Nicholas Ng

Brigham and Women's Hospital

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Raymond M. Anchan

Brigham and Women's Hospital

Mindy H. Hsieh

Genomics Institute of the Novartis Research Foundation

Shifeng Pan

Yangzhou University

Anthony A. Horner

Quest Diagnostics (United States)

Behzad Gerami‐Naini

Harvard University

Emily Disler

Tufts University

Jennifer L. Harris

University of Connecticut

Jun Liu

Guangxi Medical University

Diane P. Lam

Franklin W. Olin College of Engineering

Glenda Batzer

Penn State Milton S. Hershey Medical Center

Cooperative Institutions

Harvard University

Brigham and Women's Hospital

Genomics Institute of the Novartis Research Foundation

Novartis (United States)

Novartis (Switzerland)

Novartis Institutes for BioMedical Research

Massachusetts General Hospital

University of Michigan–Ann Arbor

Dana-Farber Cancer Institute

Harvard University Press

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

The Application of Knowledge Engineering via the Use of a Biomimetic Digital Twin Ecosystem, Phenotype-Driven Variant Analysis, and Exome Sequencing to Understand the Molecular Mechanisms of Disease

Journal of Molecular Diagnostics (2024)

W.G. Kearns Georgios Stamoulis Joseph Glick Lawrence Baisch A.T. Benner

Applied Artificial Intelligence, particularly Large Language Models, in biomedical research is accelerating, but effective discovery and validation requires a toolset without limitations or bias. On January 30, 2023, the National Academies of Sciences, Engineering, and Medicine (NAS) appointed an ad hoc committee to identify needs and opportunities to advance the mathematical, statistical, and computational foundations of digital twins in applications across science, medicine, engineering, and society. On December 15, 2023, the NAS released a 164 page report, "Foundational Research Gaps and Future Directions for Digital Twins". This report described the importance of using digital twins in biomedical research. We developed an innovative method that incorporated phenotype ranking algorithms with knowledge engineering via a biomimetic digital twin ecosystem. This ecosystem applied real-world reasoning principles to non-normalized, raw data to identify hidden or "dark data". We performed a clinical exome sequencing study on patients with endometriosis and were able to identify four VUSs potentially associated with endometriosis-related disorders in nearly all patients analyzed. One VUS was identified in all patient samples and could be a biomarker for diagnostics. To the best of our knowledge, this is the first study to incorporate the recomandations of the NAS to biomedical research. This method can be used to understand the mechanisms of any disease, for virtual clinical trials, and to identify effective new therapies.

Clinical phenotype

10.1016/j.jmoldx.2024.03.004

Cite

Citations (2)

Pax6- and Six3-Mediated Induction of Lens Cell Fate in Mouse and Human ES Cells

PLoS ONE (2014)

Raymond M. Anchan Salil A. Lachke Behzad Gerami‐Naini J. Suzanne Lindsey Nicholas Ng

Embryonic stem (ES) cells provide a potentially useful in vitro model for the study of in vivo tissue differentiation. We used mouse and human ES cells to investigate whether the lens regulatory genes Pax6 and Six3 could induce lens cell fate in vitro. To help assess the onset of lens differentiation, we derived a new mES cell line (Pax6-GFP mES) that expresses a GFP reporter under the control of the Pax6 P0 promoter and lens ectoderm enhancer. Pax6 or Six3 expression vectors were introduced into mES or hES cells by transfection or lentiviral infection and the differentiating ES cells analyzed for lens marker expression. Transfection of mES cells with Pax6 or Six3 but not with other genes induced the expression of lens cell markers and up-regulated GFP reporter expression in Pax6-GFP mES cells by 3 days post-transfection. By 7 days post-transfection, mES cell cultures exhibited a>10-fold increase over controls in the number of colonies expressing γA-crystallin, a lens fiber cell differentiation marker. RT-PCR and immunostaining revealed induction of additional lens epithelial or fiber cell differentiation markers including Foxe3, Prox1, α- and β-crystallins, and Tdrd7. Moreover, γA-crystallin- or Prox1-expressing lentoid bodies formed by 30 days in culture. In hES cells, Pax6 or Six3 lentiviral vectors also induced lens marker expression. mES cells that express lens markers reside close to but are distinct from the Pax6 or Six3 transduced cells, suggesting that the latter induce nearby undifferentiated ES cells to adopt a lens fate by non-cell autonomous mechanisms. In sum, we describe a novel mES cell GFP reporter line that is useful for monitoring induction of lens fate, and demonstrate that Pax6 or Six3 is sufficient to induce ES cells to adopt a lens fate, potentially via non-cell autonomous mechanisms. These findings should facilitate investigations of lens development.

