Publications by authors named "Dian Yang"

45 Publications

Mapping the genetic landscape of DNA double-strand break repair.

Cell 2021 10 20;184(22):5653-5669.e25. Epub 2021 Oct 20.

Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address:

Cells repair DNA double-strand breaks (DSBs) through a complex set of pathways critical for maintaining genomic integrity. To systematically map these pathways, we developed a high-throughput screening approach called Repair-seq that measures the effects of thousands of genetic perturbations on mutations introduced at targeted DNA lesions. Using Repair-seq, we profiled DSB repair products induced by two programmable nucleases (Cas9 and Cas12a) in the presence or absence of oligonucleotides for homology-directed repair (HDR) after knockdown of 476 genes involved in DSB repair or associated processes. The resulting data enabled principled, data-driven inference of DSB end joining and HDR pathways. Systematic interrogation of this data uncovered unexpected relationships among DSB repair genes and demonstrated that repair outcomes with superficially similar sequence architectures can have markedly different genetic dependencies. This work provides a foundation for mapping DNA repair pathways and for optimizing genome editing across diverse modalities.
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http://dx.doi.org/10.1016/j.cell.2021.10.002DOI Listing
October 2021

Semiparametric regression analysis of clustered interval-censored failure time data with a cured subgroup.

Stat Med 2021 Dec 11;40(30):6918-6930. Epub 2021 Oct 11.

Department of Statistics, University of Missouri, Columbia, Missouri, USA.

This article discusses regression analysis of clustered interval-censored failure time data in the presence of a cured fraction or subgroup. Such data often occur in many areas, including epidemiological studies, medical studies, and social sciences. For the problem, a class of semiparametric transformation nonmixture cure models is presented and for estimation, the maximum likelihood estimation procedure is derived. For the implementation of the proposed method, we develop a novel EM algorithm based on a Poisson variable-based augmentation. An extensive simulation study is conducted and suggests that the proposed approach works well in practical situations. Finally the method is applied to an example that motivated this study.
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http://dx.doi.org/10.1002/sim.9218DOI Listing
December 2021

Efficient C•G-to-G•C base editors developed using CRISPRi screens, target-library analysis, and machine learning.

Nat Biotechnol 2021 11 28;39(11):1414-1425. Epub 2021 Jun 28.

Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Programmable C•G-to-G•C base editors (CGBEs) have broad scientific and therapeutic potential, but their editing outcomes have proved difficult to predict and their editing efficiency and product purity are often low. We describe a suite of engineered CGBEs paired with machine learning models to enable efficient, high-purity C•G-to-G•C base editing. We performed a CRISPR interference (CRISPRi) screen targeting DNA repair genes to identify factors that affect C•G-to-G•C editing outcomes and used these insights to develop CGBEs with diverse editing profiles. We characterized ten promising CGBEs on a library of 10,638 genomically integrated target sites in mammalian cells and trained machine learning models that accurately predict the purity and yield of editing outcomes (R = 0.90) using these data. These CGBEs enable correction to the wild-type coding sequence of 546 disease-related transversion single-nucleotide variants (SNVs) with >90% precision (mean 96%) and up to 70% efficiency (mean 14%). Computational prediction of optimal CGBE-single-guide RNA pairs enables high-purity transversion base editing at over fourfold more target sites than achieved using any single CGBE variant.
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http://dx.doi.org/10.1038/s41587-021-00938-zDOI Listing
November 2021

Superior reducing carbon dots from proanthocyanidin for free-radical scavenging and for cell imaging.

Analyst 2021 Apr 24;146(7):2330-2338. Epub 2021 Feb 24.

CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science (CAS), Suzhou 215163, China.

The presence of excessive ROS can cause much harm to the human body and can even cause diseases. Therefore, it is important to detect and remove ROS, but there is no ideal method available for this at present. In this research, using procyanidins, a type of plant extract with strong reducibility, as raw materials, fluorescent carbon dots (CDs) were prepared by a hydrothermal method. The proanthocyanidin-based carbon dots (PCDs) emit a light-green colored light under UV irradiation. The PCDs retain the strong reducibility of procyanidins and are highly water-soluble compared with procyanidins. The PCDs, in addition to having good biocompatibility, also have the superior properties of radical scavenging activity and cell imaging. In in vitro experiments, 1,1-diphenyl-2-picrylhydrazyl (DPPH; 100 μM) was reduced by 30% when PCDs were added up to a concentration of 87.5 μg mL. At the same time, the fluorescence quenching correlates with the concentration of hypochlorite and hydrogen peroxide and has a good linearity in the range of 250-2250 nM and 60-180 μM with a detection limit of 3.676 nM and 0.602 μM, respectively. Based on the previously described advantages, PCDs have potential as a biomedicine.
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http://dx.doi.org/10.1039/d0an02479aDOI Listing
April 2021

Highly efficient adsorption behavior and mechanism of [email protected] for triphenyl phosphate.

