A5054745889- Neuroscience and Neuropharmacology Research
- Neural dynamics and brain function
- Receptor Mechanisms and Signaling
- Photoreceptor and optogenetics research
- Advanced Memory and Neural Computing
- Neurotransmitter Receptor Influence on Behavior
- Neural Networks and Applications
- Neuroscience and Neural Engineering
- Cancer Treatment and Pharmacology
- Gene Regulatory Network Analysis
- HER2/EGFR in Cancer Research
- Neurological disorders and treatments
- Memory and Neural Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Advanced Breast Cancer Therapies
- Simulation Techniques and Applications
- Ion channel regulation and function
- Neurobiology and Insect Physiology Research
- Melanoma and MAPK Pathways
- Computational Drug Discovery Methods
- Cell Image Analysis Techniques
- Retinal Development and Disorders
- Plant and Biological Electrophysiology Studies
- Breast Cancer Treatment Studies
- Functional Brain Connectivity Studies
University of Iowa
2024
George Mason University
2014-2023
Institute for Advanced Study
2013-2023
Stanford University
2019
Sarah Cannon
2019
Cornell University
2019
Duke Medical Center
2004-2018
Duke Cancer Institute
2014-2018
Duke University
2004-2017
Fox Chase Cancer Center
2017
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)–targeted antitumor properties of trastuzumab with cytotoxic activity microtubule-inhibitory agent DM1. The antibody and are conjugated by means a stable linker.
BackgroundThe phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Here, we report updated efficacy safety data, together exploratory biomarker analyses, from the study.Patients methodsA total of 668 postmenopausal women HR+,...
Advanced breast cancer (ABC) is a treatable but still generally incurable disease. The goals of care are to optimize both length and quality life. Due continuous research, several advances have been made, particularly for the human epidermal growth factor receptor 2 (HER-2)-positive luminal-like subtypes. Notwithstanding these advances, median overall survival patients with ABC only 2–3 years, although range wide [1–5], may be longer treated in specialized institutions [6].
Advanced Breast Cancer (ABC) is a treatable but still generally incurable disease. The goals of care are to optimize both length and quality life. Due continuous research, several advances have been made, particularly for the HER-2-positive Luminal-like subtypes. Notwithstanding these advances, median overall survival patients with ABC only 2–3 years, although range wide [1–5], may be longer treated in specialized institutions [6]. Implementation current knowledge highly variable among...
Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons the striatum occurs when glutamatergic input (from cortex) and dopaminergic substantia nigra) are received simultaneously. Subsequent to learning, with strengthened synapses more likely fire response cortical alone. This plasticity is produced by phosphorylation AMPA receptors, caused various signalling molecules. A key molecule phosphoprotein DARPP-32, highly expressed striatal neurons....
Cyclic AMP (cAMP) and its main effector Protein Kinase A (PKA) are critical for several aspects of neuronal function including synaptic plasticity. Specificity plasticity requires that cAMP activates PKA in a highly localized manner despite the speed with which diffuses. Two mechanisms have been proposed to produce elevations cAMP, known as microdomains: impeded diffusion, high phosphodiesterase (PDE) activity. This paper investigates mechanism signaling using computational model biochemical...
Striatal fast-spiking (FS) interneurons are interconnected by gap junctions into sparsely connected networks. As demonstrated for cortical FS interneurons, these in the striatum may cause synchronized spiking, which would increase influence that neurons have on spiking striatal medium spiny (MS) neurons. Dysfunction of basal ganglia is characterized changes synchrony or periodicity, thus between modulate and thereby behavior such as reward learning motor control. To explore roles activity...
ABSTRACT Background Microelectrode recordings along preplanned trajectories are often used for accurate definition of the subthalamic nucleus (STN) borders during deep brain stimulation (DBS) surgery Parkinson's disease. Usually, demarcation STN is performed manually by a neurophysiologist. The exact detection difficult, especially detecting transition between and substantia nigra pars reticulata. Consequently, may be inaccurate, leading to suboptimal location DBS lead inadequate clinical...
Modeling in neuroscience occurs at the intersection of different points view and approaches. Typically, hypothesis-driven modeling brings a question into focus so that model is constructed to investigate specific hypothesis about how system works or why certain phenomena are observed. Data-driven modeling, on other hand, follows more unbiased approach, with construction informed by computationally intensive use data. At same time, researchers employ models biological scales levels...
