HER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor ...cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy.
The number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining.
258 (40.2%) of the 642 patients were positive for CTCs (median 2; range 1-1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC.
This study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance.
Processes acting at the interface between the land surface and the atmosphere have a strong impact on the European summer climate, particularly during extreme years. These processes are to a large ...extent associated with soil moisture (SM). This study investigates the role of soil moisture-atmosphere coupling for the European summer climate over the period 1959-2006 using simulations with a regional climate model. The focus of this study is set on temperature and precipitation extremes and trends. The analysis is based on simulations performed with the regional climate model CLM, driven with ECMWF reanalysis and operational analysis data. The set of experiments consists of a control simulation (CTL) with interactive SM, and sensitivity experiments with prescribed SM: a dry and a wet run to determine the impact of extreme values of SM, as well as experiments with lowpass-filtered SM from CTL to quantify the impact of the temporal variability of SM on different time scales. Soil moisture-climate interactions are found to have significant effects on temperature extremes in the experiments, and impacts on precipitation extremes are also identified. Case studies of selected major summer heat waves reveal that the intraseasonal and interannual variability of SM account for 5-30% and 10-40% of the simulated heat wave anomaly, respectively. For extreme precipitation events on the other hand, only the wet-day frequency is impacted in the experiments with prescribed soil moisture. Simulated trends for the past decades, which appear consistent with projected changes for the 21st century, are identified to be at least partly linked to SM-atmosphere feedbacks.
In this study, we assess the role of soil moisture for heat wave persistence using simulations with a regional climate model. Several studies have investigated changes in the frequency of hot summer ...days but very few investigated changes in their persistence. We use two different heat wave thresholds, either defined by the 90th percentile of the control run or by the 90th percentile of the respective sensitivity experiment. We identify that simulations in which soil moisture is fixed to a constant value or prescribed seasonal cycle, even with prescribed constant dry conditions, present a lower intrinsic heat wave persistence than simulations with interactive soil moisture. This effect is related to the impact of soil moisture persistence in the interactive simulations and amounts to ca. 5–10% of the spell lengths of the 10% hottest days in the respective simulations. Our results highlight the key role of soil moisture memory for the persistence of heat wave events, beside the known effect of soil moisture on heat wave intensity.
The evolution of advanced cognition in vertebrates is associated with two independent innovations in the forebrain: the six-layered neocortex in mammals and the dorsal ventricular ridge (DVR) in ...sauropsids (reptiles and birds). How these innovations arose in vertebrate ancestors remains unclear. To reconstruct forebrain evolution in tetrapods, we built a cell-type atlas of the telencephalon of the salamander
. Our molecular, developmental, and connectivity data indicate that parts of the sauropsid DVR trace back to tetrapod ancestors. By contrast, the salamander dorsal pallium is devoid of cellular and molecular characteristics of the mammalian neocortex yet shares similarities with the entorhinal cortex and subiculum. Our findings chart the series of innovations that resulted in the emergence of the mammalian six-layered neocortex and the sauropsid DVR.
The combined “Blocked-Off & Discrete Ordinates” (BO/DO) approach is used within a DEM/CFD frame to model the radiative heating of stationary and moving (rotating with respect to the mesh) cubic ...particles. A single cube, placed inside a larger cubic box, is heated by radiation and its temperature evolution over time is investigated. Two different models for the particle heating are considered: the first one assumes a uniform cube temperature while the second model calculates the intra-particle heat transfer leading to a non-uniform temperature distribution as it occurs in thermally thick particles. Three different particle materials, wood, styrofoam and steel, are considered.
Initially, the radiative heating of stationary cubes, approximated by the BO approach in a CFD mesh, is compared to the heating of cubes enclosed by a corresponding body conformal mesh as a reference. The results show that deviations in cube temperature mainly result from the artificial increase of the particle surface in the BO. When applying a particle surface area ratio to compensate for the artificial surface area increase deviations in temperature can be reduced to 5.2% compared to body conformal mesh.