PAX6

Crystallin

10.1371/journal.pone.0115106

Cite

Citations (18)

An Embryonic and Induced Pluripotent Stem Cell Model for Ovarian Granulosa Cell Development and Steroidogenesis

Reproductive Sciences (2017)

S.T. Lipskind J. Suzanne Lindsey Behzad Gerami‐Naini Jennifer L. Eaton Daniel J. O’Connell

Embryoid body

Granulosa cell

10.1177/1933719117725814

Cite

Citations (29)

Contributors

Elsevier eBooks (2021)

Mohamed Al‐Sayegh Fiorella Altruda Christopher J. Anchan Raymond M. Anchan Asma Bashir

10.1016/b978-0-12-822135-8.01002-8

Cite

Citations (0)

iPSC-Derived Ovarian Tissue Restores Ovarian Function in Subfertile Mice and After Gonadotoxic Chemotherapy

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Kevin M. Elias Nicholas Ng K. Dam Ankrish Milne Emily Disler

Abstract Many reproductive age women with cancer who receive chemotherapy are exposed to gonadotoxic agents and risk diminished ovarian reserve, sterility, and premature menopause. Previously, we reported the derivation of steroidogenic ovarian cells from induced pluripotent and embryonic stem cells. Derived cells not only produced reproductive hormones, but also displayed markers of ovarian tissue and primordial gametes. Here, we describe that human follicular fluid (HFF), when added to our stem cell differentiation system, enhances the steroidogenic potential of differentiating stem cells and increases the subpopulation of cells that express the ovarian and germ cell markers GJA1 and ZP1, respectively. More importantly, using an in vivo model of chemotherapy-induced premature ovarian insufficiency in subfertile nude mice, we demonstrate that orthotopic implantation of these derived cells restores ovarian hormone synthesis and produces functional stem cell-derived oocytes. Additionally, these cells also ameliorate subfertility in nude mice, as demonstrated by the delivery of multiple litters of healthy pups from stem cell-derived oocytes. Collectively, these data support the hypothesis that stem cell-derived steroidogenic ovarian tissue could be used to promote neo-gametogenesis and treat the endocrinologic and reproductive sequelae of premature ovarian insufficiency. One Sentence Summary We show that orthotopic injection of sorted, differentiated iPSCs in ovaries of subfertile mice restores reproductive hormone synthesis and fertility.

Premature ovarian insufficiency

Ovarian Reserve

Premature ovarian failure

Anti-Müllerian hormone

10.1101/697532

Cite

Citations (0)

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Proceedings of the National Academy of Sciences (2013)

Jun Liu Shifeng Pan Mindy H. Hsieh Nicholas Ng Fangxian Sun

Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.

Porcupine

10.1073/pnas.1314239110

Cite

Citations (742)

Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors

ACS Medicinal Chemistry Letters (2016)

Cheng Dai Jun Liu Dong Han Guobao Zhang Wenqi Gao

Blockade of aberrant Wnt signaling is an attractive therapeutic approach in multiple cancers. We developed and performed a cellular high-throughput screen for inhibitors of Wnt secretion and pathway activation. A lead structure (GNF-1331) was identified from the screen. Further studies identified the molecular target of GNF-1331 as Porcupine, a membrane bound O-acyl transferase. Structure-activity relationship studies led to the discovery of a novel series of potent and selective Porcupine inhibitors. Compound 19, GNF-6231, demonstrated excellent pathway inhibition and induced robust antitumor efficacy in a mouse MMTV-WNT1 xenograft tumor model.

Acetamide

10.1021/acsmedchemlett.6b00038

Cite

Citations (38)

Activation of the Wnt Pathway in a Corneal Neovascularization Model

Investigative Ophthalmology & Visual Science (2012)

Sassan M. Azarian Rosemarie Cepeda Jun Liu Shifeng Pan Nicholas Ng

Corneal Neovascularization

Source

Cite

Citations (0)

Using house dust extracts to understand the immunostimulatory activities of living environments

Immunobiology (2007)

Glenda Batzer Diane P. Lam Petra Paulus Jared Boasen Nicholas Ng

TLR9

10.1016/j.imbio.2007.03.004

Cite

Citations (19)

Selenium binding protein 1 in ovarian cancer

International Journal of Cancer (2005)

Kuan‐Chun Huang Dong Choon Park Shu‐Kay Ng Ji Young Lee Xiaoyan Ni

Selenium binding protein 1 (SELENBP1) was identified to be the most significantly down-regulated protein in ovarian cancer cells by a membrane proteome profiling analysis. SELENBP1 expression levels in 4 normal ovaries, 8 benign ovarian tumors, 12 borderline ovarian tumors and 141 invasive ovarian cancers were analyzed with immunohistochemical assay. SELENBP1 expression was reduced in 87% cases of invasive ovarian cancer (122/141) and was significantly reduced in borderline tumors and invasive cancers (p<0.001). Cox multivariate analysis within the 141 invasive cancer tissues showed that SELENBP1 expression score was a potential prognostic indicator for unfavorable prognosis of ovarian cancer (hazard ratio [HR], 2.18; 95% CI=1.22-3.90; p=0.009). Selenium can disrupt the androgen pathway, which has been implicated in modulating SELENBP1 expression. We investigated the effects of selenium and androgen on normal human ovarian surface epithelial (HOSE) cells and cancer cells. Interestingly, SELENBP1 mRNA and protein levels were reduced by androgen and elevated by selenium treatment in the normal HOSE cells, whereas reversed responses were observed in the ovarian cancer cell lines. These results suggest that changes of SELENBP1 expression in malignant ovarian cancer are an indicator of aberration of selenium/androgen pathways and may reveal prognostic information of ovarian cancer.

10.1002/ijc.21671

Cite

Citations (94)