Protein kinases play critical roles in learning and memory long term potentiation (LTP), a form of synaptic plasticity. The induction late-phase LTP (L-LTP) the CA1 region hippocampus requires several kinases, including CaMKII PKA, which are activated by calcium-dependent signaling processes other intracellular pathways. requirement for PKA is limited to L-LTP induced using spaced stimuli, but not massed stimuli. To investigate this temporal sensitivity computational biochemical model...
Calcium through NMDA receptors (NMDARs) is necessary for the long-term potentiation (LTP) of synaptic strength; however, NMDARs differ in several properties that can influence amount calcium influx into spine. These properties, such as sensitivity to magnesium block and conductance decay kinetics, change receptor's response spike timing dependent plasticity (STDP) protocols, thereby shape integration information processing. This study investigates role GluN2 subunit differences on spine...
Dopamine release in the striatum has been implicated various forms of reward dependent learning. leads to production cAMP and activation protein kinase A (PKA), which are involved striatal synaptic plasticity PKA its targets not diffusely located throughout neuron, but confined subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking interaction with AKAPs disrupts location prevents LTP hippocampus striatum; however,...
Growing evidence supports a critical role for the dorsal striatum in cognitive as well motor control. Both lesions and <i>in vivo</i> recordings demonstrate transition engaged striatal subregion, from dorsomedial to dorsolateral, skill performance shifts an attentive phase more automatic or habitual phase. What are neural mechanisms supporting behavioral transitions learning? To pursue this question, we used T-maze training during which rats early, (dorsomedial) late (dorsolateral)...
The inhibitory circuits of the striatum are known to be critical for motor function, yet their contributions Parkinsonian deficits not clear. Altered firing in globus pallidus suggests that striatal medium spiny neurons (MSN) direct (D1 MSN) and indirect pathway (D2 imbalanced during dopamine depletion. Both MSN classes receive input from each other interneurons within striatum, specifically fast-spiking (FSI). To investigate role inhibition maintaining balance, we developed a...
The striatum is a major site of learning and memory formation for sensorimotor cognitive association. One the mechanisms used by brain storage synaptic plasticity - long-lasting, activity-dependent change in strength. All forms require an elevation intracellular calcium, common hypothesis that amplitude duration calcium transients can determine direction plasticity. utility this unclear part because dopamine required striatal diversity stimulation protocols. To test whether predict...
Signalling pathways leading to post-synaptic plasticity have been examined in many types of experimental studies, but a unified picture on how multiple biochemical collectively shape neocortical is missing. We built biochemically detailed model describing CaMKII, PKA, and PKC their contribution synaptic potentiation or depression. developed statistical AMPA-receptor-tetramer model, which permits the estimation AMPA-receptor-mediated maximal conductance based numbers GluR1s GluR2s predicted...
Striatal spiny projection (SP) neurons control movement initiation by integrating cortical inputs and inhibiting basal ganglia outputs. Central to this lies a “microcircuit” that consists of feedback pathway formed axon collaterals between GABAergic SP feedforward from fast spiking (FS) interneurons neurons. Here, somatically evoked postsynaptic potentials (PSPs) currents (PSCs) were compared for both pathways with dual whole cell patch recording in voltage- current-clamp mode using...
In order to study color constancy, the appearance of center a center–surround paradigm was measured by using multiple-alternative forced-response matching. The presented with (1) no surround, (2) an adjacent chromatic or (3) surround separated from achromatic gap. and surrounds were under various simulated illuminants ranging illuminant A D75. We found that when is present, constancy fails; however, are some degree displayed. also poor induction minimal. addition, it determined that, if...
The ability of neurons to differentially respond specific temporal and spatial input patterns underlies information storage in neural circuits. One means achieving specificity is restrict signaling molecules particular subcellular compartments using anchoring such as A-Kinase Anchoring Proteins (AKAPs). Disruption protein kinase A (PKA) AKAPs impairs a PKA-dependent form long term potentiation (LTP) the hippocampus. To investigate role localized PKA LTP, we developed stochastic...
Long-term potentiation (LTP) of excitatory afferents to the dorsal striatum likely occurs with learning encode new skills and habits, yet corticostriatal LTP is challenging evoke reliably in brain slice under physiological conditions. Here we test hypothesis that stimulating striatal theta-burst timing, similar recently reported vivo temporal patterns corresponding learning, evokes LTP. Recording from adult mouse extracellularly 1 mM Mg(2+), find dorsomedial dorsolateral preferentially...