Publications by authors named "W Patrick Devine"

80 Publications

Structure-property studies of an imidazoquinoline chemotype with antitrypanosomal activity.

RSC Med Chem 2020 Aug 10;11(8):950-959. Epub 2020 Jul 10.

Department of Chemistry & Chemical Biology , Northeastern University , 360 Huntington Avenue , Boston , MA 02115 , USA . Email:

Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound , with a particular focus on improvement of absorption, distribution, metabolism and elimination (ADME) properties. These efforts resulted in several compounds with substantially improved aqueous solubility, although these modifications typically resulted in a loss of trypanosomal activity. We herein report the results of our investigation into the antiparasitic activity, toxicity, and ADME properties of this class of compounds in the interest of informing the NTD drug discovery community and avoiding duplication of effort.
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http://dx.doi.org/10.1039/d0md00103aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496307PMC
August 2020

Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease.

Dev Cell 2021 Feb 14;56(3):292-309.e9. Epub 2020 Dec 14.

Gladstone Institutes, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94158, USA. Electronic address:

Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways-including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics-in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.
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http://dx.doi.org/10.1016/j.devcel.2020.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878434PMC
February 2021

A Membrane-Tethered Ubiquitination Pathway Regulates Hedgehog Signaling and Heart Development.

Dev Cell 2020 11 22;55(4):432-449.e12. Epub 2020 Sep 22.

Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

The etiology of congenital heart defects (CHDs), which are among the most common human birth defects, is poorly understood because of its complex genetic architecture. Here, we show that two genes implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a receptor-like ubiquitin ligase complex that catalyzes the ubiquitination and degradation of the Hedgehog pathway transducer Smoothened. Homozygous Megf8 and Mgrn1 mutations increased Smoothened abundance and elevated sensitivity to Hedgehog ligands. While mice heterozygous for loss-of-function Megf8 or Mgrn1 mutations were normal, double heterozygous embryos exhibited an incompletely penetrant syndrome of CHDs with heterotaxy. Thus, genetic interactions can arise from biochemical mechanisms that calibrate morphogen signaling strength, a conclusion broadly relevant for the many human diseases in which oligogenic inheritance is emerging as a mechanism for heritability.
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http://dx.doi.org/10.1016/j.devcel.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686252PMC
November 2020

Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

PLoS Comput Biol 2020 04 10;16(4):e1007753. Epub 2020 Apr 10.

Genomics Institute, University of California, Santa Cruz, Santa Cruz, California, United States of America.

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.
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http://dx.doi.org/10.1371/journal.pcbi.1007753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176284PMC
April 2020

Next-Generation Sequencing of Retinoblastoma Identifies Pathogenic Alterations beyond RB1 Inactivation That Correlate with Aggressive Histopathologic Features.

Ophthalmology 2020 06 12;127(6):804-813. Epub 2019 Dec 12.

Department of Ophthalmology, University of California, San Francisco, San Francisco, California; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Purpose: To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma.

Design: Cohort study.

Participants: Thirty-two children with retinoblastoma.

Methods: We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing.

Main Outcome Measures: Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features.

Results: Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease.

Conclusions: Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.
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http://dx.doi.org/10.1016/j.ophtha.2019.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246167PMC
June 2020

Rocaglates Induce Gain-of-Function Alterations to eIF4A and eIF4F.

Cell Rep 2020 02;30(8):2481-2488.e5

Department of Biochemistry, McGill University, Montreal, QC, Canada; Department of Oncology, McGill University, Montreal, QC, Canada; Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada. Electronic address:

Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5' leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.
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http://dx.doi.org/10.1016/j.celrep.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077502PMC
February 2020

Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer.

Surg Pathol Clin 2020 Mar;13(1):17-33

Department of Pathology, University of California San Francisco, 1600 Divisadero Street Room B-620, San Francisco, CA 94115, USA.

Lung cancer is the leading cause of cancer mortality. It is classified into different histologic subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma (commonly referred as non-small cell lung cancer) and small cell lung cancer. Comprehensive molecular characterization of lung cancer has expanded our understanding of the cellular origins and molecular pathways affected in each of these subtypes. Many of these genetic alterations represent potential therapeutic targets for which drugs are constantly under development. This article discusses the molecular characteristics of the main lung cancer subtypes and discusses the current guidelines and novel targeted therapies, including checkpoint immunotherapy.
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http://dx.doi.org/10.1016/j.path.2019.11.002DOI Listing
March 2020

NTRK fusion cervical sarcoma: a report of three cases, emphasising morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.

