Publications by authors named "Yongmei Zhao"

90 Publications

WITHDRAWN: Circ_0000517 contributes to hepatocellular carcinoma progression by upregulating ARID4B via sponging miR-328-3p.

Cell Signal 2021 Feb 11:109950. Epub 2021 Feb 11.

School of pharmacy, Zhengzhou University, Zhengzhou City, Henan Province 450052, China.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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http://dx.doi.org/10.1016/j.cellsig.2021.109950DOI Listing
February 2021

A multi-center cross-platform single-cell RNA sequencing reference dataset.

Sci Data 2021 02 2;8(1):39. Epub 2021 Feb 2.

Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA.

Single-cell RNA sequencing (scRNA-seq) is developing rapidly, and investigators seeking to use this technology are left with a variety of options for both experimental platform and bioinformatics methods. There is an urgent need for scRNA-seq reference datasets for benchmarking of different scRNA-seq platforms and bioinformatics methods. To be broadly applicable, these should be generated from renewable, well characterized reference samples and processed in multiple centers across different platforms. Here we present a benchmark scRNA-seq dataset that includes 20 scRNA-seq datasets acquired either as mixtures or as individual samples from two biologically distinct cell lines for which a large amount of multi-platform whole genome sequencing data are also available. These scRNA-seq datasets were generated from multiple popular platforms across four sequencing centers. We believe the datasets we describe here will provide a resource that meets this need by allowing evaluation of various bioinformatics methods for scRNA-seq analyses, including but not limited to data preprocessing, imputation, normalization, clustering, batch correction, and differential analysis.
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http://dx.doi.org/10.1038/s41597-021-00809-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854649PMC
February 2021

WeChat as a Platform for Baduanjin Intervention in Patients With Stable Chronic Obstructive Pulmonary Disease in China: Retrospective Randomized Controlled Trial.

JMIR Mhealth Uhealth 2021 Feb 2;9(2):e23548. Epub 2021 Feb 2.

Department of Respiratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Background: Pulmonary rehabilitation is a crucial part of the nonpharmacological treatment of stable chronic obstructive pulmonary disease (COPD), but management remains problematic. WeChat could serve as a useful tool in patient management. Baduanjin is a popular exercise in China that is usually applied in pulmonary rehabilitation, which has been confirmed to be effective in improving lung function and life quality.

Objective: This study aimed to explore the efficiency of WeChat in the management of Baduanjin exercise in COPD patients.

Methods: A total of 200 patients from the respiratory department of Putuo Hospital participated in the Baduanjin rehabilitation project from September 2018 to October 2019, and were randomly assigned to the WeChat and control groups and followed up using the WeChat platform or telephone for 12 weeks. The frequency of Baduanjin exercise, lung function (percentage of forced expiratory volume in 1 second predicted, FEV1% predicted), and COPD assessment test (CAT) scores were collected and compared between the two groups. The number of message exchanges and a satisfaction survey on the WeChat platform were used to assess the feasibility of WeChat management outside the hospital.

Results: The Baduanjin exercise frequency significantly differed between the control group and WeChat group (F=33.82, P<.001) and across various time points (F=214.87, P<.001). After the follow-up on WeChat, there were fewer patients not performing Baduanjin exercise. The FEV1% predicted value significantly differed before and after Baduanjin exercise in the control group (Z=-3.686, P<.001) and the WeChat group (Z=-6.985, P<.001). A significant difference in the FEV1% predicted value was observed after Baduanjin exercise between the two groups (Z=-3.679, P<.001). The CAT score significantly differed before and after Baduanjin exercise in the control group (Z=-4.937, P<.001) and the WeChat group (Z=-5.246, P<.001). A significant difference in the CAT score was observed after Baduanjin exercise between the two groups (Z=-5.246, P<.001). The number of completed Baduanjin exercises, lung function, and CAT scores in active patients were higher than those in nonactive patients. All satisfaction survey items were scored with more than 4 points. Among the items, the highest score (mean 4.54, SD 0.77) was for continued WeChat management, followed by the effective management of Baduanjin exercise (mean 4.46, SD 0.87). The patients in the WeChat group showed much higher enthusiasm for and compliance with Baduanjin exercise, resulting in better life quality and lung function. The patients were very satisfied with the WeChat management because of the obvious curative effect and home feeling.