In a further step, the cube is constantly rotating which changes the orientation of the cube's surfaces relative to the radiation source. The evolution of the cube's surface temperatures, which is dependent on the orientation, is modelled by the BO/DO approach. As expected, materials with low thermal conductivity show larger temperature gradients over time than materials with high thermal conductivity. The temperature difference between different surfaces turns out to be in the ranges 50/14/0 K (for styrofoam/wood/steel) and 134/65/0 K between surface and core, thus reflecting the correct physical behavior. The evaluation of the BO/DO approach concerning its capability to account for radiative heat transfer in DEM simulations for particles with a regular (cubic) geometry, as examined in the current paper, forms the basis to extend the description to arbitrarily shaped particles, a great potential of the BO/DO approach as will be shown in an outlook example.
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•Transient simulations of radiative heating of moving, complex particles in DEM/CFD.•Using the Blocked-Off approach in combination with the DO model.•Due to the BO approach, temperature deviates by up to 5.2%.•Particle rotation has a large impact on the heating of the particle.•Low thermal conductivity materials have large intra-particle temperature gradients.
Human neural progenitors derived from pluripotent stem cells develop into electrophysiologically active neurons at heterogeneous rates, which can confound disease-relevant discoveries in neurology ...and psychiatry. By combining patch clamping, morphological and transcriptome analysis on single-human neurons in vitro, we defined a continuum of poor to highly functional electrophysiological states of differentiated neurons. The strong correlations between action potentials, synaptic activity, dendritic complexity and gene expression highlight the importance of methods for isolating functionally comparable neurons for in vitro investigations of brain disorders. Although whole-cell electrophysiology is the gold standard for functional evaluation, it often lacks the scalability required for disease modeling studies. Here, we demonstrate a multimodal machine-learning strategy to identify new molecular features that predict the physiological states of single neurons, independently of the time spent in vitro. As further proof of concept, we selected one of the potential neurophysiological biomarkers identified in this study-GDAP1L1-to isolate highly functional live human neurons in vitro.
The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is ...also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.
Written memoranda of conversations, or memcons, provide a near‐contemporaneous record of what was said in conversation, and offer important insights into the activities of high‐profile individuals. ...We assess the impact of writing a memcon on memory for conversation. Pairs of participants engaged in conversation and were asked to recall the contents of that conversation 1 week later. One participant in each pair memorialized the content of the interaction in a memcon shortly after the conversation. Participants who generated memcons recalled more details of the conversations than participants who did not, but the content of recall was equally and largely accurate for both participants. Remarkably, only 4.7% of the details of the conversation were recalled by both of the partners after a week delay. Contemporaneous note‐taking appears to enhance memory for conversation by increasing the amount of information remembered but not the accuracy of that information. These findings have implications for evaluating the testimony of participants on conversations with major political or legal ramifications.
Metal−silicon cluster cations of the form MSi n + (M = Cu, Ag, Cr) are produced in a molecular beam with pulsed laser vaporization. These species are mass-selected in a reflectron time-of-flight ...spectrometer and studied with laser photodissociation at 532 and 355 nm. For the noble metals copper and silver, photodissociation of the n = 7 and 10 clusters proceeds primarily by the loss of metal atoms, indicating that the metal is not located within the interior of silicon cages, and that metal−silicon bonding is weaker than silicon−silicon bonding. Chromium−silicon clusters for n = 7 also lose primarily the metal atom, but at n = 15 and 16 these dissociate via the loss of silicon, producing smaller metal−silicon species. This behavior is consistent with stronger metal−silicon bonding and encapsulated metal structures, as suggested previously by theory. MSi6 + cations are produced efficiently in all of these photodissociation processes, indicating that these species have enhanced stability compared to other small clusters. Improved values are obtained for the ionization potentials of Si7 and Si10.
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