Histopathology 2020 Jul 12;77(1):100-111. Epub 2020 Jun 12.

Pathology Department, University of California, San Francisco, CA, USA.

Aims: A unique fibrosarcoma-like tumour of the uterine cervix harbouring a rearrangement of a neurotrophic tyrosine kinase receptor (NTRK) gene (NTRK1 or NTRK3) has recently been described in 11 young women, some with recurrence and/or metastasis. The aims of this study were to expand the morphological spectrum of this tumour by reporting three additional cases that showed adenosarcoma-like features not previously described, one of which is the first reported to respond to targeted therapy, and to evaluate 19 conventional uterine adenosarcomas for evidence of NTRK rearrangement.

Methods And Results: Three patients presented with a polyp or mass confined to the cervix. The constellation of polypoid growth, spindle cell morphology, entrapped endocervical glands and intraglandular stromal projections raised diagnostic consideration for adenosarcoma with stromal overgrowth. Deep cervical wall invasion was present in two cases at hysterectomy, and the third was removed by polypectomy. All three stained for S100 and pan-Trk, but were negative for a spectrum of other diagnostic markers. All three harboured NTRK rearrangements (TPM3-NTRK1, TPR-NTRK1, and SPECC1L-NTRK3). One patient developed pleural metastases at 16 months, received the NTRK inhibitor larotrectinib, and is free of disease 15 months later. Two others are alive without disease. None of the uterine adenosarcomas showed any S100 or pan-Trk staining, or rearrangement of NTRK1, NTRK2 or NTRK3 on next-generation sequencing.

Conclusions: Unusual adenosarcoma-like spindle cell neoplasms of the cervix may represent an NTRK fusion sarcoma, which can be detected by S100 and pan-Trk staining and confirmed by NTRK molecular testing. Conventional uterine adenosarcomas do not harbour NTRK rearrangements.
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http://dx.doi.org/10.1111/his.14069DOI Listing
July 2020

Practical roles for molecular diagnostic testing in ovarian adult granulosa cell tumour, Sertoli-Leydig cell tumour, microcystic stromal tumour and their mimics.

Histopathology 2020 Jan;76(1):11-24

Clinical Cancer Genomics Laboratory and Pathology Department, University of California San Francisco, San Francisco, CA, USA.

Within the last decade, molecular advances have provided insights into the genetics of several ovarian sex cord-stromal tumours that have otherwise been enigmatic. Chief among these advances are the identification of FOXL2, DICER1 and CTNNB1 mutations in adult granulosa cell tumours, Sertoli-Leydig cell tumours (SLCTs), and microcystic stromal tumours (MCSTs), respectively. As access to molecular diagnostic laboratories continues to become more widely available, the potential roles for tumour mutation testing in the pathological diagnosis of these tumours merit discussion. Furthermore, links to inherited cancer susceptibility syndromes may exist for some women with SLCT (DICER1 syndrome) and MCST [familial adenomatous polyposis (FAP)]. This review will address practical issues in deciding when and how to apply mutation testing in the diagnosis of these three sex cord-stromal tumours. The pathologist's role in recommending referral for formal risk assessment for DICER1 syndrome and FAP will also be discussed.
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http://dx.doi.org/10.1111/his.13978DOI Listing
January 2020

Amidino-Rocaglates: A Potent Class of eIF4A Inhibitors.

Cell Chem Biol 2019 11 10;26(11):1586-1593.e3. Epub 2019 Sep 10.

Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Oncology, McGill University, Montreal, Canada; Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada. Electronic address:

Rocaglates share a common cyclopenta[b]benzofuran core that inhibits eukaryotic translation initiation by modifying the behavior of the RNA helicase, eIF4A. Working as interfacial inhibitors, rocaglates stabilize the association between eIF4A and RNA, which can lead to the formation of steric barriers that block initiating ribosomes. There is significant interest in the development and expansion of rocaglate derivatives, as several members of this family have been shown to possess potent anti-neoplastic activity in vitro and in vivo. To further our understanding of rocaglate diversity and drug design, herein we explore the RNA clamping activity of >200 unique rocaglate derivatives. Through this, we report on the identification and characterization of a potent class of synthetic rocaglates called amidino-rocaglates. These compounds are among the most potent rocaglates documented to date and, taken together, this work offers important information that will guide the future design of rocaglates with improved biological properties.
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http://dx.doi.org/10.1016/j.chembiol.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874763PMC
November 2019

Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas.