Conclusions: The WeChat platform provided a feasible, effective, and sustainable management plan for Baduanjin rehabilitation.

Trial Registration: Chinese Clinical Trial Registry ChiCTR1900028248; http://www.chictr.org.cn/showprojen.aspx?proj=46995.
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http://dx.doi.org/10.2196/23548DOI Listing
February 2021

Co-delivery of Salinomycin and Curcumin for Cancer Stem Cell Treatment by Inhibition of Cell Proliferation, Cell Cycle Arrest, and Epithelial-Mesenchymal Transition.

Front Chem 2020 15;8:601649. Epub 2021 Jan 15.

NICM Health Research Institute, Western Sydney University, Sydney, NSW, Australia.

Malignant cancer is a devastating disease often associated with a poor clinical prognosis. For decades, modern drug discoveries have attempted to identify potential modulators that can impede tumor growth. Cancer stem cells however are more resistant to therapeutic intervention, which often leads to treatment failure and subsequent disease recurrence. Here in this study, we have developed a specific multi-target drug delivery nanoparticle system against breast cancer stem cells (BCSCs). Therapeutic agents curcumin and salinomycin have complementary functions of limiting therapeutic resistance and eliciting cellular death, respectively. By conjugation of CD44 cell-surface glycoprotein with poly(lactic-co-glycolic acid) (PLGA) nanoparticles that are loaded with curcumin and salinomycin, we investigated the cellular uptake of BCSCs, drug release, and therapeutic efficacy against BCSCs. We determined CD44-targeting co-delivery nanoparticles are highly efficacious against BCSCs by inducing G cell cycle arrest and limiting epithelial-mesenchymal transition. This curcumin and salinomycin co-delivery system can be an efficient treatment approach to target malignant cancer without the repercussion of disease recurrence.
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http://dx.doi.org/10.3389/fchem.2020.601649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843432PMC
January 2021

A Novel Fabrication Method for a Capacitive MEMS Accelerometer Based on Glass-Silicon Composite Wafers.

Micromachines (Basel) 2021 Jan 21;12(2). Epub 2021 Jan 21.

Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100049, China.

In this paper, we report a novel teeter-totter type accelerometer based on glass-silicon composite wafers. Unlike the ordinary micro-electro-mechanical systems (MEMS) accelerometers, the entire structure of the accelerometer, includes the mass, the springs, and the composite wafer. The composite wafer is expected to serve as the electrical feedthrough and the fixed capacitance plate at the same time, to simplify the fabrication process, and to save on chip area. It is manufactured by filling melted borosilicate glass into an etched silicon wafer and polishing the wafer flat. A sensitivity of 51.622 mV/g in the range of ±5 g (g = 9.8 m/s2), a zero-bias stability under 0.2 mg, and the noise floor with 11.28 µg/√Hz were obtained, which meet the needs of most acceleration detecting applications. The micromachining solution is beneficial for vertical interconnection and miniaturization of MEMS devices.
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http://dx.doi.org/10.3390/mi12020102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911678PMC
January 2021

A multicenter study benchmarking single-cell RNA sequencing technologies using reference samples.

Nat Biotechnol 2020 Dec 21. Epub 2020 Dec 21.

Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, CA, USA.

Comparing diverse single-cell RNA sequencing (scRNA-seq) datasets generated by different technologies and in different laboratories remains a major challenge. Here we address the need for guidance in choosing algorithms leading to accurate biological interpretations of varied data types acquired with different platforms. Using two well-characterized cellular reference samples (breast cancer cells and B cells), captured either separately or in mixtures, we compared different scRNA-seq platforms and several preprocessing, normalization and batch-effect correction methods at multiple centers. Although preprocessing and normalization contributed to variability in gene detection and cell classification, batch-effect correction was by far the most important factor in correctly classifying the cells. Moreover, scRNA-seq dataset characteristics (for example, sample and cellular heterogeneity and platform used) were critical in determining the optimal bioinformatic method. However, reproducibility across centers and platforms was high when appropriate bioinformatic methods were applied. Our findings offer practical guidance for optimizing platform and software selection when designing an scRNA-seq study.
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http://dx.doi.org/10.1038/s41587-020-00748-9DOI Listing
December 2020

A germline 1;3 translocation disrupting the gene: a novel genetic cause for von Hippel-Lindau.

J Med Genet 2020 Oct 16. Epub 2020 Oct 16.