Environ Pollut 2020 Dec 14;267:114142. Epub 2020 Feb 14.

National Engineering Laboratory for Biomass Power Generation Equipment, School of Renewable Energy, North China Electric Power University, Beijing, 102206, China. Electronic address:

The emergence of organophosphorus flame retardants and the efficient removal from aquatic environments have aroused increasing concerns. The Urea functionalized [email protected] ([email protected]) was prepared and used to adsorb triphenyl phosphate (tphp) for the first time. The tphp adsorption capacity was up to 589 mg g, and the adsorption rate reached 49.9 mg g min. Moreover, the influences of various environmental factors (pH, ionic strength and organic matter) on the tphp adsorption on the [email protected] were investigated. The initial pH of the solution significantly affected the tphp adsorption, whereas the ionic strength and HA slightly affected the adsorption. The main adsorption mechanism was attributed to electrostatic interaction and π-π interaction. We believe that urea is one of excellent functional groups for the tphp adsorption removal and the materials with urea groups as the adsorbents exhibit good prospects in the future.
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http://dx.doi.org/10.1016/j.envpol.2020.114142DOI Listing
December 2020

Altered Mitochondria Functionality Defines a Metastatic Cell State in Lung Cancer and Creates an Exploitable Vulnerability.

Cancer Res 2021 02 25;81(3):567-579. Epub 2020 Nov 25.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen at the University of Duisburg-Essen, Essen, Germany.

Lung cancer is a prevalent and lethal cancer type that leads to more deaths than the next four major cancer types combined. Metastatic cancer spread is responsible for most cancer-related deaths but the cellular changes that enable cancer cells to leave the primary tumor and establish inoperable and lethal metastases remain poorly understood. To uncover genes that are specifically required to sustain metastasis survival or growth, we performed a genome-scale pooled lentiviral-shRNA library screen in cells that represent nonmetastatic and metastatic states of lung adenocarcinoma. Mitochondrial ribosome and mitochondria-associated genes were identified as top gene sets associated with metastasis-specific lethality. Metastasis-derived cell lines and metastases analyzed from an autochthonous lung cancer mouse model had lower mitochondrial membrane potential and reduced mitochondrial functionality than nonmetastatic primary tumors. Electron microscopy of metastases uncovered irregular mitochondria with bridging and loss of normal membrane structure. Consistent with these findings, compounds that inhibit mitochondrial translation or replication had a greater effect on the growth of metastasis-derived cells. Finally, mice with established tumors developed fewer metastases upon treatment with phenformin . These results suggest that the metastatic cell state in lung adenocarcinoma is associated with a specifically altered mitochondrial functionality that can be therapeutically exploited. SIGNIFICANCE: This study characterizes altered mitochondria functionality of the metastatic cell state in lung cancer and opens new avenues for metastasis-specific therapeutic targeting.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137518PMC
February 2021

Role of Buffer Layer and Building Unit in the Monolayer CrI Growth: A First-Principles Perspective.

J Phys Chem Lett 2020 Nov 27;11(21):9453-9460. Epub 2020 Oct 27.

Frontiers Science Center for Flexible Electronics, Xi'an Institute of Flexible Electronics (IFE) and Xi'an Institute of Biomedical Materials & Engineering, Northwestern Polytechnical University, Xi'an 710072, China.

CrI, a two-dimensional layered material, has recently attracted a lot of research interest due to its exotic magnetic property. However, the synthesis of a CrI monolayer (ML) by vapor-phase deposition has not been achieved by current experimental endeavors, which require a better understanding of the vapor-phase growth mechanism involved. In this study, we theoretically simulate the growth of the CrI ML on the Si(111) surface by using a first-principles calculation. Our key finding is that an iodine buffer layer on the Si surface is crucial to the formation of the CrI ML by stabilizing the precursor and also reacting with the precursor. Moreover, our simulation reveals that the CrI cluster as the growth building unit, which can be formed by controlling the chemical potential of the I source, is preferred for the formation of CrI ML. We think that our work will provide insightful guidance for the experimental synthesis of CrI ML in the future.
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http://dx.doi.org/10.1021/acs.jpclett.0c02717DOI Listing
November 2020

Green Synthesis of Lutein-Based Carbon Dots Applied for Free-Radical Scavenging within Cells.

Materials (Basel) 2020 Sep 17;13(18). Epub 2020 Sep 17.

CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science (CAS), Suzhou 215163, China.