Leukemia 2020 01 6;34(1):138-150. Epub 2019 Jun 6.

Departments of Pathology, Hematology and Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.

MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (-)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.
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http://dx.doi.org/10.1038/s41375-019-0503-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895415PMC
January 2020

Stream Conditions after 18 Years of Passive Riparian Restoration in Small Fish-bearing Watersheds.

Environ Manage 2019 05 18;63(5):673-690. Epub 2019 Feb 18.

U.S. Department of Agriculture Forest Service, PNW Research Station, Forestry Sciences Laboratory, 3625 93rd Avenue SW, Olympia, WA, 98512-9193, USA.

Many of the ecological processes in the riparian forests and streams across the Pacific Northwest have become impaired through production forestry practices common prior to the 1990s. Some of these practices included forest harvest without stream buffers, removal of instream wood, road construction and use, and harvesting large proportions of watersheds. Passive ecological restoration (the use of natural processes of succession and disturbance to alleviate anthropogenic impacts over time) is a common practice used in the management of riparian forests previously subjected to production forestry. Eighteen years after the implementation of passive restoration of riparian forests, we used four common stream indicators (stream temperature, canopy closure, instream wood, and salmonid densities) to assess the effects of restoration in small fish-bearing streams. Summer stream temperatures have decreased below unmanaged reference levels, whereas riparian forest canopy closure has increased beyond that in reference watersheds. Instream wood and age-1 or older salmonids appear to be either stable at reduced levels or declining, compared with production forestry and unmanaged reference watersheds. Overall, second-growth riparian forests need more time to develop allowing more light into streams (increasing primary productivity), while also allowing for the continuous recruitment of larger pieces of instream wood (improving habitat for salmonids). Using only passive restoration, stream conditions in second-growth forests are unlikely to increase salmonid production in the near future.
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http://dx.doi.org/10.1007/s00267-019-01146-xDOI Listing
May 2019

Oxo-aglaiastatin-Mediated Inhibition of Translation Initiation.

Sci Rep 2019 02 4;9(1):1265. Epub 2019 Feb 4.

Department of Biochemistry, McGill University, Montreal, Québec, H3G 1Y6, Canada.

Translation is a highly regulated process that is perturbed in human cancers, often through activation of the PI3K/mTOR pathway which impacts directly on the ribosome recruitment phase of translation initiation. While significant research has focused on "drugging" components of the PI3K/mTOR network, efforts have also been directed towards inhibiting eukaryotic initiation factor (eIF) 4F-dependent translation. Small molecule inhibitors of this complex have been identified, characterized, and used to validate the rationale of targeting this step to curtail tumor cell growth and modulate chemotherapy response. One such class of compounds are the rocaglates, secondary metabolites from the plant genus Aglaia, which target the RNA helicase subunit of eIF4F, eIF4A. Here we explore the ability of synthetic derivatives of aglaiastatins and an aglaroxin derivative to target the translation process in vitro and in vivo and find the synthetic derivative oxo-aglaiastatin to possess such activity. Oxo-aglaiastatin inhibited translation in vitro and in vivo and synergized with doxorubicin, ABT-199 (a Bcl-2 antagonist), and dexamethasone when tested on hematological cancer cells. The biological activity of oxo-aglaiastatin was shown to be a consequence of inhibiting eIF4A1 activity.
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http://dx.doi.org/10.1038/s41598-018-37666-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361980PMC
February 2019

Simplified Luminal Water Imaging for the Detection of Prostate Cancer From Multiecho T MR Images.

J Magn Reson Imaging 2019 09 19;50(3):910-917. Epub 2018 Dec 19.

Centre for Medical Imaging, University College London, London, United Kingdom.

Background: Luminal water imaging (LWI) suffers less from imaging artifacts than the diffusion-weighted imaging used in multiparametric MRI of the prostate. LWI obtains multicompartment tissue information from a multiecho T dataset.