Urologic Oncology Branch, National Cancer Institue, Bethesda, Maryland, USA

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary tumour susceptibility disease caused by germline pathogenic variation of the tumour suppressor gene. Affected individuals are at risk of developing multiple malignant and benign tumours in a number of organs.In this report, a male patient in his 20s who presented to the Urologic Oncology Branch at the National Cancer Institute with a clinical diagnosis of VHL was found to have multiple cerebellar haemangioblastomas, bilateral epididymal cysts, multiple pancreatic cysts, and multiple, bilateral renal tumours and cysts. The patient had no family history of VHL and was negative for germline mutation by standard genetic testing. Further genetic analysis demonstrated a germline balanced translocation between chromosomes 1 and 3, t(1;3)(p36.3;p25) with a breakpoint on chromosome 3 within the second intron of the gene. This created a pathogenic germline alteration in by a novel mechanism that was not detectable by standard genetic testing.Karyotype analysis is not commonly performed in existing genetic screening protocols for patients with VHL. Based on this case, protocols should be updated to include karyotype analysis in patients who are clinically diagnosed with VHL but demonstrate no detectable mutation by existing genetic testing.
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http://dx.doi.org/10.1136/jmedgenet-2020-107308DOI Listing
October 2020

Serological Responses to Human Virome Define Clinical Outcomes of Italian Patients Infected with SARS-CoV-2.

medRxiv 2020 Sep 7. Epub 2020 Sep 7.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic respiratory infectious disease COVID-19. However, clinical manifestations and outcomes differ significantly among COVID-19 patients, ranging from asymptomatic to extremely severe, and it remains unclear what drives these disparities. Here, we studied 159 hospitalized Italian patients with pneumonia from the NIAID-NCI COVID-19 Consortium using a phage-display method to characterize circulating antibodies binding to 93,904 viral peptides encoded by 1,276 strains of human viruses. SARS-CoV-2 infection was associated with a marked increase in individual's immune memory antibody repertoires linked to trajectories of disease severity from the longitudinal analysis also including anti-spike protein antibodies. By applying a machine-learning-based strategy, we developed a viral exposure signature predictive of COVID-19-related disease severity linked to patient survival. These results provide a basis for understanding the roles of memory B-cell repertoires in COVID-19-related symptoms as well as a predictive tool for monitoring its clinical severity.
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http://dx.doi.org/10.1101/2020.09.04.20187088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480049PMC
September 2020

Chitosan nanoparticles for oral photothermally enhanced photodynamic therapy of colon cancer.

Int J Pharm 2020 Nov 6;589:119763. Epub 2020 Sep 6.

School of Pharmacy, Nantong University, Nantong 226001, China; Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Phototherapy exerts its anticancer effects by converting laser radiation energy into hyperthermia or reactive singlet oxygen (O). In this study, we developed chitosan nanoparticles (CS NPs) encapsulating both photothermal (IR780) and photodynamic (5-Aminolevulinic acid (5-ALA)) reagents for photothermally enhanced photodynamic therapy by noninvasive oral administration. The 5-ALA&IR780@CS NPs were stable in acidic conditions similar to the gastric environment, which greatly improved drug oral absorption and local accumulation in subcutaneous mouse colon tumors (CT-26 cells) following oral gavage. Mechanistic studies revealed that the co-delivery system can lead to photothermally enhanced photodynamic effects against cancer cells by increasing oxidative stress, including the elevation of ROS, superoxide and O production. Additionally, significant therapeutic efficacy for cancer treatment were observed in vivo after oral administration of 5-ALA&IR780@CS NPs, without causing any overt adverse effects. Our work highlights the great potential of photothermally enhanced photodynamic therapy by CS NPs for colon cancer management via oral route.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119763DOI Listing
November 2020

Novel, abundant Drosha isoforms are deficient in miRNA processing in cancer cells.

RNA Biol 2020 11 30;17(11):1603-1612. Epub 2020 Aug 30.

RNA Biology Laboratory, National Cancer Institute, National Institutes of Health , Frederick, MD, USA.

