Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: design of the TEXT and SOFT trials

OBJECTIVES In 2003 the International Breast Cancer Study Group (IBCSG) initiated the TEXT and SOFT randomized phase III trials to answer two questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer: 1-What is the role of aromatase inhibitors (AI) for women treated with ovarian function suppression (OFS)? 2-What is the role of OFS for women who remain premenopausal and are treated with tamoxifen? METHODS TEXT randomized patients to receive exemestane or tamoxifen with OFS. SOFT randomized patients to receive exemestane with OFS, tamoxifen with OFS, or tamoxifen alone. Treatment was for 5 years from randomization. RESULTS TEXT and SOFT successfully met their enrollment goals in 2011. The 5738 enrolled women had lower-risk disease and lower observed disease-free survival (DFS) event rates than anticipated. Consequently, 7 and 13 additional years of follow-up for TEXT and SOFT, respectively, were required to reach the targeted DFS events (median follow-up about 10.5 and 15 years). To provide timely answers, protocol amendments in 2011 specified analyses based on chronological time and median follow-up. To assess the AI question, exemestane + OFS versus tamoxifen + OFS, a combined analysis of TEXT and SOFT became the primary analysis (n = 4717). The OFS question became the primary analysis from SOFT, assessing the unique comparison of tamoxifen + OFS versus tamoxifen alone (n = 2045). The first reports are anticipated in mid- and late-2014. CONCLUSIONS We present the original designs of TEXT and SOFT and adaptations to ensure timely answers to two questions concerning optimal adjuvant endocrine treatment for premenopausal women with endocrine-responsive breast cancer. Trial Registration TEXT: Clinicaltrials.govNCT00066703 SOFT: Clinicaltrials.govNCT00066690.

Electronic Communications as a Distinct and Unique Object of Regulation

The present paper is an abridged version of the first chapter to the book EC Electronic Communications and Competition Law (London: Cameron May, 2007). It is intended to pinpoint the contours of the communications sector as an object of regulation - an exercise that is essential to any thoughts on appropriate regulatory design. The communications sector is defined through its salient features of being (i) network-bound; (ii) dynamic; (iii) converging; (iv) sensitive to regulation and society’s reactions; and as one (v) with special societal role and as (vi) part of the new economy.

The role of controlled attention and selective encoding for kindergarteners' learning

Selectivity in encoding, aspects of attentional control and their contribution to learning performance were explored in a sample of preschoolers. While the children are performing a learning task, their encoding of relevant and attention towards irrelevant information was recorded through an eye-tracking device. Recognition of target items was used as measure of learning outcome, and individual differences in resistance to interference and inhibition of attention to task-irrelevant stimuli (i.e. distractibility) were used as measures of executive control of attention. Results indicated well-developed selectivity during encoding in young children. Recognition performance was related to selective encoding and aspects of attentional control, explaining individual differences in learning. Copyright © 2011 John Wiley & Sons, Ltd.

Simulating Carbon Stocks and Fluxes of an African Tropical Montane Forest with an Individual-Based Forest Model

Tropical forests are carbon-dense and highly productive ecosystems. Consequently, they play an important role in the global carbon cycle. In the present study we used an individual-based forest model (FORMIND) to analyze the carbon balances of a tropical forest. The main processes of this model are tree growth, mortality, regeneration, and competition. Model parameters were calibrated using forest inventory data from a tropical forest at Mt. Kilimanjaro. The simulation results showed that the model successfully reproduces important characteristics of tropical forests (aboveground biomass, stem size distribution and leaf area index). The estimated aboveground biomass (385 t/ha) is comparable to biomass values in the Amazon and other tropical forests in Africa. The simulated forest reveals a gross primary production of 24 tcha-1yr-1. Modeling above- and belowground carbon stocks, we analyzed the carbon balance of the investigated tropical forest. The simulated carbon balance of this old-growth forest is zero on average. This study provides an example of how forest models can be used in combination with forest inventory data to investigate forest structure and local carbon balances.