Purpose: To compare a simplified LWI technique with apparent diffusion coefficient (ADC) in classifying lesions based on groupings of PI-RADS v2 scores. Secondary aims were to investigate whether LWI differentiates between histologically confirmed tumor and normal tissue as effectively as ADC, and whether LWI is correlated with the multicompartment parameters of the vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT) diffusion model.

Study Type: A subset of a larger prospective study.

Population: In all, 65 male patients aged 49-79 were scanned.

Field Strength/sequence: A 32-echo T and a six b-value diffusion sequence (0, 90, 500, 1500, 2000, 3000 s/mm ) at 3T.

Assessment: Regions of interest were placed by a board-certified radiologist in areas of lesion and benign tissue and given PI-RADS v2 scores.

Statistical Tests: Receiver operating characteristic and logistic regression analyses were performed.

Results: LWI classifies tissue as PI-RADS 1,2 or PI-RADS 3,4,5 with an area under curve (AUC) value of 0.779, compared with 0.764 for ADC. LWI differentiated histologically confirmed malignant from nonmalignant tissue with AUC, sensitivity, and specificity values of 0.81, 75%, and 87%, compared with 0.75, 83%, and 67% for ADC. The microstructural basis of the LWI technique is further suggested by the correspondence with the VERDICT diffusion-based microstructural imaging technique, with α, A , A , and LWF showing significant correlations.

Data Conclusion: LWI alone can predict PI-RADS v2 score groupings and detect histologically confirmed tumors with an ability similar to ADC alone without the limitations of diffusion-weighted MRI. This is important, given that ADC has an advantage in these tests as it already informs PI-RADS v2 scoring. LWI also provides multicompartment information that has an explicit biophysical interpretation, unlike ADC.

Level Of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:910-917.
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http://dx.doi.org/10.1002/jmri.26608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767562PMC
September 2019

Identification of high-risk human papillomavirus and Rb/E2F pathway genomic alterations in mutually exclusive subsets of colorectal neuroendocrine carcinoma.

Mod Pathol 2019 02 20;32(2):290-305. Epub 2018 Sep 20.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Colorectal neuroendocrine carcinomas, both small cell and large cell types, are highly aggressive tumors with poor prognosis compared with colorectal adenocarcinoma. The molecular drivers of neuroendocrine carcinoma are best defined in small cell lung cancer, which shows near-universal genomic alterations in TP53 and RB1. The genetics of colorectal neuroendocrine carcinoma remain poorly understood; recent studies demonstrated infrequent RB1 alterations and genetics closely resembling colorectal adenocarcinoma. To better define the molecular pathogenesis of colorectal neuroendocrine carcinoma, we performed capture-based next-generation sequencing on 25 cases and evaluated for expression of p53, Rb, p16, and high-risk human papillomavirus (HR-HPV) subtypes using immunohistochemistry, in situ hybridization, and polymerase chain reaction. Rb/E2F pathway dysregulation was identified in nearly all cases (23/25, 92%) and occurred via three distinct mechanisms. First, RB1 genomic alteration was present in 56% (14/25) of cases and was accompanied by Rb protein loss, high p16 expression, and absence of HR-HPV; these cases also had frequent genomic alterations in TP53, the PI3K/Ras and Wnt pathways, as well as in DNA repair genes, with 4/14 cases being hypermutated. Second, 16% (4/25) of cases, all left-sided, had TP53 alteration without RB1 alteration; half of these harbored high-level amplifications in CCNE1 and MYC or MYCN and arose in patients with ulcerative colitis. Finally, 28% (7/25) of cases, all rectal or anal, lacked genomic alterations in RB1 or TP53 but were positive for HR-HPV. Our data demonstrate that Rb/E2F pathway dysregulation is essential in the pathogenesis of colorectal neuroendocrine carcinoma, akin to neuroendocrine carcinomas in other anatomic sites. Moreover, colorectal neuroendocrine carcinomas stratify into three distinct molecular subgroups, which can be differentiated based on Rb protein and HR-HPV status. HR-HPV infection represents a distinct mechanism for Rb and p53 inactivation in cases lacking genomic alterations in either gene. Differential treatment strategies for hypermutated and HPV-driven cases could improve patient outcomes.
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http://dx.doi.org/10.1038/s41379-018-0131-6DOI Listing
February 2019

Airway ciliary dysfunction and respiratory symptoms in patients with transposition of the great arteries.

PLoS One 2018 14;13(2):e0191605. Epub 2018 Feb 14.