Reactive oxygen species (ROS) in the body play an important role in various processes. It is well known that harmful high levels of ROS can cause many problems in living organisms in a variety of ways. One effective way to remove intracellular ROS is to use reducing materials that can enter the cell. Herein, we developed a strong reducing carbon nano-dot from a natural product, lutein, as an initial raw material. This is a hydrothermal synthesis method with the advantages of simplicity, high yield, mild reaction conditions, and environmental friendliness. The prepared carbon dots exhibit bright blue fluorescence, and have good water solubility and biocompatibility. In particular, the carbon dots can easily enter the cell and effectively remove ROS. Therefore, the carbon dots are thought to protect cells from oxidative damage by high levels of ROS.
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http://dx.doi.org/10.3390/ma13184146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560362PMC
September 2020

Collection and disinfection of forensic biological specimens in five cases concerning COVID-19 in Guangzhou, China.

Forensic Sci Int Synerg 2020 2;2:210-214. Epub 2020 Jul 2.

Guangzhou Forensic Science Institute, Guangzhou, China.

There have been many cases of pneumonia caused by novel coronavirus infections in China and around the world. This will inevitably lead to a rise in the number of patients. At the present time, clinical and forensic autopsies have given guidance and explanations in relation to the problem of COVID-19 transmission and defense. However, less attention is paid to the handling of COVID-19 biological samples in forensic practice. Particularly, COVID-19 can survive on some surfaces for days. Since there were many cases involving COVID-19 during the epidemic, this article shares the methods and strategies for handling such inspection materials and the biological samples related specifically to COVID-19 cases.
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http://dx.doi.org/10.1016/j.fsisyn.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330571PMC
July 2020

Application of Y-chromosomal microdeletions in a homicide case.

Forensic Sci Int 2020 Sep 25;314:110370. Epub 2020 Jun 25.

AGCU ScienTech Incorporation, Wuxi, 214174, People's Republic of China. Electronic address:

A case study involving an intentional homicide case in November 2018, in which the autosomal genotypes of the suspect were unavailable and only part of deletions of Y-STR loci were identified by Y-chromosomal typing. The suspect, male, was charged with beating the decedent, female, over the head with an iron water pipe to death. The use of standard autosomal DNA profiling to identify the suspect was unattainable due to the extensive volume blood of the decedent on the murder weapon which was inevitably cleaned by running water at the crime scene. As a result, autosomal genotypes of the suspect were unavailable and only partial samples of deletions of Y-STR loci were identified by Y-chromosomal typing. Y-STR analysis (Yfiler™ plus and AGCU Y36) was used on the collected DNA extracts and compared to reference samples of the suspect, as well as his father and brother in an attempt to positively identify the suspect as the perpetrator of the murder. Subsequent Y-STR genotyping for the suspect, his father and brother indicated that Y-STR genotype of the suspect was consistent with that discovered on the physical evidence and the deleted Y-STR loci were identical for both. No deletions of Y-STR genotype were observed in the suspect's father and brother. After changing a Y-STR kit, the deleted loci were still present in the suspect. In Addition, sequencing of the whole Y-chromosomal genes was performed on the samples taken from the suspect and his father and brother. Segmental deletions at Yq 11.222-Yq 11.23 of the suspect were observed and the deleted Y-STR markers were right on the deleted Y-chromosomal segments. In this case, although the suspect could not be identified by the autosomal STR profiles detected on the physical evidence, the discovery of identical Y-STR genotype and the identical deletions of Y-chromosomal segments made it plausible that DNA on the murder weapon was left behind by the suspect. This case study shows that in criminal cases like this, where the autosomal STR evidence is unattainable, Y-STR evidence can be used effectively as a substitute to identify the suspect.
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http://dx.doi.org/10.1016/j.forsciint.2020.110370DOI Listing
September 2020

Spatiotemporal trends and ecological determinants in maternal mortality ratios in 2,205 Chinese counties, 2010-2013: A Bayesian modelling analysis.

PLoS Med 2020 05 15;17(5):e1003114. Epub 2020 May 15.

National Office for Maternal and Child Health Surveillance of China, Department of Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.

Background: As one of its Millennium Development Goals (MDGs), China has achieved a dramatic reduction in the maternal mortality ratio (MMR), although a distinct spatial heterogeneity still persists. Evidence of the quantitative effects of determinants on MMR in China is limited. A better understanding of the spatiotemporal heterogeneity and quantifying determinants of the MMR would support evidence-based policymaking to sustainably reduce the MMR in China and other developing areas worldwide.

