Prolonged survival of patients receiving trastuzumab beyond disease progression for HER2 overexpressing metastatic breast cancer (MBC)

Background: The aim of this retrospective analysis was to evaluate the impact of trastuzumab-based regimens on the survival of patients with HER2-overexpressing metastatic breast cancer (MBC). The study specifically focussed on the influence of the continuation of trastuzumab-based treatment despite tumor progression on survival. Patients and Methods: Patients with HER2 overexpressing MBC were included in this retrospective analysis. HER2 overexpression was determined by the immunohistochemical staining score (DAKO Hercep Test (TM)). Trastuzumab was applied at a loading dose of 4 mg/kg and a maintenance dose of 2 mg/kg. Results: Among 136 HER2 overexpressing patients (DAKO score 3+), 66 patients received first-line trastuzumab, 47 patients received trastuzumab as second-line therapy and 23 patients received trastuzumab beyond disease progression. There was no significant difference regarding the duration of trastuzumab-based treatment (first-line: 29.5 weeks vs. second-line: 25 weeks). Moreover, there was no difference in the response rate (first-line: 37.9% vs. second-line: 35.7%) or the median survival (p = 0.47 log rank). Patients who received >= 2 trastuzumab-based regimens for MBC survived significantly longer compared to those who had received only 1 regimen (>= 2 regimens: 62.4 months vs. 1 regimen: 38.5 months; p = 0.01 log rank). Conclusions: Trastuzumab is highly effective in the treatment of HER2 overexpressing MBC. Compared to historical controls, overall survival appears to be markedly prolonged, particularly in patients who received sequential trastuzumab-based treatment beyond disease progression

Assessment of Attractiveness of Plants as Roosting Sites for the Melon Fly, Bactrocera cucurbitae, and Oriental Fruit Fly, Bactrocera dorsalis

The use of toxic protein bait sprays to suppress melon fly, Bactrocera cucurbitae (Coquillett) (Diptera: Tephritidae), populations typically involves application to vegetation bordering agricultural host areas where the adults seek shelter (“roost”). Although bait spray applications for suppression of oriental fruit fly, Bactrocera dorsalis (Hendel), populations have traditionally been applied to the host crop, rather than to crop borders, roosting by oriental fruit flies in borders of some crop species, such as papaya, Carica papaya L. (Brassicales: Caricaceae), suggests that bait spray applications to crop borders could also help in suppression of B. dorsalis populations. In order to develop improved recommendations for application of bait sprays to border plants for suppression of melon fly and oriental fruit fly populations, the relative attractiveness of a range of plant species, in a vegetative (non-flowering) stage, was tested to wild melon fly and oriental fruit fly populations established in a papaya orchard in Hawaii. A total of 20 plant species were evaluated, divided into four categories: 1) border plants, including corn, Zea mays L. (Poales: Poaceae), windbreaks and broad-leaved ornamentals, 7 species; 2) weed plants commonly found in agricultural fields in Hawaii, 6 species; 3) host crop plants, 1 species- zucchini, Cucurbita pepo L. (Violales: Curcurbitaceae), and 4) locally grown fruit trees, 6 species. Plants were established in pots and placed in an open field, in clusters encircling protein bait traps, 20 m away from the papaya orchard. Castor bean, Ricinus communis L. (Euphorbiales: Euphorbiaceae), panax, Polyscias guilfoylei (Bull) Bailey (Apiales: Araliaceae), tiger's claw, Erythnna variegata L. (Fabales: Fabaceae), and guava, Psidium guajava L. (Myrtales: Myrtaceae) were identified as preferred roosting hosts for the melon fly, and tiger's claw, panax, castor bean, Canada cocklebur, Xanthium strumarium L. (Asterales: Asteraceae), Brazilian pepper tree, Schinus terebinthifolius Raddi (Sapindales: Anacardiaceae), ti plant, Cordyline terminate (L.) Chev.(Liliales: Liliaceae), guava and several Citrus spp. were identified as preferred roosting hosts for oriental fruit fly. Guava had not previously been identified as a preferred roosting host for melon fly. Other than for the use of panax as a roosting host, there has previously been little attention to roosting hosts for oriental fruit fly. Establishment of preferred roosting hosts as crop borders may help to improve suppression of both fruit fly species by providing sites for bait spray applications. Further research is needed to assess the use of vegetation bordering other host crops as roosting hosts, especially for oriental fruit fly

Intra-trackway morphological variations due to substrate consistency: the El Frontal dinosaur tracksite (Lower Cretaceous, Spain).