Dept. of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

Background: Our prior work on congenital heart disease (CHD) with heterotaxy, a birth defect involving randomized left-right patterning, has shown an association of a high prevalence of airway ciliary dysfunction (CD; 18/43 or 42%) with increased respiratory symptoms. Furthermore, heterotaxy patients with ciliary dysfunction were shown to have more postsurgical pulmonary morbidities. These findings are likely a reflection of the common role of motile cilia in both airway clearance and left-right patterning. As CHD comprising transposition of the great arteries (TGA) is commonly thought to involve disturbance of left-right patterning, especially L-TGA with left-right ventricular inversion, we hypothesize CHD patients with transposition of great arteries (TGA) may have high prevalence of airway CD with increased respiratory symptoms.

Methods And Results: We recruited 75 CHD patients with isolated TGA, 28% L and 72% D-TGA. Patients were assessed using two tests typically used for evaluating airway ciliary dysfunction in patients with primary ciliary dyskinesia (PCD), a recessive sinopulmonary disease caused by respiratory ciliary dysfunction. This entailed the measurement of nasal nitric oxide (nNO), which is typically low with PCD. We also obtained nasal scrapes and conducted videomicroscopy to assess respiratory ciliary motion (CM). We observed low nNO in 29% of the patients, and abnormal CM in 57%, with 22% showing both low nNO and abnormal CM. No difference was observed for the prevalence of either low nNO or abnormal ciliary motion between patients with D vs. L-TGA. Respiratory symptoms were increased with abnormal CM, but not low nNO. Sequencing analysis showed no compound heterozygous or homozygous mutations in 39 genes known to cause PCD, nor in CFTR, gene causing cystic fibrosis. As both are recessive disorders, these results indicate TGA patients with ciliary dysfunction do not have PCD or cystic fibrosis (which can cause low nNO or abnormal ciliary motion).

Conclusions: TGA patients have high prevalence of abnormal CM and low nNO, but ciliary dysfunction was not correlated with TGA type. Differing from PCD, respiratory symptoms were increased with abnormal CM, but not low nNO. Together with the negative findings from exome sequencing analysis, this would suggest TGA patients with ciliary dysfunction do not have PCD but nevertheless may suffer from milder airway clearance deficiency. Further studies are needed to investigate whether such ciliary dysfunction is associated with increased postsurgical complications as previously observed in CHD patients with heterotaxy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191605PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812576PMC
March 2018

A novel reporter allele for monitoring expression within the embryonic and adult mouse.

Biol Open 2018 Mar 12;7(3). Epub 2018 Mar 12.

Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA

Canonical Notch signaling requires the presence of a membrane bound ligand and a corresponding transmembrane Notch receptor. Receptor engagement induces multiple proteolytic cleavage events culminating in the nuclear accumulation of the Notch intracellular domain and its binding to a transcriptional co-factor to mediate gene expression. Notch signaling networks are essential regulators of vascular patterning and angiogenesis, as well as myriad other biological processes. () encodes the earliest Notch ligand detected in arterial cells, and is enriched in sprouting endothelial tip cells. expression has often been inferred by proxy using a knockin reporter allele. This is problematic, as a single copy of is haploinsufficient. Additionally, Notch activity regulates transcription, making it unclear whether these reporter lines accurately reflect expression. Accordingly, precisely defining expression is essential for determining its role in development and disease. To address these limitations, we generated a novel BAC transgenic allele with a nuclear-localized β-galactosidase reporter (). Through a comparative analysis, we show the BAC line overcomes previous issues of haploinsufficiency, it recapitulates expression , and allows superior visualization and imaging. As such, this novel reporter is an important addition to the growing Notch toolkit.
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http://dx.doi.org/10.1242/bio.026799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898260PMC
March 2018

The complex genetics of hypoplastic left heart syndrome.

Nat Genet 2017 Jul 22;49(7):1152-1159. Epub 2017 May 22.

Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Congenital heart disease (CHD) affects up to 1% of live births. Although a genetic etiology is indicated by an increased recurrence risk, sporadic occurrence suggests that CHD genetics is complex. Here, we show that hypoplastic left heart syndrome (HLHS), a severe CHD, is multigenic and genetically heterogeneous. Using mouse forward genetics, we report what is, to our knowledge, the first isolation of HLHS mutant mice and identification of genes causing HLHS. Mutations from seven HLHS mouse lines showed multigenic enrichment in ten human chromosome regions linked to HLHS. Mutations in Sap130 and Pcdha9, genes not previously associated with CHD, were validated by CRISPR-Cas9 genome editing in mice as being digenic causes of HLHS. We also identified one subject with HLHS with SAP130 and PCDHA13 mutations. Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, whereas Pcdha9 increases penetrance of aortic valve abnormalities, both signature HLHS defects. These findings show that HLHS can arise genetically in a combinatorial fashion, thus providing a new paradigm for the complex genetics of CHD.
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http://dx.doi.org/10.1038/ng.3870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737968PMC
July 2017

Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma.

Sci Transl Med 2017 05;9(389)

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Multiple myeloma (MM) is a frequently incurable hematological cancer in which overactivity of MYC plays a central role, notably through up-regulation of ribosome biogenesis and translation. To better understand the oncogenic program driven by MYC and investigate its potential as a therapeutic target, we screened a chemically diverse small-molecule library for anti-MM activity. The most potent hits identified were rocaglate scaffold inhibitors of translation initiation. Expression profiling of MM cells revealed reversion of the oncogenic MYC-driven transcriptional program by CMLD010509, the most promising rocaglate. Proteome-wide reversion correlated with selective depletion of short-lived proteins that are key to MM growth and survival, most notably MYC, MDM2, CCND1, MAF, and MCL-1. The efficacy of CMLD010509 in mouse models of MM confirmed the therapeutic relevance of these findings in vivo and supports the feasibility of targeting the oncogenic MYC-driven translation program in MM with rocaglates.
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http://dx.doi.org/10.1126/scitranslmed.aal2668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718051PMC
May 2017

Antiparasitic Lead Discovery: Toward Optimization of a Chemotype with Activity Against Multiple Protozoan Parasites.

ACS Med Chem Lett 2017 Mar 5;8(3):350-354. Epub 2017 Feb 5.

Department of Chemistry & Chemical Biology, Northeastern University , 360 Huntington Avenue, Boston, Massachusetts 02115, United States.

Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis present a significant burden across the developing world. Existing therapeutics for these protozoal neglected tropical diseases suffer from severe side effects and toxicity. Previously, NEU-1045 () was identified as a promising lead with cross-pathogen activity, though it possessed poor physicochemical properties. We have designed a library of analogues with improved calculated physicochemical properties built on the quinoline scaffold of incorporating small, polar aminoheterocycles in place of the 4-(3-fluorobenzyloxy)aniline substituent. We report the biological activity of these inhibitors against (HAT), (Chagas disease), and (cutaneous leishmaniasis) and describe the identification of -(5-chloropyrimidin-2-yl)-6-(4-(morpholinosulfonyl)phenyl)quinolin-4-amine () as a promising inhibitor of proliferation and 6-(4-(morpholinosulfonyl)phenyl)--(pyrimidin-4-yl)quinolin-4-amine (), a potent inhibitor of proliferation with improved drug-like properties.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346991PMC
March 2017

From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis.

ACS Infect Dis 2017 03 8;3(3):225-236. Epub 2017 Feb 8.

Department of Chemistry & Chemical Biology, Northeastern University 360 Huntington Avenue, Boston, Massachusetts, United States.

Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structure-activity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.
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http://dx.doi.org/10.1021/acsinfecdis.6b00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346068PMC
March 2017

Brain Dysplasia Associated with Ciliary Dysfunction in Infants with Congenital Heart Disease.

J Pediatr 2016 Nov 26;178:141-148.e1. Epub 2016 Aug 26.

Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Objective: To test for associations between abnormal respiratory ciliary motion (CM) and brain abnormalities in infants with congenital heart disease (CHD) STUDY DESIGN: We recruited 35 infants with CHD preoperatively and performed nasal tissue biopsy to assess respiratory CM by videomicroscopy. Cranial ultrasound scan and brain magnetic resonance imaging were obtained pre- and/or postoperatively and systematically reviewed for brain abnormalities. Segmentation was used to quantitate cerebrospinal fluid and regional brain volumes. Perinatal and perioperative clinical variables were collected.