Soft gluon resummation in the signal-background interference process of gg(→ h ∗) → ZZ

We present a precise theoretical prediction for the signal-background interference process of gg(→ h ∗) → ZZ, which is useful to constrain the Higgs boson decay width and to measure Higgs couplings to the SM particles. The approximate NNLO K-factor is in the range of 2.05 − 2.45 (1.85 − 2.25), depending on M ZZ , at the 8 (13) TeV LHC. And the soft gluon resummation can increase the approximate NNLO result by about 10% at both the 8 TeV and 13 TeV LHC. The theoretical uncertainties including the scale, uncalculated multi-loop amplitudes of the background and PDF+αs are roughly O(10%) at NNLL′. We also confirm that the approximate K-factors in the interference and the pure signal processes are the same.

A Nicotiana attenuata cell wall invertase inhibitor (NaCWII) reduces growth and increases secondary metabolite biosynthesis in herbivore-attacked plants

Plant invertases are sucrolytic enzymes that are essential for the regulation of carbohydrate metabolism and source–sink relationships. While their activity has been well documented during abiotic and biotic stresses, the role of proteinaceous invertase inhibitors in regulating these changes is unknown. Here, we identify a putative Nicotiana attenuata cell wall invertase inhibitor (NaCWII) which is strongly up-regulated in a jasmonate (JA)-dependent manner following simulated attack by the specialist herbivore Manduca sexta. To understand the role of NaCWII in planta, we silenced its expression by RNA interference and measured changes in primary and secondary metabolism and plant growth following simulated herbivory. NaCWII-silenced plants displayed a stronger depletion of carbohydrates and a reduced capacity to increase secondary metabolite pools relative to their empty vector control counterparts. This coincided with the attenuation of herbivore-induced CWI inhibition and growth suppression characteristic of wild-type plants. Together our findings suggest that NaCWII may act as a regulatory switch located downstream of JA accumulation which fine-tunes the plant's balance between growth and defense metabolism under herbivore attack. Although carbohydrates are not typically viewed as key factors in plant growth and defense, our study shows that interfering with their catabolism strongly influences plant responses to herbivory.

Factors Controlling Species Richness in Alpine Plant Communities: An Assessment of the Importance of Stress and Disturbance

This study explores whether the high variability of vascular plant diversity among alpine plant communities can be explained by stress and/or disturbance intensities. Species numbers of 14 alpine plant communities were sampled in the Swiss Alps. To quantify the intensity of 13 stress and 6 disturbance factors potentially controlling plant life in these communities, a survey was conducted by asking numerous specialists in alpine vegetation to assess the importance of the different factors for each community. The estimated values were combined in stress- and disturbance-indices which were compared with diversity according to the Intermediate Stress Hypothesis, the Intermediate Disturbance Hypothesis, and the Dynamic Equilibrium Model, respectively. Each of these theories explained a part of the variability in the species richness, but only the Dynamic Equilibrium Model provided a complete and consistent explanation. The last model suggests that community species richness within the alpine life zone is generally controlled by stress intensity. Disturbance and competition seem to play a secondary role by fine-tuning diversity in specific communities. As diversity is primarily limited by stress, a moderation of temperature-related stress factors, as a result of global warming, may cause a shift of the equilibrium between stress, disturbance, and competition in alpine ecosystems.

Human rights and international trade

Economic globalization and respect for human rights are both highly topical issues. In theory, more trade should increase economic welfare and protection of human rights should ensure individual dignity. Both fields of law protect certain freedoms: economic development should lead to higher human rights standards, and UN embargoes are used to secure compliance with human rights agreements. However the interaction between trade liberalisation and human rights protection is complex, and recently, tension has arisen between these two areas. Do WTO obligations covering intellectual property prevent governments from implementing their human rights obligations, including rights to food or health? Is it fair to accord the benefits of trade subject to a clean human rights record? This book first examines the theoretical framework of the interaction between the disciplines of international trade law and human rights. It builds upon the well-known debate between Professor Ernst-Ulrich Petersmann, who construes trade obligations as human rights, and Professor Philip Alston, who warns of a merger and acquisition of human rights by trade law. From this starting point, further chapters explore the differing legal matrices of the two fields and examine how cooperation between them might be improved, both in international law-making and institutions,in dispute settlement. The interaction between trade and human rights is then explored through seven case studies:freedom of expression and competition law; IP protection and health; agricultural trade and the right to food; trade restrictions on conflict WHO convention on tobacco control; and, finally, human rights conditionalities in preferential trade schemes.

