9 results on '"Chandross, Karen J"'
Search Results
2. Calibration and Uncertainty in Neural Time-to-Event Modeling
- Author
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Chapfuwa, Paidamoyo, Tao, Chenyang, Li, Chunyuan, Khan, Irfan, Chandross, Karen J., Pencina, Michael J., Carin, Lawrence, and Henao, Ricardo
- Abstract
Models for predicting the time of a future event are crucial for risk assessment, across a diverse range of applications. Existing time-to-event (survival) models have focused primarily on preserving pairwise ordering of estimated event times (i.e., relative risk). We propose neural time-to-event models that account for calibration and uncertainty while predicting accurate absolute event times. Specifically, an adversarial nonparametric model is introduced for estimating matched time-to-event distributions for probabilistically concentrated and accurate predictions. We also consider replacing the discriminator of the adversarial nonparametric model with a survival-function matching estimator that accounts for model calibration. The proposed estimator can be used as a means of estimating and comparing conditional survival distributions while accounting for the predictive uncertainty of probabilistic models. Extensive experiments show that the distribution matching methods outperform existing approaches in terms of both calibration and concentration of time-to-event distributions.
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- 2023
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3. Technology-Enabled Clinical Trials
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Marquis-Gravel, Guillaume, Roe, Matthew T., Turakhia, Mintu P., Boden, William, Temple, Robert, Sharma, Abhinav, Hirshberg, Boaz, Slater, Paul, Craft, Noah, Stockbridge, Norman, McDowell, Bryan, Waldstreicher, Joanne, Bourla, Ariel, Bansilal, Sameer, Wong, Jennifer L., Meunier, Claire, Kassahun, Helina, Coran, Philip, Bataille, Lauren, Patrick-Lake, Bray, Hirsch, Brad, Reites, John, Mehta, Rajesh, Muse, Evan D., Chandross, Karen J., Silverstein, Jonathan C., Silcox, Christina, Overhage, J. Marc, Califf, Robert M., and Peterson, Eric D.
- Abstract
Supplemental Digital Content is available in the text.The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.
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- 2019
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4. High-Content Phenotypic Screening and Triaging Strategy to Identify Small Molecules Driving Oligodendrocyte Progenitor Cell Differentiation
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Peppard, Jane V., Rugg, Catherine A., Smicker, Matthew A., Powers, Elaine, Harnish, Erica, Prisco, Joy, Cirovic, Dragan, Wright, Paul S., August, Paul R., and Chandross, Karen J.
- Abstract
Multiple Sclerosis is a demyelinating disease of the CNS and the primary cause of neurological disability in young adults. Loss of myelinating oligodendrocytes leads to neuronal dysfunction and death and is an important contributing factor to this disease. Endogenous oligodendrocyte precursor cells (OPCs), which on differentiation are responsible for replacing myelin, are present in the adult CNS. As such, therapeutic agents that can stimulate OPCs to differentiate and remyelinate demyelinated axons under pathologic conditions may improve neuronal function and clinical outcome. We describe the details of an automated, cell-based, morphometric-based, high-content screen that is used to identify small molecules eliciting the differentiation of OPCs after 3 days. Primary screening was performed using rat CG-4 cells maintained in culture conditions that normally support a progenitor cell–like state. From a library of 73,000 diverse small molecules within the Sanofi collection, 342 compounds were identified that increased OPC morphological complexity as an indicator of oligodendrocyte maturation. Subsequent to the primary high-content screen, a suite of cellular assays was established that identified 22 nontoxic compounds that selectively stimulated primary rat OPCs but not C2C12 muscle cell differentiation. This rigorous triaging yielded several chemical series for further expansion and bio- or cheminformatics studies, and their compelling biological activity merits further investigation.
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- 2015
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5. Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation
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Sim, Fraser J., Lang, Jennifer K., Waldau, Ben, Roy, Neeta S., Schwartz, Theodore E., Pilcher, Webster H., Chandross, Karen J., Natesan, Sridaran, Merrill, Jean E., and Goldmanm, Steven A.
- Published
- 2006
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6. Tracking oligodendrocytes during development and regeneration
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Chandross, Karen J., Champagne, Benedicte, Auble, Kathryn, and Hudson, Lynn D.