Results: A total of 10 (28.5%) patients with CHD had abnormal CM. Abnormal CM was not associated with brain injury but was correlated with increased extraaxial cerebrospinal fluid volume (P < .001), delayed brain maturation (P < .05), and a spectrum of subtle dysplasia including the hippocampus (P < .0078) and olfactory bulb (P < .034). Abnormal CM was associated with higher composite dysplasia score (P < .001), and both were correlated with elevated preoperative serum lactate (P < .001).

Conclusions: Abnormal respiratory CM in infants with CHD is associated with a spectrum of brain dysplasia. These findings suggest that ciliary defects may play a role in brain dysplasia in patients with CHD and have the potential to prognosticate neurodevelopmental risks.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085835PMC
http://dx.doi.org/10.1016/j.jpeds.2016.07.041DOI Listing
November 2016

Fine-tuning of macrophage activation using synthetic rocaglate derivatives.

Sci Rep 2016 Apr 18;6:24409. Epub 2016 Apr 18.

Pulmonary Center, Department of Medicine, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, 02118, USA.

Drug-resistant bacteria represent a significant global threat. Given the dearth of new antibiotics, host-directed therapies (HDTs) are especially desirable. As IFN-gamma (IFNγ) plays a central role in host resistance to intracellular bacteria, including Mycobacterium tuberculosis, we searched for small molecules to augment the IFNγ response in macrophages. Using an interferon-inducible nuclear protein Ipr1 as a biomarker of macrophage activation, we performed a high-throughput screen and identified molecules that synergized with low concentration of IFNγ. Several active compounds belonged to the flavagline (rocaglate) family. In primary macrophages a subset of rocaglates 1) synergized with low concentrations of IFNγ in stimulating expression of a subset of IFN-inducible genes, including a key regulator of the IFNγ network, Irf1; 2) suppressed the expression of inducible nitric oxide synthase and type I IFN and 3) induced autophagy. These compounds may represent a basis for macrophage-directed therapies that fine-tune macrophage effector functions to combat intracellular pathogens and reduce inflammatory tissue damage. These therapies would be especially relevant to fighting drug-resistant pathogens, where improving host immunity may prove to be the ultimate resource.
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http://dx.doi.org/10.1038/srep24409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834551PMC
April 2016

Genetic link between renal birth defects and congenital heart disease.

Nat Commun 2016 Mar 22;7:11103. Epub 2016 Mar 22.

Program in Molecular Medicine, University of Massachusetts Medical School, Biotech II, Suite 213 373 Plantation Street Worcester, Massachusetts 01605, USA.

Structural birth defects in the kidney and urinary tract are observed in 0.5% of live births and are a major cause of end-stage renal disease, but their genetic aetiology is not well understood. Here we analyse 135 lines of mice identified in large-scale mouse mutagenesis screen and show that 29% of mutations causing congenital heart disease (CHD) also cause renal anomalies. The renal anomalies included duplex and multiplex kidneys, renal agenesis, hydronephrosis and cystic kidney disease. To assess the clinical relevance of these findings, we examined patients with CHD and observed a 30% co-occurrence of renal anomalies of a similar spectrum. Together, these findings demonstrate a common shared genetic aetiology for CHD and renal anomalies, indicating that CHD patients are at increased risk for complications from renal anomalies. This collection of mutant mouse models provides a resource for further studies to elucidate the developmental link between renal anomalies and CHD.
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http://dx.doi.org/10.1038/ncomms11103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804176PMC
March 2016

Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery.

J Med Chem 2015 Jul 8;58(14):5522-37. Epub 2015 Jul 8.

§Experimental Therapeutics, Walter Reed Army Institute for Research, 2460 Linden Lane, Silver Spring, Maryland 20910, United States.

Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515785PMC
July 2015

Global genetic analysis in mice unveils central role for cilia in congenital heart disease.

Nature 2015 May 25;521(7553):520-4. Epub 2015 Mar 25.

Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA.

Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births; the incidence of CHD is up to tenfold higher in human fetuses. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.
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http://dx.doi.org/10.1038/nature14269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617540PMC
May 2015

Identification and characterization of hundreds of potent and selective inhibitors of Trypanosoma brucei growth from a kinase-targeted library screening campaign.

PLoS Negl Trop Dis 2014 Oct 23;8(10):e3253. Epub 2014 Oct 23.

Department of Chemistry and Chemical Biology and Center for Drug Discovery, Northeastern University, Boston, Massachusetts, United States of America.