MicroRNAs (miRNAs) are a class of small noncoding RNAs about 22-nucleotide (nt) in length that collectively regulate more than 60% of coding genes. Aberrant miRNA expression is associated with numerous diseases, including cancer. miRNA biogenesis is licenced by the ribonuclease (RNase) III enzyme Drosha, the regulation of which is critical in determining miRNA levels. We and others have previously revealed that alternative splicing regulates the subcellular localization of Drosha. To further investigate the alternative splicing landscape of Drosha transcripts, we performed PacBio sequencing in different human cell lines. We identified two novel isoforms resulting from partial intron-retention in the region encoding the Drosha catalytic domain. One isoform (AS27a) generates a truncated protein that is unstable in cells. The other (AS32a) produces a full-length Drosha with a 14 amino acid insertion in the RIIID domain. By taking advantage of Drosha knockout cells in combination with a previously established reporter assay, we demonstrated that Drosha-AS32a lacks cleavage activity. Furthermore, neither Drosha-27a nor Drosha-32a were able to rescue miRNA expression in the Drosha knockout cells. Interestingly, both isoforms were abundantly detected in a wide range of cancer cell lines (up to 15% of all Drosha isoforms). Analysis of the RNA-seq data from over 1000 breast cancer patient samples revealed that the AS32a is relatively more abundant in tumours than in normal tissue, suggesting that AS32a may play a role in cancer development.
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http://dx.doi.org/10.1080/15476286.2020.1813439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567492PMC
November 2020

Optimization for Sequencing and Analysis of Degraded FFPE-RNA Samples.

J Vis Exp 2020 06 8(160). Epub 2020 Jun 8.

NCI CCR Sequencing Facility, Frederick National Laboratory for Cancer Research;

Gene expression analysis by RNA sequencing (RNA-seq) enables unique insights into clinical samples that can potentially lead to mechanistic understanding of the basis of various diseases as well as resistance and/or susceptibility mechanisms. However, FFPE tissues, which represent the most common method for preserving tissue morphology in clinical specimens, are not the best sources for gene expression profiling analysis. The RNA obtained from such samples is often degraded, fragmented, and chemically modified, which leads to suboptimal sequencing libraries. In turn, these generate poor quality sequence data that may not be reliable for gene expression analysis and mutation discovery. In order to make the most of FFPE samples and obtain the best possible data from low quality samples, it is important to take certain precautions while planning experimental design, preparing sequencing libraries, and during data analysis. This includes the use of appropriate metrics for precise sample quality control (QC), identifying the best methods for various steps during the sequencing library generation, and careful library QC. In addition, applying correct software tools and parameters for sequence data analysis is critical in order to identify artifacts in RNA-seq data, filter out contamination and low quality reads, assess uniformity of gene coverage, and measure the reproducibility of gene expression profiles among biological replicates. These steps can ensure high accuracy and reproducibility for profiling of very heterogeneous RNA samples. Here we describe the various steps for sample QC, library preparation and QC, sequencing, and data analysis that can help to increase the amount of useful data obtained from low quality RNA, such as that obtained from FFPE-RNA tissues.
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http://dx.doi.org/10.3791/61060DOI Listing
June 2020

A Viral Exposure Signature Defines Early Onset of Hepatocellular Carcinoma.

Cell 2020 Jul 10;182(2):317-328.e10. Epub 2020 Jun 10.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:

Hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence and mortality rate continuing to rise, although early detection and surveillance are suboptimal. We performed serological profiling of the viral infection history in 899 individuals from an NCI-UMD case-control study using a synthetic human virome, VirScan. We developed a viral exposure signature and validated the results in a longitudinal cohort with 173 at-risk patients who had long-term follow-up for HCC development. Our viral exposure signature significantly associated with HCC status among at-risk individuals in the validation cohort (area under the curve: 0.91 [95% CI 0.87-0.96] at baseline and 0.98 [95% CI 0.97-1] at diagnosis). The signature identified cancer patients prior to a clinical diagnosis and was superior to alpha-fetoprotein. In summary, we established a viral exposure signature that can predict HCC among at-risk patients prior to a clinical diagnosis, which may be useful in HCC surveillance.
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http://dx.doi.org/10.1016/j.cell.2020.05.038DOI Listing
July 2020

Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses.