Methods And Findings: We used data on MMR collected by the National Maternal and Child Health Surveillance System (NMCHSS) at the county level in China from 2010 to 2013. We employed a Bayesian space-time model to investigate the spatiotemporal trends in the MMR from 2010 to 2013. We used Bayesian multivariable regression and GeoDetector models to address 3 main ecological determinants of the MMR, including per capita income (PCI), the proportion of pregnant women who delivered in hospitals (PPWDH), and the proportion of pregnant women who had at least 5 check-ups (PPWFC). Among the 2,205 counties, there were 925 (42.0%) hotspot counties, located mostly in China's western and southwestern regions, with a higher MMR, and 764 (34.6%) coldspot counties with a lower MMR than the national level. China's westernmost regions, including Tibet and western Xinjiang, experienced a weak downward trend over the study period. Nationwide, medical intervention was the major determinant of the change in MMR. The MMR decreased by 1.787 (95% confidence interval [CI]: 1.424-2.142, p < 0.001) per 100,000 live births when PPWDH increased by 1% and decreased by 0.623 (95% CI 0.436-0.798, p < 0.001) per 100,000 live births when PPWFC increased by 1%. The major determinants for the MMR in China's western and southwestern regions were PCI and PPWFC, while that in China's eastern and southern coastlands was PCI. The MMR in western and southwestern regions decreased nonsignificantly by 1.111 (95% CI -1.485-3.655, p = 0.20) per 100,000 live births when PCI in these regions increased by 1,000 Chinese Yuan and decreased by 1.686 (95% CI 1.275-2.090, p < 0.001) when PPWFC increased by 1%. Additionally, the western and southwestern regions showed the strongest interactive effects between different factors, in which the corresponding explanatory power of any 2 interacting factors reached up to greater than 80.0% (p < 0.001) for the MMR. Limitations of this study include a relatively short study period and lack of full coverage of eastern coastlands with especially low MMR.

Conclusions: Although China has accomplished a 75% reduction in the MMR, spatial heterogeneity still exists. In this study, we have identified 925 (hotspot) high-risk counties, mostly located in western and southwestern regions, and among which 332 counties are experiencing a slower pace of decrease than the national downward trend. Nationally, medical intervention is the major determinant. The major determinants for the MMR in western and southwestern regions, which are developing areas, are PCI and PPWFC, while that in China's developed areas is PCI. The interactive influence of any two of the three factors, PCI, PPWDH, and PPWFC, in western and southwestern regions was up to and in excess of 80% (p < 0.001).
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http://dx.doi.org/10.1371/journal.pmed.1003114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228041PMC
May 2020

Axon-like protrusions promote small cell lung cancer migration and metastasis.

Elife 2019 12 13;8. Epub 2019 Dec 13.

Cancer Biology Program, Stanford University School of Medicine, Stanford, United States.

Metastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic cancer types. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.
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http://dx.doi.org/10.7554/eLife.50616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940020PMC
December 2019

Two-Step Hydrothermal Preparation of Carbon Dots for Calcium Ion Detection.

ACS Appl Mater Interfaces 2019 Nov 12;11(47):44566-44572. Epub 2019 Nov 12.

CAS Key Laboratory of Biomedical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology , Chinese Academy of Science (CAS) , 88 Keling Road , Suzhou 215163 , Jiangsu , People's Republic of China.

It is well known that the calcium ion is essential for maintaining life activities in living organisms, and it is of great significance to detect the intracellular calcium concentration. For the detection of calcium ions, we developed a new type of fluorescent carbon dots (CDs), whose surface was modified by ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA) through a secondary hydrothermal method. This is a simple and convenient chemical preparation method because all reactions are carried out in the same autoclave, and the final product is directly the EGTA-modified CDs. The CDs exhibit bright blue fluorescence, and as the calcium concentration increases, the fluorescence intensity drops sharply. The fluorescence quenching correlates with the concentration of calcium ions and has a good linearity in the range of 15-300 μM with a detection limit of 0.38 μM. The experimental results confirmed that the detection of calcium ions by CDs is a static fluorescence quenching process. Also, cytotoxicity test and cellular imaging experiments have shown that the CDs are nontoxic and biocompatible.
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http://dx.doi.org/10.1021/acsami.9b13737DOI Listing
November 2019

Molecular recording of mammalian embryogenesis.

Nature 2019 06 13;570(7759):77-82. Epub 2019 May 13.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.

Ontogeny describes the emergence of complex multicellular organisms from single totipotent cells. This field is particularly challenging in mammals, owing to the indeterminate relationship between self-renewal and differentiation, variation in progenitor field sizes, and internal gestation in these animals. Here we present a flexible, high-information, multi-channel molecular recorder with a single-cell readout and apply it as an evolving lineage tracer to assemble mouse cell-fate maps from fertilization through gastrulation. By combining lineage information with single-cell RNA sequencing profiles, we recapitulate canonical developmental relationships between different tissue types and reveal the nearly complete transcriptional convergence of endodermal cells of extra-embryonic and embryonic origins. Finally, we apply our cell-fate maps to estimate the number of embryonic progenitor cells and their degree of asymmetric partitioning during specification. Our approach enables massively parallel, high-resolution recording of lineage and other information in mammalian systems, which will facilitate the construction of a quantitative framework for understanding developmental processes.
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http://dx.doi.org/10.1038/s41586-019-1184-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229772PMC
June 2019

Bilayer hydrogel mixed composites that respond to multiple stimuli for environmental sensing and underwater actuation.

