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JAMA Cardiology Jun 2023There is a growing interest in understanding whether cardiovascular magnetic resonance (CMR) myocardial tissue characterization helps identify risk of cancer...
IMPORTANCE
There is a growing interest in understanding whether cardiovascular magnetic resonance (CMR) myocardial tissue characterization helps identify risk of cancer therapy-related cardiac dysfunction (CTRCD).
OBJECTIVE
To describe changes in CMR tissue biomarkers during breast cancer therapy and their association with CTRCD.
DESIGN, SETTING, AND PARTICIPANTS
This was a prospective, multicenter, cohort study of women with ERBB2 (formerly HER2)-positive breast cancer (stages I-III) who were scheduled to receive anthracycline and trastuzumab therapy with/without adjuvant radiotherapy and surgery. From November 7, 2013, to January 16, 2019, participants were recruited from 3 University of Toronto-affiliated hospitals. Data were analyzed from July 2021 to June 2022.
EXPOSURES
Sequential therapy with anthracyclines, trastuzumab, and radiation.
MAIN OUTCOMES AND MEASURES
CMR, high-sensitivity cardiac troponin I (hs-cTnI), and B-type natriuretic peptide (BNP) measurements were performed before anthracycline treatment, after anthracycline and before trastuzumab treatment, and at 3-month intervals during trastuzumab therapy. CMR included left ventricular (LV) volumes, LV ejection fraction (EF), myocardial strain, early gadolinium enhancement imaging to assess hyperemia (inflammation marker), native/postcontrast T1 mapping (with extracellular volume fraction [ECV]) to assess edema and/or fibrosis, T2 mapping to assess edema, and late gadolinium enhancement (LGE) to assess replacement fibrosis. CTRCD was defined using the Cardiac Review and Evaluation Committee criteria. Fixed-effects models or generalized estimating equations were used in analyses.
RESULTS
Of 136 women (mean [SD] age, 51.1 [9.2] years) recruited from 2013 to 2019, 37 (27%) developed CTRCD. Compared with baseline, tissue biomarkers of myocardial hyperemia and edema peaked after anthracycline therapy or 3 months after trastuzumab initiation as demonstrated by an increase in mean (SD) relative myocardial enhancement (baseline, 46.3% [16.8%] to peak, 56.2% [18.6%]), native T1 (1012 [26] milliseconds to 1035 [28] milliseconds), T2 (51.4 [2.2] milliseconds to 52.6 [2.2] milliseconds), and ECV (25.2% [2.4%] to 26.8% [2.7%]), with P <.001 for the entire follow-up. The observed values were mostly within the normal range, and the changes were small and recovered during follow-up. No new replacement fibrosis developed. Increase in T1, T2, and/or ECV was associated with increased ventricular volumes and BNP but not hs-cTnI level. None of the CMR tissue biomarkers were associated with changes in LVEF or myocardial strain. Change in ECV was associated with concurrent and subsequent CTRCD, but there was significant overlap between patients with and without CTRCD.
CONCLUSIONS AND RELEVANCE
In women with ERBB2-positive breast cancer receiving sequential anthracycline and trastuzumab therapy, CMR tissue biomarkers suggest inflammation and edema peaking early during therapy and were associated with ventricular remodeling and BNP elevation. However, the increases in CMR biomarkers were transient, were not associated with LVEF or myocardial strain, and were not useful in identifying traditional CTRCD risk.
Topics: Humans; Female; Middle Aged; Cardiotoxicity; Breast Neoplasms; Cohort Studies; Contrast Media; Prospective Studies; Gadolinium; Hyperemia; Magnetic Resonance Imaging, Cine; Trastuzumab; Heart Diseases; Fibrosis; Receptor, ErbB-2; Anthracyclines; Magnetic Resonance Spectroscopy; Inflammation
PubMed: 37043251
DOI: 10.1001/jamacardio.2023.0494 -
Nature Aug 2023Spider pulsars are neutron stars that have a companion star in a close orbit. The companion star sheds material to the neutron star, spinning it up to millisecond...
Spider pulsars are neutron stars that have a companion star in a close orbit. The companion star sheds material to the neutron star, spinning it up to millisecond rotation periods, while the orbit shortens to hours. The companion is eventually ablated and destroyed by the pulsar wind and radiation. Spider pulsars are key for studying the evolutionary link between accreting X-ray pulsars and isolated millisecond pulsars, pulsar irradiation effects and the birth of massive neutron stars. Black widow pulsars in extremely compact orbits (as short as 62 minutes) have companions with masses much smaller than 0.1 M. They may have evolved from redback pulsars with companion masses of about 0.1-0.4 M and orbital periods of less than 1 day. If this is true, then there should be a population of millisecond pulsars with moderate-mass companions and very short orbital periods, but, hitherto, no such system was known. Here we report radio observations of the binary millisecond pulsar PSR J1953+1844 (M71E) that show it to have an orbital period of 53.3 minutes and a companion with a mass of around 0.07 M. It is a faint X-ray source and located 2.5 arcminutes from the centre of the globular cluster M71.