Sci Transl Med 2020 02;12(530)

Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Solid tumors elicit a detectable immune response including the infiltration of tumor-associated macrophages (TAMs). Unfortunately, this immune response is co-opted into contributing toward tumor growth instead of preventing its progression. We seek to reestablish an antitumor immune response by selectively targeting surface receptors and endogenous signaling processes of the macrophage subtypes driving cancer progression. RP-182 is a synthetic 10-mer amphipathic analog of host defense peptides that selectively induces a conformational switch of the mannose receptor CD206 expressed on TAMs displaying an M2-like phenotype. RP-182-mediated activation of this receptor in human and murine M2-like macrophages elicits a program of endocytosis, phagosome-lysosome formation, and autophagy and reprograms M2-like TAMs to an antitumor M1-like phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy. Antitumor activity of RP-182 was also observed in CD206 patient-derived xenotransplantation models. Mechanistically, via selective reduction of immunosuppressive M2-like TAMs, RP-182 improved adaptive and innate antitumor immune responses, including increased cancer cell phagocytosis by reprogrammed TAMs.
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http://dx.doi.org/10.1126/scitranslmed.aax6337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832040PMC
February 2020

A Novel Piezoresistive MEMS Pressure Sensors Based on Temporary Bonding Technology.

Sensors (Basel) 2020 Jan 7;20(2). Epub 2020 Jan 7.

Engineering Research Center for Semiconductor Integrated Technology, Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100083, China.

A miniature piezoresistive pressure sensor fabricated by temporary bonding technology was reported in this paper. The sensing membrane was formed on the device layer of an SOI (Silicon-On-Insulator) wafer, which was bonded to borosilicate glass (Borofloat 33, BF33) wafer for supporting before releasing with Cu-Cu bonding after boron doping and electrode patterning. The handle layer was bonded to another BF33 wafer after thinning and etching. Finally, the substrate BF33 wafer was thinned by chemical mechanical polishing (CMP) to reduce the total device thickness. The copper temporary bonding layer was removed by acid solution after dicing to release the sensing membrane. The chip area of the fabricated pressure sensor was of 1600 μm × 650 μm × 104 μm, and the size of a sensing membrane was of 100 μm × 100 μm × 2 μm. A higher sensitivity of 36 μV/(V∙kPa) in the range of 0-180 kPa was obtained. By further reducing the width, the fabricated miniature pressure sensor could be easily mounted in a medical catheter for the blood pressure measurement.
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http://dx.doi.org/10.3390/s20020337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013386PMC
January 2020

Recent Progress of Miniature MEMS Pressure Sensors.

Micromachines (Basel) 2020 Jan 1;11(1). Epub 2020 Jan 1.

Engineering Research Center for Semiconductor Integrated Technology, Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100083, China.

Miniature Microelectromechanical Systems (MEMS) pressure sensors possess various merits, such as low power consumption, being lightweight, having a small volume, accurate measurement in a space-limited region, low cost, little influence on the objects being detected. Accurate blood pressure has been frequently required for medical diagnosis. Miniature pressure sensors could directly measure the blood pressure and fluctuation in blood vessels with an inner diameter from 200 to 1000 m. Glaucoma is a group of eye diseases usually resulting from abnormal intraocular pressure. The implantable pressure sensor for real-time inspection would keep the disease from worsening; meanwhile, these small devices could alleviate the discomfort of patients. In addition to medical applications, miniature pressure sensors have also been used in the aerospace, industrial, and consumer electronics fields. To clearly illustrate the "miniature size", this paper focuses on miniature pressure sensors with an overall size of less than 2 mm × 2 mm or a pressure sensitive diaphragm area of less than 1 mm × 1 mm. In this paper, firstly, the working principles of several types of pressure sensors are briefly introduced. Secondly, the miniaturization with the development of the semiconductor processing technology is discussed. Thirdly, the sizes, performances, manufacturing processes, structures, and materials of small pressure sensors used in the different fields are explained in detail, especially in the medical field. Fourthly, problems encountered in the miniaturization of miniature pressure sensors are analyzed and possible solutions proposed. Finally, the probable development directions of miniature pressure sensors in the future are discussed.
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http://dx.doi.org/10.3390/mi11010056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020044PMC
January 2020

Single-Cell Profiling Defines Transcriptomic Signatures Specific to Tumor-Reactive versus Virus-Responsive CD4 T Cells.