J Mater Chem B 2018 Dec 26;6(48):8170-8179. Epub 2018 Nov 26.

College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China.

Bilayer-type hydrogel composites that respond to multiple stimuli provide a useful approach for manufacturing soft actuators and intelligent sensors. In this study, we propose two types of bilayer hydrogel composites (referred to as "N" type and "D" type). The "N" type and the "D" type separately consist of poly(N-isopropylacrylamide) (PNIPAM) and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) bilayer hydrogels, with acrylamide (AM) as the co-monomer. The "N" type hydrogel composite exhibits oriented bending as temperature increases or as environmental salt concentration increases. The "D" type also presents oriented bending as temperature increases. Additionally, it demonstrates bending and changes color based on the pH of the surrounding solution, since it is doped with an acid-based pH-indicator. In a demonstration, we present several straight rods composed of a mixture of "N" and "D" type hydrogel composites that are able to morph into the letters "SOS" under environmental changes (temperature or pH). This can be used as a visual environmental indicator, or as an alarm. Furthermore, we show structures composed of a mixture of "N" and "D" composites imitating the flexible motions of a ballet dancer or a Tai Chi master. These mixed bilayer polymer composites may be used for applications in soft robotics, biomimetic devices, and environmental sensors.
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http://dx.doi.org/10.1039/c8tb02242aDOI Listing
December 2018

Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin.

Cancer Discov 2018 10 18;8(10):1316-1331. Epub 2018 Sep 18.

Cancer Biology Program, Stanford University, Stanford, California.

The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vulnerabilities in advanced tumors. Here, using genetically defined mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplification of the transcription factor NFIB and a widespread increase in chromatin accessibility, whereas in the other model, tumors become metastatic in the absence of NFIB-driven chromatin alterations. Gene-expression and chromatin accessibility analyses identify distinct mechanisms as well as markers predictive of metastatic progression in both groups. Underlying the difference between the two programs was the cell type of origin of the tumors, with NFIB-independent metastases arising from mature neuroendocrine cells. Our findings underscore the importance of the identity of cell type of origin in influencing tumor evolution and metastatic mechanisms. We show that SCLC can arise from different cell types of origin, which profoundly influences the eventual genetic and epigenetic changes that enable metastatic progression. Understanding intertumoral heterogeneity in SCLC, and across cancer types, may illuminate mechanisms of tumor progression and uncover how the cell type of origin affects tumor evolution. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195211PMC
October 2018

A Soft Tube-Climbing Robot.

Soft Robot 2018 04 30;5(2):133-137. Epub 2017 Nov 30.

1 Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts.

This article demonstrates a pneumatically actuated soft robot capable of navigating the inside of a tube. This robot was built using buckling pneumatic actuators (vacuum-actuated muscle-inspired pneumatic structures, or VAMPs). The tube climber can navigate through a tube with turns, inclines, and varying diameters. The robot is also able to remove obstacles (of more than 10 times its own weight) from tubes to perform a clearing function. It maintains climbing and clearing performance in wet conditions and under water. The tube climber is lightweight and completely soft and thus has the potential to be collaborative (i.e., work with humans) and also to interact safely with delicate environments.
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http://dx.doi.org/10.1089/soro.2016.0078DOI Listing
April 2018

Soft, Rotating Pneumatic Actuator.

Soft Robot 2017 Sep 30;4(3):297-304. Epub 2017 May 30.

1 Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts.

This article describes a soft pneumatic actuator that generates cyclical motion. The actuator consists of several (three, four, or five) chambers (arranged around the circumference of a circle surrounding a central rod) that can be actuated independently using negative pressure (or partial vacuum). Sequential actuation of the four-chamber device using reduced pressure moves the central rod cyclically in an approximately square path. We characterize the trajectory of the actuator and the force exerted by it, as we vary the material used for fabrication, the number of chambers, and the size of the actuator. We demonstrate two applications of this actuator: to deliver fluid while stirring (by replacing the central rod with a needle) and for locomotion that mimics a reptilian gait (by combining four actuators together).
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http://dx.doi.org/10.1089/soro.2017.0017DOI Listing
September 2017

Janus Gold Nanoplatform for Synergetic Chemoradiotherapy and Computed Tomography Imaging of Hepatocellular Carcinoma.

ACS Nano 2017 12 17;11(12):12732-12741. Epub 2017 Nov 17.

CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences , Suzhou 215163, China.