In the interest of identification of new kinase-targeting chemotypes for target and pathway analysis and drug discovery in Trypanosomal brucei, a high-throughput screen of 42,444 focused inhibitors from the GlaxoSmithKline screening collection was performed against parasite cell cultures and counter-screened against human hepatocarcinoma (HepG2) cells. In this way, we have identified 797 sub-micromolar inhibitors of T. brucei growth that are at least 100-fold selective over HepG2 cells. Importantly, 242 of these hit compounds acted rapidly in inhibiting cellular growth, 137 showed rapid cidality. A variety of in silico and in vitro physicochemical and drug metabolism properties were assessed, and human kinase selectivity data were obtained, and, based on these data, we prioritized three compounds for pharmacokinetic assessment and demonstrated parasitological cure of a murine bloodstream infection of T. brucei rhodesiense with one of these compounds (NEU-1053). This work represents a successful implementation of a unique industrial-academic collaboration model aimed at identification of high quality inhibitors that will provide the parasitology community with chemical matter that can be utilized to develop kinase-targeting tool compounds. Furthermore these results are expected to provide rich starting points for discovery of kinase-targeting tool compounds for T. brucei, and new HAT therapeutics discovery programs.
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http://dx.doi.org/10.1371/journal.pntd.0003253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207660PMC
October 2014

Airway ciliary dysfunction and sinopulmonary symptoms in patients with congenital heart disease.

Ann Am Thorac Soc 2014 Nov;11(9):1426-32

1 Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center (UPMC), and.

Rationale: Patients with congenital heart disease with heterotaxy exhibit a high prevalence of abnormal airway ciliary motion and low nasal nitric oxide, characteristics associated with primary ciliary dyskinesia, a reflection of the role of motile cilia in airway clearance and left-right patterning.

Objectives: To assess the potential broader clinical significance of airway ciliary dysfunction in congenital heart disease, we assessed the prevalence of ciliary dysfunction versus respiratory symptoms in patients with congenital heart disease with or without heterotaxy.

Methods: Patients with a broad spectrum of congenital heart disease were recruited (n = 218), 39 with heterotaxy. Nasal nitric oxide measurements and nasal biopsies for ciliary motion video microscopy were conducted. Sinopulmonary symptoms were reviewed by questionnaire.

Measurements And Main Results: A high prevalence of ciliary motion defects (51.8%) and low or borderline low nasal nitric oxide levels (35.5%) were observed in patients with congenital heart disease with or without heterotaxy. Patients with ciliary motion defects or low nasal nitric oxide showed increased sinopulmonary symptoms, with most respiratory symptoms seen in those with both abnormal ciliary motion and low nitric oxide. Multivariate analysis showed that abnormal ciliary motion and low nasal nitric oxide were more important in determining risk of sinopulmonary symptoms than heterotaxy status.

Conclusions: Patients with congenital heart disease without heterotaxy exhibit a high prevalence of abnormal ciliary motion and low nasal nitric oxide. This was associated with more sinopulmonary symptoms. These findings suggest that patients with a broad spectrum of congenital heart disease and respiratory symptoms may benefit from screening for ciliary dysfunction and implementation of medical interventions to reduce sinopulmonary morbidities.
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http://dx.doi.org/10.1513/AnnalsATS.201405-222OCDOI Listing
November 2014

Early patterning and specification of cardiac progenitors in gastrulating mesoderm.

Elife 2014 Oct 8;3. Epub 2014 Oct 8.

Gladstone Institute of Cardiovascular Disease, San Francisco, United States.

Mammalian heart development requires precise allocation of cardiac progenitors. The existence of a multipotent progenitor for all anatomic and cellular components of the heart has been predicted but its identity and contribution to the two cardiac progenitor 'fields' has remained undefined. Here we show, using clonal genetic fate mapping, that Mesp1+ cells in gastrulating mesoderm are rapidly specified into committed cardiac precursors fated for distinct anatomic regions of the heart. We identify Smarcd3 as a marker of early specified cardiac precursors and identify within these precursors a compartment boundary at the future junction of the left and right ventricles that arises prior to morphogenesis. Our studies define the timing and hierarchy of cardiac progenitor specification and demonstrate that the cellular and anatomical fate of mesoderm-derived cardiac cells is specified very early. These findings will be important to understand the basis of congenital heart defects and to derive cardiac regeneration strategies.
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http://dx.doi.org/10.7554/eLife.03848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356145PMC
October 2014