An assessment of long duration geodynamo simulations using new paleomagnetic modeling criteria (Q PM)

Long-term temporal variations of the magnetic field (timescales >10 Myr), characterized from paleomagnetic data, have been hypothesized to reflect the evolution of Earth's deep interior and couplings between the core and mantle. By tying observed changes in the paleomagnetic record to mechanisms predicted from numerical geodynamo simulations, we have a unique tool for assessing changes in the deep interior back in time. However, numerical simulations are not run in an Earth-like parameter regime and assessing how well they reproduce the geomagnetic field is difficult. Criteria have been proposed to determine the level of spatial and temporal agreement between simulations and observations spanning historical and Holocene timescales, but no such criteria exist for longer timescales. Here we present a new set of five criteria (Quality of Paleomagnetic Modeling criteria, QPM) that assess the degree of semblance between a simulated dynamo and the temporal and spatial variations of the long-term (∼10 Myr) paleomagnetic field. These criteria measure inclination anomaly, virtual geomagnetic pole dispersion at the equator, latitudinal variation in virtual geomagnetic pole dispersion, normalized width of virtual dipole moment distribution, and dipole field reversals. We have assessed 46 geodynamo simulations using the QPM criteria. The simulations have each been run for the equivalent of at least ∼300 kyr, span reversing and non-reversing regimes, and include either homogeneous or heterogeneous heat flux boundary conditions. We find that none of our simulations reproduce all salient aspects of the long-term paleomagnetic field behavior for the past 10 Myr. Nevertheless, our simulations bracket Earth values, suggesting that an Earth-like simulation is feasible within the available computationally accessible parameter space. This new set of criteria can inform future simulations that aim to reproduce all aspects of Earth's long-term magnetic field behavior

Dynamo constraints on the long-term evolution of Earth's magnetic field strength

Elucidating the processes in the liquid core that have produced observed palaeointensity changes over the last 3.5 Gyr is crucial for understanding the dynamics and long-term evolution of Earth’s deep interior. We combine numerical geodynamo simulations with theoretical scaling laws to investigate the variation of Earth’s magnetic field strength over geological time. Our approach follows the study of Aubert et al., adapted to include recent advances in numerical simulations, mineral physics and palaeomagnetism. We first compare the field strength within the dynamo region and on the core–mantle boundary (CMB) between a suite of 314 dynamo simulations and two power-based theoretical scaling laws. The scaling laws are both based on a Quasi-Geostropic (QG) force balance at leading order and a Magnetic, Archimedian, and Coriolis (MAC) balance at first order and differ in treating the characteristic length scale of the convection as fixed (QG-MAC-fixed) or determined as part of the solution (QG-MAC-free). When the data set is filtered to retain only simulations with magnetic to kinetic energy ratios greater than at least two we find that the internal field together with the root-mean-square and dipole CMB fields exhibit power-law behaviour that is compatible with both scalings within uncertainties arising from different heating modes and boundary conditions. However, while the extrapolated intensity based on the QG-MAC-free scaling matches Earth’s modern CMB field, the QG-MAC-fixed prediction shoots too high and also significantly overestimates palaeointensities over the last 3.5 Gyr. We combine the QG-MAC-free scaling with outputs from 275 realizations of core–mantle thermal evolution to construct synthetic true dipole moment (TDM) curves spanning the last 3.5 Gyr. Best-fitting TDMs reproduce binned PINT data during the Bruhnes and before inner core nucleation (ICN) within observational uncertainties, but PINT does not contain the predicted strong increase and subsequent high TDMs during the early stages of inner core growth. The best-fitting models are obtained for a present-day CMB heat flow of 11–16 TW, increasing to 17–22 TW at 4 Ga, and predict a minimum TDM at ICN

A quantitative analysis of lymphatic vessels in human breast cancer, based on LYVE-1 immunoreactivity