Wound models for periodontal and bone regeneration: the role of biologic research

The ultimate goals of periodontal therapy remain the complete regeneration of those periodontal tissues lost to the destructive inflammatory-immune response, or to trauma, with tissues that possess the same structure and function, and the re-establishment of a sustainable health-promoting biofilm from one characterized by dysbiosis. This volume of Periodontology 2000 discusses the multiple facets of a transition from therapeutic empiricism during the late 1960s, toward regenerative therapies, which is founded on a clearer understanding of the biophysiology of normal structure and function. This introductory article provides an overview on the requirements of appropriate in vitro laboratory models (e.g. cell culture), of preclinical (i.e. animal) models and of human studies for periodontal wound and bone repair. Laboratory studies may provide valuable fundamental insights into basic mechanisms involved in wound repair and regeneration but also suffer from a unidimensional and simplistic approach that does not account for the complexities of the in vivo situation, in which multiple cell types and interactions all contribute to definitive outcomes. Therefore, such laboratory studies require validatory research, employing preclinical models specifically designed to demonstrate proof-of-concept efficacy, preliminary safety and adaptation to human disease scenarios. Small animal models provide the most economic and logistically feasible preliminary approaches but the outcomes do not necessarily translate to larger animal or human models. The advantages and limitations of all periodontal-regeneration models need to be carefully considered when planning investigations to ensure that the optimal design is adopted to answer the specific research question posed. Future challenges lie in the areas of stem cell research, scaffold designs, cell delivery and choice of growth factors, along with research to ensure appropriate gingival coverage in order to prevent gingival recession during the healing phase.

Pain hypersensitivity and spinal nociceptive hypersensitivity in chronic pain: prevalence and associated factors.

Hypersensitivity of pain pathways is considered a relevant determinant of symptoms in chronic pain patients, but data on its prevalence are very limited. To our knowledge, no data on the prevalence of spinal nociceptive hypersensitivity are available. We studied the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity in 961 consecutive patients with various chronic pain conditions. Pain threshold and nociceptive withdrawal reflex threshold to electrical stimulation were used to assess pain hypersensitivity and spinal nociceptive hypersensitivity, respectively. Using 10th percentile cutoff of previously determined reference values, the prevalence of pain hypersensitivity and spinal nociceptive hypersensitivity (95% confidence interval) was 71.2 (68.3-74.0) and 80.0 (77.0-82.6), respectively. As a secondary aim, we analyzed demographic, psychosocial, and clinical characteristics as factors potentially associated with pain hypersensitivity and spinal nociceptive hypersensitivity using logistic regression models. Both hypersensitivity parameters were unaffected by most factors analyzed. Depression, catastrophizing, pain-related sleep interference, and average pain intensity were significantly associated with hypersensitivity. However, none of them was significant for both unadjusted and adjusted analyses. Furthermore, the odds ratios were very low, indicating modest quantitative impact. To our knowledge, this is the largest prevalence study on central hypersensitivity and the first one on the prevalence of spinal nociceptive hypersensitivity in chronic pain patients. The results revealed an impressively high prevalence, supporting a high clinical relevance of this phenomenon. Electrical pain thresholds and nociceptive withdrawal reflex explore aspects of pain processing that are mostly independent of sociodemographic, psychological, and clinical pain-related characteristics.