Cell Rep 2019 12;29(10):3019-3032.e6

Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address:

Most current tumor immunotherapy strategies leverage cytotoxic CD8 T cells. Despite evidence for clinical potential of CD4 tumor-infiltrating lymphocytes (TILs), their functional diversity limits our ability to harness their activity. Here, we use single-cell mRNA sequencing to analyze the response of tumor-specific CD4 TILs and draining lymph node (dLN) T cells. Computational approaches to characterize subpopulations identify TIL transcriptomic patterns strikingly distinct from acute and chronic anti-viral responses and dominated by diversity among T-bet-expressing T helper type 1 (Th1)-like cells. In contrast, the dLN response includes T follicular helper (Tfh) cells but lacks Th1 cells. We identify a type I interferon-driven signature in Th1-like TILs and show that it is found in human cancers, in which it is negatively associated with response to checkpoint therapy. Our study provides a proof-of-concept methodology to characterize tumor-specific CD4 T cell effector programs. Targeting these programs should help improve immunotherapy strategies.
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http://dx.doi.org/10.1016/j.celrep.2019.10.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934378PMC
December 2019

Improved Neuroprotective Effects of Gallic Acid-Loaded Chitosan Nanoparticles Against Ischemic Stroke.

Rejuvenation Res 2020 Aug 12;23(4):284-292. Epub 2019 Dec 12.

Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Ischemic stroke is a typical cerebrovascular illness with high morbidity and mortality worldwide. Nevertheless, strategies for the prevention and treatment of cerebral ischemia/reperfusion injury (CIRI) are limited. Gallic acid (GA) is a plant polyphenol that has been used against CIRI. However, the pharmacokinetic (PK) properties of GA, such as its low absorption, poor bioavailability, and quick elimination, have negative effects on its application. To strengthen its effectiveness, a delivery system of GA-loaded o-carboxymethyl chitosan nanoparticles (GA-NPs) was synthesized in our study. In PKs study, GA-NPs apparently increases the area under the curve of plasma concentration-time and prolonged half-life of GA. Then, we measured the and effects of the GA-NPs in the oxygen glucose deprivation model and the middle cerebral artery occlusion model. The results from our pharmacodynamic studies, including assessment of neurological deficit, cerebral infarction, levels of inflammation, and oxidative stress, showed that GA-NPs possess better neuroprotection compared with GA. In conclusion, GA-NPs may be used as an efficacious delivery vehicle for GA in the treatment of CIRI.
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http://dx.doi.org/10.1089/rej.2019.2230DOI Listing
August 2020

Remote Light-Responsive Nanocarriers for Controlled Drug Delivery: Advances and Perspectives.

Small 2019 11 10;15(45):e1903060. Epub 2019 Oct 10.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, QLD, 4072, Brisbane, Australia.

Engineering of smart photoactivated nanomaterials for targeted drug delivery systems (DDS) has recently attracted considerable research interest as light enables precise and accurate controlled release of drug molecules in specific diseased cells and/or tissues in a highly spatial and temporal manner. In general, the development of appropriate light-triggered DDS relies on processes of photolysis, photoisomerization, photo-cross-linking/un-cross-linking, and photoreduction, which are normally sensitive to ultraviolet (UV) or visible (Vis) light irradiation. Considering the issues of poor tissue penetration and high phototoxicity of these high-energy photons of UV/Vis light, recently nanocarriers have been developed based on light-response to low-energy photon irradiation, in particular for the light wavelengths located in the near infrared (NIR) range. NIR light-triggered drug release systems are normally achieved by using two-photon absorption and photon upconversion processes. Herein, recent advances of light-responsive nanoplatforms for controlled drug release are reviewed, covering the mechanism of light responsive small molecules and polymers, UV and Vis light responsive nanocarriers, and NIR light responsive nanocarriers. NIR-light triggered drug delivery by two-photon excitation and upconversion luminescence strategies is also included. In addition, the challenges and future perspectives for the development of light triggered DDS are highlighted.
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http://dx.doi.org/10.1002/smll.201903060DOI Listing
November 2019

Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer.

Cancer Cell 2019 10 3;36(4):418-430.e6. Epub 2019 Oct 3.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:

Cellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and between tumors and diverse landscapes of tumor microenvironment (TME). Strikingly, tumors with higher transcriptomic diversity were associated with patient's worse overall survival. We found a link between hypoxia-dependent vascular endothelial growth factor expression in tumor diversity and TME polarization. Moreover, T cells from higher heterogeneous tumors showed lower cytolytic activities. Consistent results were found using bulk genomic and transcriptomic profiles of 765 liver tumors. Our results offer insight into the diverse ecosystem of liver cancer and its impact on patient prognosis.
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http://dx.doi.org/10.1016/j.ccell.2019.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801104PMC
October 2019

A Thpok-Directed Transcriptional Circuitry Promotes Bcl6 and Maf Expression to Orchestrate T Follicular Helper Differentiation.