- Abstract
Over the past decade, advances in strategies to tag cells have opened new avenues for examining the development of myelin‐forming glial cells and for monitoring transplanted cells in animal models of myelin insufficiency. The strategies for labelling glial cells have encompassed a range of genetic modifications as well as methods for directly attaching labels to cells. Genetically modified oligodendrocytes have been engineered to express enzymatic (e.g., β‐galactosidase, alkaline phosphatase), naturally fluorescent (e.g., green fluorescent protein), and antibiotic resistance (e.g., neomycin, zeomycin) reporters. Genes have been introduced in vivo and in vitro with viral or plasmid vectors to somatically label glial cells. To generate germ‐line transmission of tagged oligodendrocytes, transgenic mice have been created both by direct injection into mouse fertilized eggs and by “knock‐in” of reporters targetted to myelin gene loci in embryonic stem cells. Each experimental approach has advantages and limitations that need to be considered for individual applications. The availability of tagged glial cells has expanded our basic understanding of how oligodendrocytes are specified from stem cells and should continue to fill in the gaps in our understanding of how oligodendrocytes differentiate, myelinate, and maintain their myelin sheaths. Moreover, the ability to select oligodendrocytes by virtue of their acquired antibiotic resistance has provided an important new tool for isolating and purifying oligodendrocytes. Tagged glial cells have also been invaluable in evaluating cell transplant therapies in the nervous system. The tracking technologies that have driven these advances in glial cell biology are continuing to evolve and present new opportunities for examining oligodendrocytes in living systems. Microsc. Res. Tech. 52:766–777, 2001. Published 2001 Wiley‐Liss, Inc.
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- 2001
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7. TNFα Inhibits Schwann Cell Proliferation, Connexin46 Expression, and Gap Junctional Communication
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Chandross, Karen J., Spray, David C., Cohen, Rick I., Kumar, Nalin M., Kremer, Marian, Dermietzel, Rolf, and Kessler, John A.
- Abstract
Schwann cell responses to nerve injury are stimulated, in part, by inflammatory cytokines. This study compares changes in the phenotype of cultured Schwann cells after exposure to the cytokine tumor necrosis factor (TNF)-α or the mitogen neu differentiation factor (NDF)-β. TNFα inhibited proliferation in a dose-dependent manner without altering Schwann cell survival. TNFα also reduced both gap junctional conductance and Lucifer yellow dye coupling between Schwann cells. Moreover, both P0and glial fibrillary acidic protein (GFAP) immunoreactivity were reduced. By contrast, NDFβ initially had little effect on cell division although it reduced junctional coupling within 8h. However, by 48 h, NDFβ stimulated proliferation with a concomitant increase in coupling. Dividing Schwann cells (BrdU+) were preferentially dye coupled compared to nondividing cells, indicating an association between proliferation and coupling. Moreover, cultured Schwann cells expressed connexin46 mRNA and protein, and changes in the levels of the protein correlated with the degree of proliferation and coupling. The data thus provide evidence for cytokine-induced modulation of Schwann cell antigenic phenotype, proliferation, and gap junction properties. These observations suggest that enhanced gap junctional communication among Schwann cells after nerve injury could help to coordinate cellular responses to the injury, and that TNFα may be a signal which terminates proliferation as well as junctional communication.
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- 1996
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8. Altered Connexin Expression after Peripheral Nerve Injury
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Chandross, Karen J., Kessler, John A., Cohen, Rick I., Simburger, Eva, Spray, David C., Bieri, Phyllis, and Dermietzel, Rolf
- Abstract
The identification of connexin32 (Cx32) in myelinating Schwann cells and the association of Cx32 mutations with peripheral neuropathies suggest a functional role for gap junction proteins in the nerve. However, after nerve crush injury, Cx32 expression dramatically decreases in Schwann cells in the degenerating region, returning to control levels at newly formed nodes of Ranvier and Schmidt–Lantermann incisures by 30 days. The present study examined increases in expression of other connexins that occur after peripheral nerve injury. A 56/58-kDa connexin46 (Cx46) protein species was detected in adult rat sciatic nerve, along with very low levels of Cx46 mRNA. However, by 3 days after crush injury, coincident with changes in Schwann cell phenotype, Cx46 mRNA rapidly increased in the degenerating regions. Additionally, the 56/58-kDa Cx46 protein species present in adult nerve decreased and a 53-kDa Cx46 species, which was also present in cultured Schwann cells, became apparent. Connexin43 (Cx43) mRNA and protein, which was localized to perineurial cells in adult nerve, dramatically increased in endoneurial fibroblasts in the crush and distal regions by 3 days, coincident with macrophage infiltration. By 12 days after injury, Cx43 decreased and was comparable to normal nerve. These results suggest that enhanced expression of Cx46 and Cx43, by nonneuronal cells, may be important for the injury and regenerative responses of peripheral nerves.
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- 1996
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9. Corrections
- Author
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Sim, Fraser J., Lang, Jennifer K., Waldau, Ben, Roy, Neeta S., Schwartz, Theodore E., Pilcher, Webster H., Chandross, Karen J., Natesan, Sridaran, Merrill, Jean E., and Goldman, Steven A.
- Published
- 2006
- Full Text
- View/download PDF
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