An ichnological and sedimentological study of the El Frontal dinosaur tracksite (Early Cretaceous, Cameros basin, Soria, Spain) highlights the pronounced intra-trackway variation found in track morphologies of four theropod trackways. Photogrammetric 3D digital models revealed various and distinct intra-trackway morphotypes, which reflect changes in footprint parameters such as the pace length, the track length, depth, and height of displacement rims. Sedimentological analyses suggest that the original substrate was non-homogenous due to lateral changes in adjoining microfacies. Multidata analyses indicate that morphological differences in these deep and shallow tracks represent a part of a continuum of track morphologies and geometries produced by a gradient of substrate consistencies across the site. This implies that the large range of track morphologies at this site resulted from similar trackmakers crossing variable facies. The trackways at the El Frontal site present an exemplary case of how track morphology, and consequently potential ichnotaxa, can vary, even when produced by a single trackmaker

Oxidative Stress Mediates Physiological Costs of Begging in Magpie (Pica pica) Nestlings

[Background] Theoretical models predict that a cost is necessary to guarantee honesty in begging displays given by offspring to solicit food from their parents. There is evidence for begging costs in the form of a reduced growth rate and immunocompetence. Moreover, begging implies vigorous physical activity and attentiveness, which should increase metabolism and thus the releasing of pro-oxidant substances. Consequently, we predict that soliciting offspring incur a cost in terms of oxidative stress, and growth rate and immune response (processes that generate pro-oxidants substances) are reduced in order to maintain oxidative balance. [Methodology/Principal Findings] We test whether magpie (Pica pica) nestlings incur a cost in terms of oxidative stress when experimentally forced to beg intensively, and whether oxidative balance is maintained by reducing growth rate and immune response. Our results show that begging provokes oxidative stress, and that nestlings begging for longer bouts reduce growth and immune response, thereby maintaining their oxidative status. [Conclusions/Significance] These findings help explaining the physiological link between begging and its associated growth and immunocompetence costs, which seems to be mediated by oxidative stress. Our study is a unique example of the complex relationships between the intensity of a communicative display (begging), oxidative stress, and life-history traits directly linked to viability.GM-R was supported by the Spanish Government (Ministerio de Ciencia y Tecnología, “Juan de la Cierva” program), and TR was supported by the Consejo Superior de Investigaciones Científicas (CSIC; Proyectos Intramurales Especiales)

Earth: Atmospheric Evolution of a Habitable Planet

Our present-day atmosphere is often used as an analog for potentially habitable exoplanets, but Earth's atmosphere has changed dramatically throughout its 4.5 billion year history. For example, molecular oxygen is abundant in the atmosphere today but was absent on the early Earth. Meanwhile, the physical and chemical evolution of Earth's atmosphere has also resulted in major swings in surface temperature, at times resulting in extreme glaciation or warm greenhouse climates. Despite this dynamic and occasionally dramatic history, the Earth has been persistently habitable--and, in fact, inhabited--for roughly 4 billion years. Understanding Earth's momentous changes and its enduring habitability is essential as a guide to the diversity of habitable planetary environments that may exist beyond our solar system and for ultimately recognizing spectroscopic fingerprints of life elsewhere in the Universe. Here, we review long-term trends in the composition of Earth's atmosphere as it relates to both planetary habitability and inhabitation. We focus on gases that may serve as habitability markers (CO2, N2) or biosignatures (CH4, O2), especially as related to the redox evolution of the atmosphere and the coupled evolution of Earth's climate system. We emphasize that in the search for Earth-like planets we must be mindful that the example provided by the modern atmosphere merely represents a single snapshot of Earth's long-term evolution. In exploring the many former states of our own planet, we emphasize Earth's atmospheric evolution during the Archean, Proterozoic, and Phanerozoic eons, but we conclude with a brief discussion of potential atmospheric trajectories into the distant future, many millions to billions of years from now. All of these 'Alternative Earth' scenarios provide insight to the potential diversity of Earth-like, habitable, and inhabited worlds.Comment: 34 pages, 4 figures, 4 tables. Review chapter to appear in Handbook of Exoplanet