PubMed: 37339734
DOI: 10.1038/s41586-023-06308-w -
Optics Letters Jun 2022We recently introduced a novel, to the best of our knowledge, infrared laser ellipsometer for sub-decisecond spectroscopy [Opt. Lett.44, 4387 (2019)10.1364/OL.44.004387]...
We recently introduced a novel, to the best of our knowledge, infrared laser ellipsometer for sub-decisecond spectroscopy [Opt. Lett.44, 4387 (2019)10.1364/OL.44.004387] and 0.03 mm spot-sized hyperspectral imaging [Opt. Lett.44, 4893 (2019)10.1364/OL.44.004893]. Here we report on the next device generation for thin-film sensitive simultaneous single-shot amplitude and phase measurements. The multi-timescale ellipsometer achieves 10 µs time resolution and long-term stability over hours at high spectral resolution (0.2 cm). We investigate the temporal stages (from minutes to milliseconds) of fatty acid thin-film formation upon solvent evaporation from acetone-diluted microliter droplets. Optical thickness variations, structure modifications, and molecular interactions are probed during the liquid-to-solid phase transition. Multi-timescale ellipsometry could greatly impact fields like in situ biosensing, microfluidics, and polymer analytics, but also operando applications in membrane research, catalysis, and studies of interface processes and surface reactions.
PubMed: 35648942
DOI: 10.1364/OL.457688 -
Optics Express Nov 2023Two decades after its introduction, optogenetics - a biological technique to control the activity of neurons or other cell types with light - remains a cutting edge and...
Two decades after its introduction, optogenetics - a biological technique to control the activity of neurons or other cell types with light - remains a cutting edge and promising tool to study biological processes. Its increasing usage in research varies widely from causally exploring biological mechanisms and neural computations, to neurostimulation and sensory restauration. To stimulate neurons in the brain, a variety of approaches have been developed to generate precise spatiotemporal light patterns. Yet certain constrains still exists in the current optical techniques to activate a neuronal population with both cellular resolution and millisecond precision. Here, we describe an experimental setup allowing to stimulate a few tens of neurons in a plane at sub-millisecond rates using 2-photon activation. A liquid crystal on silicon spatial light modulator (LCoS-SLM) was used to generate spatial patterns in 2 dimensions. The image of the patterns was formed on the plane of a digital micromirror device (DMD) that was used as a fast temporal modulator of each region of interest. Using fluorescent microscopy and patch-clamp recording of neurons in culture expressing the light-gated ion channels, we characterized the temporal and spatial resolution of the microscope. We described the advantages of combining the LCoS-SLM with the DMD to maximize the temporal precision, modulate the illumination amplitude, and reduce background activation. Finally, we showed that this approach can be extended to patterns in 3 dimensions. We concluded that the methodology is well suited to address important questions about the role of temporal information in neuronal coding.
Topics: Photons; Photic Stimulation; Holography; Neurons; Brain
PubMed: 38018006
DOI: 10.1364/OE.498644 -
Frontiers in Cellular Neuroscience 2019The axon provides a sole output of the neuron which propagates action potentials reliably to the axon terminal and transmits neuronal information to the postsynaptic... (Review)
Review
The axon provides a sole output of the neuron which propagates action potentials reliably to the axon terminal and transmits neuronal information to the postsynaptic neuron across the synapse. A classical view of neuronal signaling is based on these two processes, namely binary (all or none) signaling along the axon and graded (tunable) signaling at the synapse. Recent studies, however, have revealed that the excitability of the axon is subject to dynamic tuning for a short period after axonal action potentials. This was first described as post-spike hyperexcitability, as measured by the changes in stimulus threshold for a short period after an action potential. Later on, direct recordings from central nervous system (CNS) axons or axon terminals using subcellular patch-clamp recording showed that axonal spikes are often followed by afterdepolarization (ADP) lasting for several tens of milliseconds and has been suggested to mediate post-spike hyperexcitability. In this review article, I focused on the mechanisms as well as the functional significance of ADP in fine-scale modulation of axonal spike signaling in the CNS, with special reference to hippocampal mossy fibers, one of the best-studied CNS axons. As a common basic mechanism underlying axonal ADP, passive propagation by the capacitive discharge of the axonal membrane as well as voltage-dependent K conductance underlies the generation of ADP. Small but prolonged axonal ADP lasting for several tens of milliseconds may influence the subsequent action potential and transmitter release from the axon terminals. Both duration and amplitude of axonal spike are subject to such modulation by preceding action potential-ADP sequence, deviating from the conventional assumption of digital nature of axonal spike signaling. Impact on the transmitter release is also discussed in the context of axonal spike plasticity. Axonal spike is subject to dynamic control on a fine-scale and thereby contributes to the short-term plasticity at the synapse.
