Publications by authors named "Robert W Hsieh"

6 Publications

  • Page 1 of 1

Single-cell transcriptional diversity is a hallmark of developmental potential.

Science 2020 01;367(6476):405-411

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.

Single-cell RNA sequencing (scRNA-seq) is a powerful approach for reconstructing cellular differentiation trajectories. However, inferring both the state and direction of differentiation is challenging. Here, we demonstrate a simple, yet robust, determinant of developmental potential-the number of expressed genes per cell-and leverage this measure of transcriptional diversity to develop a computational framework (CytoTRACE) for predicting differentiation states from scRNA-seq data. When applied to diverse tissue types and organisms, CytoTRACE outperformed previous methods and nearly 19,000 annotated gene sets for resolving 52 experimentally determined developmental trajectories. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. This study thus establishes a key RNA-based feature of developmental potential and a platform for delineation of cellular hierarchies.
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http://dx.doi.org/10.1126/science.aax0249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694873PMC
January 2020

Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis.

Nat Commun 2017 11 21;8(1):1669. Epub 2017 Nov 21.

Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, 265 Campus Drive, Stanford, CA, 94305, USA.

Previous studies have proposed that epithelial to mesenchymal transition (EMT) in breast cancer cells regulates metastasis, stem cell properties and chemo-resistance; most studies were based on in vitro culture of cell lines and mouse transgenic cancer models. However, the identity and function of cells expressing EMT-associated genes in normal murine mammary gland homeostasis and human breast cancer still remains under debate. Using in vivo lineage tracing and triple negative breast cancer (TNBC) patient derived xenografts we demonstrate that the repopulating capacity in normal mammary epithelial cells and tumorigenic capacity in TNBC is independent of expression of EMT-associated genes. In breast cancer, while a subset of cells with epithelial and mesenchymal phenotypes have stem cell activity, in many cells that have lost epithelial characteristics with increased expression of mesenchymal genes, have decreased tumor-initiating capacity and plasticity. These findings have implications for the development of effective therapeutic agents targeting tumor-initiating cells.
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http://dx.doi.org/10.1038/s41467-017-01666-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698470PMC
November 2017

Cryptococcal osteomyelitis and meningitis in a patient with non-hodgkin's lymphoma treated with PEP-C.

BMJ Case Rep 2012 Sep 7;2012. Epub 2012 Sep 7.

Department of Internal Medicine, Scripps Clinic/Green Hospital, La Jolla, California, USA.

The authors present the first case report of a patient with lymphoma who developed disseminated cryptococcal osteomyelitis and meningitis while being treated with the PEP-C (prednisone, etoposide, procarbazine and cyclophosphamide) chemotherapy regimen. During investigation of fever and new bony lesions, fungal culture from a rib biopsy revealed that the patient had cryptococcal osteomyelitis. Further evaluation demonstrated concurrent cryptococcal meningitis. The patient's disseminated cryptococcal infections completely resolved after a full course of antifungal treatment. Cryptococcal osteomyelitis is itself an extremely rare diagnosis, and the unique presentation with concurrent cryptococcal meningitis in our patient with lymphoma was likely due to his PEP-C treatment. It is well recognised that prolonged intensive chemotherapeutic regimens place patients at risk for atypical infections; yet physicians should recognise that even chronic low-dose therapies can put patients at risk for fungal infections. Physicians should consider fungal infections as part of the infectious investigation of a lymphopaenic patient on PEP-C.
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http://dx.doi.org/10.1136/bcr.08.2011.4578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448757PMC
September 2012

Molecular characterization of a B-ring unsaturated estrogen: implications for conjugated equine estrogen components of premarin.

Steroids 2008 Jan 11;73(1):59-68. Epub 2007 Sep 11.

The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.

Conjugated equine estrogens (CEEs) are routinely used for hormone replacement therapy (HRT), making it important to understand the activities of individual estrogenic components. Although 17beta-estradiol (17beta-E2), the most potent estrogen in CEE, has been extensively characterized, the actions of nine additional less potent estrogens are not well understood. Structural differences between CEEs and 17beta-E2 result in altered interactions with the two estrogen receptors (ERalpha and ERbeta) and different biological activities. To better understand these interactions, we have determined the crystal structure of the CEE analog, 17beta-methyl-17alpha-dihydroequilenin (NCI 122), in complex with the ERalpha ligand-binding domain and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator. NCI 122 has chemical properties, including an unsaturated B-ring and 17alpha-hydroxyl group, which are shared with some of the estrogens found in CEEs. Structural analysis of the NCI 122-ERalpha LBD-GRIP1 complex, combined with biochemical and cell-based comparisons of CEE components, suggests that factors such as decreased ligand flexibility, decreased ligand hydrophobicity and loss of a hydrogen bond between the 17-hydroxyl group and His524, contribute significantly to the reduced potency of CEEs on ERalpha.
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http://dx.doi.org/10.1016/j.steroids.2007.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2225582PMC
January 2008

Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity.

J Biol Chem 2006 Jun 28;281(26):17909-19. Epub 2006 Apr 28.

Ben May Institute for Cancer Research, University of Chicago W330, 929 E. 57th Street, Chicago, IL 60637, USA.

Estrogen receptors alpha (ERalpha) and beta (ERbeta) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ERbeta-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10-50-fold selective for ERbeta in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ERbeta regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ERbeta-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ERalpha ligand-binding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ERbeta selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ERbeta and Met-421 in ERalpha. These bicyclic ligands show promise as lead compounds that can target ERbeta. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class.
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http://dx.doi.org/10.1074/jbc.M513684200DOI Listing
June 2006

Label-free detection of protein-protein interactions on biochips.

Angew Chem Int Ed Engl 2005 Aug;44(34):5480-3

Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA.

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http://dx.doi.org/10.1002/anie.200501363DOI Listing
August 2005