Expression of P. falciparum var Genes Involves Exchange of the Histone Variant H2A.Z at the Promoter

Plasmodium falciparum employs antigenic variation to evade the human immune response by switching the expression of different variant surface antigens encoded by the var gene family. Epigenetic mechanisms including histone modifications and sub-nuclear compartmentalization contribute to transcriptional regulation in the malaria parasite, in particular to control antigenic variation. Another mechanism of epigenetic control is the exchange of canonical histones with alternative variants to generate functionally specialized chromatin domains. Here we demonstrate that the alternative histone PfH2A.Z is associated with the epigenetic regulation of var genes. In many eukaryotic organisms the histone variant H2A.Z mediates an open chromatin structure at promoters and facilitates diverse levels of regulation, including transcriptional activation. Throughout the asexual, intraerythrocytic lifecycle of P. falciparum we found that the P. falciparum ortholog of H2A.Z (PfH2A.Z) colocalizes with histone modifications that are characteristic of transcriptionally-permissive euchromatin, but not with markers of heterochromatin. Consistent with this finding, antibodies to PfH2A.Z co-precipitate the permissive modification H3K4me3. By chromatin-immunoprecipitation we show that PfH2A.Z is enriched in nucleosomes around the transcription start site (TSS) in both transcriptionally active and silent stage-specific genes. In var genes, however, PfH2A.Z is enriched at the TSS only during active transcription in ring stage parasites. Thus, in contrast to other genes, temporal var gene regulation involves histone variant exchange at promoter nucleosomes. Sir2 histone deacetylases are important for var gene silencing and their yeast ortholog antagonises H2A.Z function in subtelomeric yeast genes. In immature P. falciparum parasites lacking Sir2A or Sir2B high var transcription levels correlate with enrichment of PfH2A.Z at the TSS. As Sir2A knock out parasites mature the var genes are silenced, but PfH2A.Z remains enriched at the TSS of var genes; in contrast, PfH2A.Z is lost from the TSS of de-repressed var genes in mature Sir2B knock out parasites. This result indicates that PfH2A.Z occupancy at the active var promoter is antagonized by PfSir2A during the intraerythrocytic life cycle. We conclude that PfH2A.Z contributes to the nucleosome architecture at promoters and is regulated dynamically in active var genes

Comparative Transcriptional and Genomic Analysis of Plasmodium falciparum Field Isolates

Mechanisms for differential regulation of gene expression may underlie much of the phenotypic variation and adaptability of malaria parasites. Here we describe transcriptional variation among culture-adapted field isolates of Plasmodium falciparum, the species responsible for most malarial disease. It was found that genes coding for parasite protein export into the red cell cytosol and onto its surface, and genes coding for sexual stage proteins involved in parasite transmission are up-regulated in field isolates compared with long-term laboratory isolates. Much of this variability was associated with the loss of small or large chromosomal segments, or other forms of gene copy number variation that are prevalent in the P. falciparum genome (copy number variants, CNVs). Expression levels of genes inside these segments were correlated to that of genes outside and adjacent to the segment boundaries, and this association declined with distance from the CNV boundary. This observation could not be explained by copy number variation in these adjacent genes. This suggests a local-acting regulatory role for CNVs in transcription of neighboring genes and helps explain the chromosomal clustering that we observed here. Transcriptional co-regulation of physical clusters of adaptive genes may provide a way for the parasite to readily adapt to its highly heterogeneous and strongly selective environment

Membrane remodeling by the M2 amphipathic helix drives influenza virus membrane scission

Membrane scission is a crucial step in all budding processes, from endocytosis to viral budding. Many proteins have been associated with scission, though the underlying molecular details of how scission is accomplished often remain unknown. Here, we investigate the process of M2-mediated membrane scission during the budding of influenza viruses. Residues 50–61 of the viral M2 protein bind membrane and form an amphipathic α-helix (AH). Membrane binding requires hydrophobic interactions with the lipid tails but not charged interactions with the lipid headgroups. Upon binding, the M2AH induces membrane curvature and lipid ordering, constricting and destabilizing the membrane neck, causing scission. We further show that AHs in the cellular proteins Arf1 and Epsin1 behave in a similar manner. Together, they represent a class of membrane-induced AH domains that alter membrane curvature and fluidity, mediating the scission of constricted membrane necks in multiple biological pathways