There is a pressing need to develop nanoplatforms that integrate multimodal therapeutics to improve treatment responses and prolong the survival of patients with unresectable hepatocellular carcinoma (HCC). Mesoporous silica-coated gold nanomaterials have emerged as a novel multifunctional platform combining tunable surface plasmon resonance and mesoporous properties that exhibit multimodality properties in cancer theranostics. However, their reduced radiation-absorption efficiency and limited surface area hinder their further radiochemotherapeutic applications. To address these issues, we designed Janus-structured gold-mesoporous silica nanoparticles using a modified sol-gel method. This multifunctional theranostic nanoplatform was subsequently modified via the conjugation of folic acid for enhanced HCC targeting and internalization. The loaded anticancer agent doxorubicin can be released from the mesopores in a pH-responsive manner, facilitating selective and safe chemotherapy. Additionally, the combination of chemotherapy and radiotherapy induced synergistic anticancer effects in vitro and exhibited remarkable inhibition of tumor growth in vivo along with significantly reduced systematic toxicity. Additionally, the Janus NPs acted as targeted computed tomography (CT)-imaging agents for HCC diagnosis. Given their better performance in chemoradiotherapy and CT imaging as compared with that of their core-shell counterparts, this new nanoplatform designed with dual functionalities provides a promising strategy for unresectable HCC theranostics.
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http://dx.doi.org/10.1021/acsnano.7b07486DOI Listing
December 2017

Janus Gold Nanoplatform for Synergetic Chemoradiotherapy and Computed Tomography Imaging of Hepatocellular Carcinoma.

ACS Nano 2017 12 17;11(12):12732-12741. Epub 2017 Nov 17.

CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences , Suzhou 215163, China.

There is a pressing need to develop nanoplatforms that integrate multimodal therapeutics to improve treatment responses and prolong the survival of patients with unresectable hepatocellular carcinoma (HCC). Mesoporous silica-coated gold nanomaterials have emerged as a novel multifunctional platform combining tunable surface plasmon resonance and mesoporous properties that exhibit multimodality properties in cancer theranostics. However, their reduced radiation-absorption efficiency and limited surface area hinder their further radiochemotherapeutic applications. To address these issues, we designed Janus-structured gold-mesoporous silica nanoparticles using a modified sol-gel method. This multifunctional theranostic nanoplatform was subsequently modified via the conjugation of folic acid for enhanced HCC targeting and internalization. The loaded anticancer agent doxorubicin can be released from the mesopores in a pH-responsive manner, facilitating selective and safe chemotherapy. Additionally, the combination of chemotherapy and radiotherapy induced synergistic anticancer effects in vitro and exhibited remarkable inhibition of tumor growth in vivo along with significantly reduced systematic toxicity. Additionally, the Janus NPs acted as targeted computed tomography (CT)-imaging agents for HCC diagnosis. Given their better performance in chemoradiotherapy and CT imaging as compared with that of their core-shell counterparts, this new nanoplatform designed with dual functionalities provides a promising strategy for unresectable HCC theranostics.
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http://dx.doi.org/10.1021/acsnano.7b07486DOI Listing
December 2017

Janus Silver/Silica Nanoplatforms for Light-Activated Liver Cancer Chemo/Photothermal Therapy.

ACS Appl Mater Interfaces 2017 Sep 1;9(36):30306-30317. Epub 2017 Sep 1.

CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences , Suzhou 215163, China.

Stimuli-triggered nanoplatforms have become attractive candidates for combined strategies for advanced liver cancer treatment. In this study, we designed a light-responsive nanoplatform with folic acid-targeting properties to surmount the poor aqueous stability and photostability of indocyanine green (ICG). In this Janus nanostructure, ICG was released on-demand from mesoporous silica compartments in response to near-infrared (NIR) irradiation, exhibiting predominant properties to convert light to heat in the cytoplasm to kill liver cancer cells. Importantly, the silver ions released from the silver compartment that were triggered by light could induce efficient chemotherapy to supplement photothermal therapy. Under NIR irradiation, ICG-loaded Janus nanoplatforms exhibited synergistic therapeutic capabilities both in vitro and in vivo compared with free ICG and ICG-loaded mesoporous silica nanoparticles themselves. Hence, our Janus nanoplatform could integrate ICG-based photothermal therapy and silver ion-based chemotherapy in a cascade manner, which might provide an efficient and safe strategy for combined liver cancer therapy.
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http://dx.doi.org/10.1021/acsami.7b06446DOI Listing
September 2017

BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer.

Cancer Discov 2017 10 8;7(10):1184-1199. Epub 2017 Aug 8.

Department of Genetics, Stanford University School of Medicine, Stanford, California.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. By generating a genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor BLIMP1 as a driver of PDAC metastasis. The highly metastatic PDAC subpopulation is enriched for hypoxia-induced genes, and hypoxia-mediated induction of BLIMP1 contributes to the regulation of a subset of hypoxia-associated gene expression programs. These findings support a model in which upregulation of BLIMP1 links microenvironmental cues to a metastatic stem cell character. PDAC is an almost uniformly lethal cancer, largely due to its tendency for metastasis. We define a highly metastatic subpopulation of cancer cells, uncover a key transcriptional regulator of metastatic ability, and define hypoxia as an important factor within the tumor microenvironment that increases metastatic proclivity. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628145PMC
October 2017

Janus silver mesoporous silica nanobullets with synergistic antibacterial functions.

