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Systems pharmacology modeling in neuroscience: Prediction and outcome of PF-04995274, a 5-HT4 partial agonist, in a clinical scopolamine impairment trial

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Advances in Alzheimer's Disease 2013年第3期2卷 83-98页

作者： timothy nicholas.sridhar duvvuri Claire Leurent David Raunig Tracey Rapp Phil Iredale Carolyn Rowinski Robert Carr Patrick Roberts Athan Spiros Hugo Geerts ICON North Wales USA In Silico Biosciences Lexington USA Pfizer Global Research and Development Groton USA

Background: 5-HT4receptors in cortex and hippocampus area are considered as a possible target for modulation of cognitive functions in Alzheimer’s disease (AD). A systems pharmacology approach was adopted to evaluate the potential of the 5-HT4 modulation in providing beneficialeffects on cognition in AD. Methods: A serotonergic synaptic cleft model was developed by integrating serotonin firing, release, synaptic half-life, drug/tracer properties (affinity and agonism) as inputs and5-HT4 activity as output. The serotonergic model was calibrated using bothinvivo data on free 5-HT levels in preclinical models and human imaging data. The model was further expanded to other neurontransmitter systems and incorporated into a computer-based cortical network model which implemented the physiology of 12 different membrane CNS targets. A biophysically realistic, multi-compartment model of 80 pyramidal cells and 40 interneurons was further calibrated usingdata reported for working memory tasks in healthyhumans and schizophrenia patients. Model output was the duration of the network firing activity in response to an external stimulus. Alzheimer’s disease (AD) pathology, in particular synapse and neuronal cell loss in addition to cholinergic deficits, was calibrated to align with the natural clinical disease progression. The model was used to provide insights into the effect of 5-HT4 activation on working memory and to prospectively simulate the response of PF- 04995274, a 5-HT4partial agonist, in a scopolamine-reversal trial in healthy human subjects. Results: The model output suggested a beneficial effect of 5-HT4 agonism on working memory. The model also projected no effect or an exacerbation of scopolamine impairment for low in- trinsic activity 5-HT4agonists, which was supported by the subsequent human trial outcome. The clinical prediction of the disease model strongly suggests that 5-HT4 agonists with high intrinsic activity may have a beneficial effect on cognition in AD

关键词： Systems Pharmacology 5-HT4 Receptor Partial Agonist Scopolamine-Reversal

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Novel color center platforms enabling fundamental scientific discovery

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InfoMat 2021年第8期3卷 869-890页

作者： Victoria A.Norman sridhar Majety Zhipan Wang William H.Casey nicholas Curro Marina Radulaski Department of Electrical and Computer Engineering University of California at DavisDavisCalifornia Department of Physics University of California at DavisDavisCalifornia Department of Chemistry Department of Earth and Planetary SciencesUniversity of California at DavisDavisCalifornia

Color centers are versatile systems that generate quantum light,sense magnetic fields and produce spin-photon *** review how these properties have pushed the limits of fundamental knowledge in a variety of scientific disciplines,from rejecting local-realistic theories to sensing superconducting phase *** the light of recent progress in material processing and device fabrication,we identify new opportunities for interdisciplinary fundamental discoveries in physics and geochemistry.

关键词： color centers magnetometry nano-sensing photonics quantum information

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Pulmonary Resection for Metachronous Lung Cancer Following Contralateral Pneumonectomy

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Open Journal of Thoracic Surgery 2013年第1期3卷 15-18页

作者： Thomas Tsitsias Prity Gupta Kelvin W. Lau nicholas Harvey sridhar Rathinam Department of Cardiothoracic Anesthesia Uni- versity Hospitals of Leicester Leicester UK. Department of Thoracic Surgery University Hospitals of Leicester Leicester UK

Patients who undergo pneumonectomy for lung cancer are at risk of recurrent disease and metachronous tumours in the remaining lung. Establishing a diagnosis can be difficult as biopsy may induce a pneumothorax, whilst resection is limited by remaining lung function. However, pneumonectomy should not be a contraindication to further lung resection. We report two cases of lung cancer resection in the residual lung 6 and 11 years following pneumonectomy respectively. A limited resection can be safely performed for a new pulmonary parenchymal lesion on a background of a previous pneumonectomy.

关键词： Metachronous Lung Cancer Intermittent Apnea Limited Resection

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