECs using a model that accounts for the effective thickness of the filament at low salt condition and a simple phenomenological description that quantifies the formation of non-specific secondary structure at low forces.

Effect of sex and prior exposure to a cafeteria diet on the distribution of sex hormones between plasma and blood cells

It is generally assumed that steroid hormones are carried in the blood free and/or bound to plasma proteins. We investigated whether blood cells were also able to bind/carry sex-related hormones: estrone, estradiol, DHEA and testosterone. Wistar male and female rats were fed a cafeteria diet for 30 days, which induced overweight. The rats were fed the standard rat diet for 15 additional days to minimize the immediate effects of excess ingested energy. Controls were always kept on standard diet. After the rats were killed, their blood was used for 1) measuring plasma hormone levels, 2) determining the binding of labeled hormones to washed red blood cells (RBC), 3) incubating whole blood with labeled hormones and determining the distribution of label between plasma and packed cells, discounting the trapped plasma volume, 4) determining free plasma hormone using labeled hormones, both through membrane ultrafiltration and dextrancharcoal removal. The results were computed individually for each rat. Cells retained up to 32% estrone, and down to 10% of testosterone, with marked differences due to sex and diet (the latter only for estrogens, not for DHEA and testosterone). Sex and diet also affected the concentrations of all hormones, with no significant diet effects for estradiol and DHEA, but with considerable interaction between both factors. Binding to RBC was non-specific for all hormones. Estrogen distribution in plasma compartments was affected by sex and diet. In conclusion: a) there is a large non-specific RBC-carried compartment for estrone, estradiol, DHEA and testosterone deeply affected by sex; b) Prior exposure to a cafeteria (hyperlipidic) diet induced hormone distribution changes, affected by sex, which hint at sex-related structural differences in RBC membranes; c) We postulate that the RBC compartment may contribute to maintain free (i.e., fully active) sex hormone levels in a way similar to plasma proteins non-specific binding.

Elastic properties and secondary structure formation of single-stranded DNA at monovalent and divalent salt conditions

Single-stranded DNA (ssDNA) plays a major role in several biological processes. It is therefore of fundamental interest to understand how the elastic response and the formation of secondary structures are modulated by the interplay between base pairing and electrostatic interactions. Here we measure force-extension curves (FECs) of ssDNA molecules in optical tweezers set up over two orders of magnitude of monovalent and divalent salt conditions, and obtain its elastic parameters by fitting the FECs to semiflexible models of polymers. For both monovalent and divalent salts, we find that the electrostatic contribution to the persistence length is proportional to the Debye screening length, varying as the inverse of the square root of cation concentration. The intrinsic persistence length is equal to 0.7 nm for both types of salts, and the effectivity of divalent cations in screening electrostatic interactions appears to be 100-fold as compared with monovalent salt, in line with what has been recently reported for single-stranded RNA. Finally, we propose an analysis of the FECs using a model that accounts for the effective thickness of the filament at low salt condition and a simple phenomenological description that quantifies the formation of non-specific secondary structure at low forces.

Pathology and immune response of the blue mussel (Mytilus edulis L.) after an exposure to the harmful dinoflagellate Prorocentrum minimum

The harmful dinoflagellate Prorocentrum minimum has different effects upon various species of grazing bivalves, and these effects also vary with life-history stage. Possible effects of this dinoflagellate upon mussels have not been reported; therefore, experiments exposing adult blue mussels, Mytilus edulis, to P. minimum were conducted. Mussels were exposed to cultures of toxic P. minimum or benign Rhodomonas sp. in glass aquaria. After a short period of acclimation, samples were collected on day 0 (before the exposure) and after 3, 6, and 9 days of continuous-exposure experiment. Hemolymph was extracted for flow-cytometric analyses of hemocyte, immune-response functions, and soft tissues were excised for histopathology. Mussels responded to P. minimum exposure with diapedesis of hemocytes into the intestine, presumably to isolate P. minimum cells within the gut, thereby minimizing damage to other tissues. This immune response appeared to have been sustained throughout the 9-day exposure period, as circulating hemocytes retained hematological and functional properties. Bacteria proliferated in the intestines of the P. minimum-exposed mussels. Hemocytes within the intestine appeared to be either overwhelmed by the large number of bacteria or fully occupied in the encapsulating response to P. minimum cells; when hemocytes reached the intestine lumina, they underwent apoptosis and bacterial degradation. This experiment demonstrated that M. edulis is affected by ingestion of toxic P. minimum; however, the specific responses observed in the blue mussel differed from those reported for other bivalve species. This finding highlights the need to study effects of HABs on different bivalve species, rather than inferring that results from one species reflect the exposure responses of all bivalves.