Colloids Surf B Biointerfaces 2017 Sep 4;157:199-206. Epub 2017 Jun 4.

CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China. Electronic address:

In this study, we exploited a one-pot method to fabricate cetyltrimethylammonium bromide (CTAB)-loaded Janus silver mesoporous silica nanoparticles (Janus [email protected]). These bullet-like nanoparticles had a silver head (80nm in diameter) attached to a mesoporous silica stick (200-300nm in length). The CTAB-loaded nanobullets exhibited a marked affinity for the bacterial cell surface and the simultaneously sustained release behavior of CTAB and silver ions. The minimum inhibitory concentrations (MIC) of Janus [email protected] were determined to be 10μg/mL and 20μg/mL for E. coli and S. Aureus, respectively. Importantly, Janus [email protected] provided a single-particle nanoplatform with a synergistic effect against both Gram-positive and Gram-negative bacteria. A thorough investigation indicated that CTAB induces a dramatic loss of bacterial membrane integrity, which facilitated the internalization of silver. This report described an efficient and convenient method of synthesizing Janus silver mesoporous silica nanoparticles, and these nanobullets show promising potential in biomedical applications.
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http://dx.doi.org/10.1016/j.colsurfb.2017.05.079DOI Listing
September 2017

Core-Shell Magnetic Gold Nanoparticles for Magnetic Field-Enhanced Radio-Photothermal Therapy in Cervical Cancer.

Nanomaterials (Basel) 2017 May 11;7(5). Epub 2017 May 11.

CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, No. 88 Keling Road, Suzhou 215163, China.

The combination of radiotherapy (RT) and photothermal therapy (PTT) has been considered an attractive strategy in cervical cancer treatment. However, it remains a challenge to simultaneously enhance the radio-sensitivity of tumor tissue, develop tumor tissue-focused radiation therapies and combine dual therapeutic modalities. In this study, core-shell type magnetic gold (Fe₃O₄@Au) nanoparticles are exploited to achieve the synergistic efficacy of radio-photothermal therapy in cervical cancer. Fe₃O₄@Au nanoparticles (NPs) with uniform morphology exhibited superior surface plasmon resonance properties, excellent superparamagnetic properties, good biocompatibility and high photothermal conversion efficiency. For the in vitro tests, a low concentration of Fe₃O₄@Au NPs after a short period of near-infrared irradiation lead to the time-dependent death of cervical cancer cells. Further, the combination of RT and PTT induced synergistic anti-cancer effects in vitro. More importantly, an external magnetic field could significantly enhance the synergistic efficacy of Fe₃O₄@Au NPs by improving their internalization. Hence, the reported Fe₃O₄@Au NPs have the potential to be good nanoagents with excellent magnetic targeting ability for cervical cancer radio-photothermal treatment.
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http://dx.doi.org/10.3390/nano7050111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449992PMC
May 2017

Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer.

Nature 2017 05 10;545(7654):360-364. Epub 2017 May 10.

Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA.

The Notch signalling pathway mediates cell fate decisions and is tumour suppressive or oncogenic depending on the context. During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine fate. In small-cell lung cancer, an aggressive neuroendocrine lung cancer, loss-of-function mutations in NOTCH genes and the inhibitory effects of ectopic Notch activation indicate that Notch signalling is tumour suppressive. Here we show that Notch signalling can be both tumour suppressive and pro-tumorigenic in small-cell lung cancer. Endogenous activation of the Notch pathway results in a neuroendocrine to non-neuroendocrine fate switch in 10-50% of tumour cells in a mouse model of small-cell lung cancer and in human tumours. This switch is mediated in part by Rest (also known as Nrsf), a transcriptional repressor that inhibits neuroendocrine gene expression. Non-neuroendocrine Notch-active small-cell lung cancer cells are slow growing, consistent with a tumour-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumour cells, consistent with a pro-tumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumour growth and delays relapse in pre-clinical models. Thus, small-cell lung cancer tumours generate their own microenvironment via activation of Notch signalling in a subset of tumour cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small-cell lung cancer.
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http://dx.doi.org/10.1038/nature22323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776014PMC
May 2017

Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis.

Nat Med 2017 Mar 13;23(3):291-300. Epub 2017 Feb 13.

Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

Lung cancer is the leading cause of cancer deaths worldwide, with the majority of mortality resulting from metastatic spread. However, the molecular mechanism by which cancer cells acquire the ability to disseminate from primary tumors, seed distant organs, and grow into tissue-destructive metastases remains incompletely understood. We combined tumor barcoding in a mouse model of human lung adenocarcinoma with unbiased genomic approaches to identify a transcriptional program that confers metastatic ability and predicts patient survival. Small-scale in vivo screening identified several genes, including Cd109, that encode novel pro-metastatic factors. We uncovered signaling mediated by Janus kinases (Jaks) and the transcription factor Stat3 as a critical, pharmacologically targetable effector of CD109-driven lung cancer metastasis. In summary, by coupling the systematic genomic analysis of purified cancer cells in distinct malignant states from mouse models with extensive human validation, we uncovered several key regulators of metastatic ability, including an actionable pro-metastatic CD109-Jak-Stat3 axis.
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http://dx.doi.org/10.1038/nm.4285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453542PMC
March 2017

An in vivo multiplexed small-molecule screening platform.

Nat Methods 2016 10 12;13(10):883-889. Epub 2016 Sep 12.

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Phenotype-based small-molecule screening is a powerful method to identify molecules that regulate cellular functions. However, such screens are generally performed in vitro under conditions that do not necessarily model complex physiological conditions or disease states. Here, we use molecular cell barcoding to enable direct in vivo phenotypic screening of small-molecule libraries. The multiplexed nature of this approach allows rapid in vivo analysis of hundreds to thousands of compounds. Using this platform, we screened >700 covalent inhibitors directed toward hydrolases for their effect on pancreatic cancer metastatic seeding. We identified multiple hits and confirmed the relevant target of one compound as the lipase ABHD6. Pharmacological and genetic studies confirmed the role of this enzyme as a regulator of metastatic fitness. Our results highlight the applicability of this multiplexed screening platform for investigating complex processes in vivo.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088491PMC
http://dx.doi.org/10.1038/nmeth.3992DOI Listing
October 2016

Nfib Promotes Metastasis through a Widespread Increase in Chromatin Accessibility.

Cell 2016 Jul 30;166(2):328-342. Epub 2016 Jun 30.

Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Metastases are the main cause of cancer deaths, but the mechanisms underlying metastatic progression remain poorly understood. We isolated pure populations of cancer cells from primary tumors and metastases from a genetically engineered mouse model of human small cell lung cancer (SCLC) to investigate the mechanisms that drive the metastatic spread of this lethal cancer. Genome-wide characterization of chromatin accessibility revealed the opening of large numbers of distal regulatory elements across the genome during metastatic progression. These changes correlate with copy number amplification of the Nfib locus, and differentially accessible sites were highly enriched for Nfib transcription factor binding sites. Nfib is necessary and sufficient to increase chromatin accessibility at a large subset of the intergenic regions. Nfib promotes pro-metastatic neuronal gene expression programs and drives the metastatic ability of SCLC cells. The identification of widespread chromatin changes during SCLC progression reveals an unexpected global reprogramming during metastatic progression.
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http://dx.doi.org/10.1016/j.cell.2016.05.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004630PMC
July 2016

Identification and Targeting of Long-Term Tumor-Propagating Cells in Small Cell Lung Cancer.

Cell Rep 2016 07 30;16(3):644-56. Epub 2016 Jun 30.

Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Small cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC are linked to TPCs. SCLC TPCs possess a distinct transcriptional profile compared to non-TPCs, including elevated MYC activity. Genetic and pharmacological inhibition of MYC in SCLC cells to non-TPC levels inhibits long-term propagation but not short-term growth. These studies identify a highly tumorigenic population of SCLC cells in mouse models, cell lines, and patient tumors and a means to target them in this most fatal form of lung cancer.
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http://dx.doi.org/10.1016/j.celrep.2016.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956576PMC
July 2016

CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer.

J Clin Invest 2016 07 13;126(7):2610-20. Epub 2016 Jun 13.

Small-cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with limited treatment options. CD47 is a cell-surface molecule that promotes immune evasion by engaging signal-regulatory protein alpha (SIRPα), which serves as an inhibitory receptor on macrophages. Here, we found that CD47 is highly expressed on the surface of human SCLC cells; therefore, we investigated CD47-blocking immunotherapies as a potential approach for SCLC treatment. Disruption of the interaction of CD47 with SIRPα using anti-CD47 antibodies induced macrophage-mediated phagocytosis of human SCLC patient cells in culture. In a murine model, administration of CD47-blocking antibodies or targeted inactivation of the Cd47 gene markedly inhibited SCLC tumor growth. Furthermore, using comprehensive antibody arrays, we identified several possible therapeutic targets on the surface of SCLC cells. Antibodies to these targets, including CD56/neural cell adhesion molecule (NCAM), promoted phagocytosis in human SCLC cell lines that was enhanced when combined with CD47-blocking therapies. In light of recent clinical trials for CD47-blocking therapies in cancer treatment, these findings identify disruption of the CD47/SIRPα axis as a potential immunotherapeutic strategy for SCLC. This approach could enable personalized immunotherapeutic regimens in patients with SCLC and other cancers.
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http://dx.doi.org/10.1172/JCI81603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922696PMC
July 2016
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