This study was undertaken to determine the highly sensitive method for detecting tumour lymphatic vessels in all the fields of each slide (LV), lymphatic microvessel density (LMVD) and lymphatic vessel invasion (LVI) and to compare them with other prognostic parameters using immunohistochemical staining with polyclonal (PCAB) and monoclonal antibodies (MCAB) to the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), and the pan-endothelial marker factorVIII in a series of 67 human breast cancers. In all LYVE-1-stained sections, LV (some of which contained red blood cells) were frequently found localised in extralobular stroma, dermis, connective tissue stroma and adjacent to artery and vein, but were rare within the intralobular stroma or the tumour body (3/67 cases) or areas of widespread invasion. In contrast small blood vessels were observed in intra- and extralobular stroma in the factor VIII-stained sections. Quantitation of vessel numbers revealed that LYVE-1/PCAB detected a significantly larger number of LV than either H&E or LYVE-1/MCAB (P<0.0001). LYVE-1/PCAB detected LVI in 25/67 cases (37.3%) and their presence was significantly associated with both lymph node metastasis (χ2=4.698, P=0.0248) and unfavourable overall survival (OS) (P=0.0453), while not relapse- free survival (RFS) (P=0.2948). LMVD had no influence for RFS and OS (P=0.4879, P=0.1463, respectively). Our study demonstrates that immunohistochemistry with LYVE-1/PCAB is a highly sensitive method for detecting tumour LV/LVI in breast cancer and LVI is a useful prognostic indicator for lymphatic tumour dissemination

Current and Emerging Treatment Options for Castration-Resistant Prostate Cancer: A Focus on Immunotherapy

BACKGROUND: Castration-resistant prostate cancer is a disease with limited treatment options. However, the ongoing elucidation of the mechanisms underlying this disease continues to support the development of not only novel agents, but also innovative approaches. Among these therapies, immunotherapy has emerged as a promising strategy. DESIGN: This review article summarizes the most recent data from investigations of immunotherapies in castration-resistant prostate cancer (literature and congress searches current as of August 2011). RESULTS: Immunotherapeutic strategies such as passive immunization, vaccines, and particularly checkpoint blockade have demonstrated some efficacy as single agents. Elucidation of effective combinations of agents and drug regimens is ongoing but will require continued careful investigation, including the standardization of surrogate endpoints in clinical trials. CONCLUSIONS: It is hypothesized that the combination of immunotherapeutic agents with traditional and novel chemotherapeutics will potentiate the efficacy of the chemotherapeutics while maintaining manageable toxicity

Predation success by a plant-ant indirectly favours the growth and fitness of its host myrmecophyte

Mutualisms, or interactions between species that lead to net fitness benefits for each species involved, are stable and ubiquitous in nature mostly due to "byproduct benefits" stemming from the intrinsic traits of one partner that generate an indirect and positive outcome for the other. Here we verify if myrmecotrophy (where plants obtain nutrients from the refuse of their associated ants) can explain the stability of the tripartite association between the myrmecophyte Hirtella physophora, the ant Allomerus decemarticulatus and an Ascomycota fungus. The plant shelters and provides the ants with extrafloral nectar. The ants protect the plant from herbivores and integrate the fungus into the construction of a trap that they use to capture prey; they also provide the fungus and their host plant with nutrients. During a 9-month field study, we over-provisioned experimental ant colonies with insects, enhancing colony fitness (i.e., more winged females were produced). The rate of partial castration of the host plant, previously demonstrated, was not influenced by the experiment. Experimental plants showed higher δ¹⁵N values (confirming myrmecotrophy), plus enhanced vegetative growth (e.g., more leaves produced increased the possibility of lodging ants in leaf pouches) and fitness (i.e., more fruits produced and more flowers that matured into fruit). This study highlights the importance of myrmecotrophy on host plant fitness and the stability of ant-myrmecophyte mutualisms