Species interactions and random dispersal rather than habitat filtering drive community assembly during early plant succession

Theory on plant succession predicts a temporal increase in the complexity of spatial community structure and of competitive interactions: initially random occurrences of early colonising species shift towards spatially and competitively structured plant associations in later successional stages. Here we use long-term data on early plant succession in a German post mining area to disentangle the importance of random colonisation, habitat filtering, and competition on the temporal and spatial development of plant community structure. We used species co-occurrence analysis and a recently developed method for assessing competitive strength and hierarchies (transitive versus intransitive competitive orders) in multispecies communities. We found that species turnover decreased through time within interaction neighbourhoods, but increased through time outside interaction neighbourhoods. Successional change did not lead to modular community structure. After accounting for species richness effects, the strength of competitive interactions and the proportion of transitive competitive hierarchies increased through time. Although effects of habitat filtering were weak, random colonization and subsequent competitive interactions had strong effects on community structure. Because competitive strength and transitivity were poorly correlated with soil characteristics, there was little evidence for context dependent competitive strength associated with intransitive competitive hierarchies.

The Effects of Density, Spatial Pattern, and Competitive Symmetry on Size Variation in Simulated Plant Populations

Patterns of size inequality in crowded plant populations are often taken to be indicative of the degree of size asymmetry of competition, but recent research suggests that some of the patterns attributed to size‐asymmetric competition could be due to spatial structure. To investigate the theoretical relationships between plant density, spatial pattern, and competitive size asymmetry in determining size variation in crowded plant populations, we developed a spatially explicit, individual‐based plant competition model based on overlapping zones of influence. The zone of influence of each plant is modeled as a circle, growing in two dimensions, and is allometrically related to plant biomass. The area of the circle represents resources potentially available to the plant, and plants compete for resources in areas in which they overlap. The size asymmetry of competition is reflected in the rules for dividing up the overlapping areas. Theoretical plant populations were grown in random and in perfectly uniform spatial patterns at four densities under size‐asymmetric and size‐symmetric competition. Both spatial pattern and size asymmetry contributed to size variation, but their relative importance varied greatly over density and over time. Early in stand development, spatial pattern was more important than the symmetry of competition in determining the degree of size variation within the population, but after plants grew and competition intensified, the size asymmetry of competition became a much more important source of size variation. Size variability was slightly higher at higher densities when competition was symmetric and plants were distributed nonuniformly in space. In a uniform spatial pattern, size variation increased with density only when competition was size asymmetric. Our results suggest that when competition is size asymmetric and intense, it will be more important in generating size variation than is local variation in density. Our results and the available data are consistent with the hypothesis that high levels of size inequality commonly observed within crowded plant populations are largely due to size‐asymmetric competition, not to variation in local density.

How to be in a good shape? The influence of clone morphology on cell competition

Cell competition is a conserved mechanism where slow proliferating cells (so called losers) are eliminated by faster proliferating neighbors (so called winners) through apoptosis.(1) It is an important process which prevents developmental malformations and maintains tissue fitness in aging adults.(2) Recently, we have shown that the probability of elimination of loser cells correlates with the surface of contact between losers and winners in Myc-induced competition.(3) Moreover, we have characterized an active mechanism that increases the surface of contact between losers and winners, hence accelerating the elimination of loser cells. This is the first indication that cell shape and mechanics can influence cell competition. Here, we will discuss the consequence of the relationship between shape and competition, as well as the relevance of this model for other modes of competition.

LeProT1, a Transporter for Proline, Glycine Betaine, and γ-Amino Butyric Acid in Tomato Pollen

During maturation, pollen undergoes a period of dehydration accompanied by the accumulation of compatible solutes.Solute import across the pollen plasma membrane, which occurs via proteinaceous transporters, is required to support pollen development and also for subsequent germination and pollen tube growth. Analysis of the free amino acid composition of various tissues in tomato revealed that the proline content in flowers was 60 times higher than in any other organ analyzed. Within the floral organs, proline was confined predominantly to pollen, where it represented >70 of total free amino acids. Uptake experiments demonstrated that mature as well as germinated pollen rapidly take up proline. To identify proline transporters in tomato pollen, we isolated genes homologous to Arabidopsis proline transporters. LeProT1 was specifically expressed both in mature and germinating pollen, as demonstrated by RNA in situ hybridization. Expression in a yeast mutant demonstrated that LeProT1 transports proline and γ-amino butyric acid with low affinity and glycine betaine with high affinity. Direct uptake and competition studies demonstrate that LeProT1 constitutes a general transporter for compatible solutes.