PubMed: 31555100
DOI: 10.3389/fncel.2019.00407 -
Proceedings of the National Academy of... Feb 2023Cells throughout the human body detect mechanical forces. While it is known that the rapid (millisecond) detection of mechanical forces is mediated by force-gated ion...
Cells throughout the human body detect mechanical forces. While it is known that the rapid (millisecond) detection of mechanical forces is mediated by force-gated ion channels, a detailed quantitative understanding of cells as sensors of mechanical energy is still lacking. Here, we combine atomic force microscopy with patch-clamp electrophysiology to determine the physical limits of cells expressing the force-gated ion channels (FGICs) Piezo1, Piezo2, TREK1, and TRAAK. We find that, depending on the ion channel expressed, cells can function either as proportional or nonlinear transducers of mechanical energy and detect mechanical energies as little as ~100 fJ, with a resolution of up to ~1 fJ. These specific energetic values depend on cell size, channel density, and cytoskeletal architecture. We also make the surprising discovery that cells can transduce forces either nearly instantaneously (<1 ms) or with a substantial time delay (~10 ms). Using a chimeric experimental approach and simulations, we show how such delays can emerge from channel-intrinsic properties and the slow diffusion of tension in the membrane. Overall, our experiments reveal the capabilities and limits of cellular mechanosensing and provide insights into molecular mechanisms that different cell types may employ to specialize for their distinct physiological roles.
Topics: Humans; Mechanotransduction, Cellular; Ion Channels; Cytoskeleton
PubMed: 36795747
DOI: 10.1073/pnas.2215747120 -
NeuroImage Oct 2022Spontaneous neural activity in human as assessed with resting-state functional magnetic resonance imaging (fMRI) exhibits brain-wide coordinated patterns in the...
Spontaneous neural activity in human as assessed with resting-state functional magnetic resonance imaging (fMRI) exhibits brain-wide coordinated patterns in the frequency of < 0.1 Hz. However, understanding of fast brain-wide networks at the timescales of neuronal events (milliseconds to sub-seconds) and their spatial, spectral, and transitional characteristics remain limited due to the temporal constraints of hemodynamic signals. With milli-second resolution and whole-head coverage, scalp-based electroencephalography (EEG) provides a unique window into brain-wide networks with neuronal-timescale dynamics, shedding light on the organizing principles of brain functions. Using the state-of-the-art signal processing techniques, we reconstructed cortical neural tomography from resting-state EEG and extracted component-based co-activation patterns (cCAPs). These cCAPs revealed brain-wide intrinsic networks and their dynamics, indicating the configuration/reconfiguration of resting human brains into recurring and transitional functional states, which are featured with the prominent spatial phenomena of global patterns and anti-state pairs of co-(de)activations. Rich oscillational structures across a wide frequency band (i.e., 0.6 Hz, 5 Hz, and 10 Hz) were embedded in the nonstationary dynamics of these functional states. We further identified a superstructure that regulated between-state immediate and long-range transitions involving the entire set of identified cCAPs and governed a significant aspect of brain-wide network dynamics. These findings demonstrated how resting-state EEG data can be functionally decomposed using cCAPs to reveal rich dynamic structures of brain-wide human neural activations.
Topics: Brain; Brain Mapping; Electroencephalography; Humans; Magnetic Resonance Imaging; Rest
PubMed: 35820583
DOI: 10.1016/j.neuroimage.2022.119461 -
Methods in Molecular Biology (Clifton,... 2021Optical manipulation is a powerful way to control neural activity in vitro and in vivo with millisecond precision. Patterning of light provides the remarkable ability to...
Optical manipulation is a powerful way to control neural activity in vitro and in vivo with millisecond precision. Patterning of light provides the remarkable ability to simultaneously target spatially segregated neurons from a population. Commercially available projectors provide one of the simplest and most economical ways of achieving spatial light modulation at millisecond timescales. Here, we describe the protocol for constructing a projector-based spatio-temporal light patterning system integrated with a microscope on a typical electrophysiology rig. The set-up is well suited for applications requiring rapid, distinct, and combinatorial inputs, akin to brain activity. This equipment involved is fairly economical (<$5000 including all optical and mechanical components), and the set-up is easy to assemble and program.
Topics: Animals; Humans; Light; Microscopy; Neurons; Optogenetics; Photic Stimulation; Vision, Ocular
PubMed: 32865745
DOI: 10.1007/978-1-0716-0830-2_11 -
Science (New York, N.Y.) Oct 2022A noninvasive imaging technique measures neuronal activity at a millisecond time scale.
A noninvasive imaging technique measures neuronal activity at a millisecond time scale.
Topics: Neurons
PubMed: 36227978
DOI: 10.1126/science.ade4938