Molecular Biomarker Analyses Using Circulating Tumor Cells

Evaluation of cancer biomarkers from blood could significantly enable biomarker assessment by providing a relatively non-invasive source of representative tumor material. Circulating Tumor Cells (CTCs) isolated from blood of metastatic cancer patients hold significant promise in this regard.Using spiked tumor-cells we evaluated CTC capture on different CTC technology platforms, including CellSearch and two biochip platforms, and used the isolated CTCs to develop and optimize assays for molecular characterization of CTCs. We report similar performance for the various platforms tested in capturing CTCs, and find that capture efficiency is dependent on the level of EpCAM expression. We demonstrate that captured CTCs are amenable to biomarker analyses such as HER2 status, qRT-PCR for breast cancer subtype markers, KRAS mutation detection, and EGFR staining by immunofluorescence (IF). We quantify cell surface expression of EGFR in metastatic lung cancer patient samples. In addition, we determined HER2 status by IF and FISH in CTCs from metastatic breast cancer patients. In the majority of patients (89%) we found concordance with HER2 status from patient tumor tissue, though in a subset of patients (11%), HER2 status in CTCs differed from that observed in the primary tumor. Surprisingly, we found CTC counts to be higher in ER+ patients in comparison to HER2+ and triple negative patients, which could be explained by low EpCAM expression and a more mesenchymal phenotype of tumors belonging to the basal-like molecular subtype of breast cancer.Our data suggests that molecular characterization from captured CTCs is possible and can potentially provide real-time information on biomarker status. In this regard, CTCs hold significant promise as a source of tumor material to facilitate clinical biomarker evaluation. However, limitations exist from a purely EpCAM based capture system and addition of antibodies to mesenchymal markers could further improve CTC capture efficiency to enable routine biomarker analysis from CTCs

Impaired access of lymphocytes to neoplastic prostate tissue is associated with neoangiogenesis in the tumour site

Recent reports demonstrated that neovasculature of certain murine tumours inhibits migration of lymphocytes to malignant tissues. We examined the possible existence of this phenomenon in human prostate adenocarcinoma by relating extent, patterns and composition of leucocyte infiltrates in adenocarinoma specimens (N=28) to microvessel density and percentages of these vessels expressing adhesion molecules CD54, CD106 and CD62E. Specimens of nodular hyperplasia (N=30) were used as a control for nonmalignant prostate. Increased microvessel density was detected in foci of adenocarcinoma, as compared with adjacent benign areas (P=0.004) or hyperplastic specimens (P=0.001). Only CD54 was detected on prostate vasculature; percentages of CD54-expressing vessels in adenocarcinoma lesions and adjacent areas were higher than in hyperplasia (P=0.041 and P=0.014, respectively). Infiltrating leucocytes were either scattered diffusely in tissue or organised into clusters mainly composed of CD4-positive lymphocytes; smaller percentage of tissue was occupied by clustered infiltrates in adenocarcinoma foci (mean=0.7; median=0; range=0–5) than in adjacent tissue (mean=2.5; median=1; range=0–15; P=.021) and hyperplasia (mean=1.9; median=2; range=0–5; P=.006). In adenocarcinoma foci, microvessel density tended to negatively correlate with percentage of tissue occupied by an overall leucocyte infiltrate (mean=8.6; median=7.5; range=30) and negatively correlated with percentage of tissue occupied by clustered infiltrate (P=0.045). Percentage of CD54-expressing vessels positively correlated with percentage of tissue occupied by an overall (mean=12; median=10; range=30; P=0.01) and clustered (P=0.023) infiltrate in hyperplasia, whereas in carcinoma-adjacent benign areas, correlation was detected only for clustered infiltrates (P=0.02). The results indicate that impaired access of lymphocytes to malignant lesions is associated with increased numbers of newly formed blood vessels, whereas vascular CD54 likely contributes to extravasation of lymphocytes only in benign prostate tissue

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma

Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40425-016-0198-x) contains supplementary material, which is available to authorized users