Immunity 2019 09 15;51(3):465-478.e6. Epub 2019 Aug 15.

Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address:

The generation of high-affinity neutralizing antibodies, the objective of most vaccine strategies, occurs in B cells within germinal centers (GCs) and requires rate-limiting "help" from follicular helper CD4 T (Tfh) cells. Although Tfh differentiation is an attribute of MHC II-restricted CD4 T cells, the transcription factors driving Tfh differentiation, notably Bcl6, are not restricted to CD4 T cells. Here, we identified a requirement for the CD4-specific transcription factor Thpok during Tfh cell differentiation, GC formation, and antibody maturation. Thpok promoted Bcl6 expression and bound to a Thpok-responsive region in the first intron of Bcl6. Thpok also promoted the expression of Bcl6-independent genes, including the transcription factor Maf, which cooperated with Bcl6 to mediate the effect of Thpok on Tfh cell differentiation. Our findings identify a transcriptional program that links the CD4 lineage with Tfh differentiation, a limiting factor for efficient B cell responses, and suggest avenues to optimize vaccine generation.
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http://dx.doi.org/10.1016/j.immuni.2019.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904114PMC
September 2019

A novel nanoparticle drug delivery system based on PEGylated hemoglobin for cancer therapy.

Drug Deliv 2019 Dec;26(1):717-723

f QIMR Berghofer Medical Research Institute , Brisbane , Australia.

Proteins such as albumin, gelatin, casein, transferrin, and collagen are widely used as drug delivery systems. However, only albumin-based paclitaxel (PTX) formulation Abraxane (PTX-albumin NPs prepared by nab-technology) has been successfully developed for treating metastatic breast cancer clinically due to abundant materials, simple industrial scale-up process, and well tumor-targeting ability. Hemoglobin (Hb) is another protein used for drug delivery with similar advantages. In this study, we successfully synthesized PEG-Hb nanoparticles loading with PTX based on previously well-established acid-denatured method. PEG-Hb-PTX NPs showed enhanced cellular uptake and great cellular inhibition ability . Moreover, our animal study showed that PEGylated NPs greatly accumulated in tumor tissues and exhibited excellent anticancer activity We found that PEG-Hb-PTX NPs possess a better antitumor effect than the commercially available Taxol formulation. We believe that PEG-Hb has great potential as an efficient drug delivery system for further clinic study.
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http://dx.doi.org/10.1080/10717544.2019.1639846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691922PMC
December 2019

Research on the Protrusions Near Silicon-Glass Interface during Cavity Fabrication.

Micromachines (Basel) 2019 Jun 23;10(6). Epub 2019 Jun 23.

Research Center of Engineering for Semiconductor Integrated Technology, Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100083, China.

Taking advantage of good hermeticity, tiny parasitic capacitance, batch mode fabrication, and compatibility with multiple bonding techniques, the glass-silicon composite substrate manufactured by the glass reflow process has great potential to achieve 3D wafer-level packaging for high performance. However, the difference in etching characteristics between silicon and glass inevitably leads to the formation of the undesired micro-protrusions near the silicon-glass interface when preparing a shallow cavity etched around a few microns in the composite substrate. The micro-protrusions have a comparable height with the depth of the cavity, which increases the risks of damages to sensitive structures and may even trigger electrical breakdown, resulting in thorough device failure. In this paper, we studied the characteristics of the chemical composition and etching mechanisms at the interface carefully and proposed the corresponding optimized solutions that utilized plasma accumulation at the interface to accelerate etching and bridge the gap in etching rates between different chemical compositions. Finally, a smooth transition of 131.1 nm was achieved at the interface, obtaining an ideal etching cavity surface and experimentally demonstrating the feasibility of our proposal. The micromachining solution is beneficial for improving the yield and structural design flexibility of higher performance micro-electromechanical systems (MEMS) devices.
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http://dx.doi.org/10.3390/mi10060420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631805PMC
June 2019

Zinc accumulation in mitochondria promotes ischemia-induced BBB disruption through Drp1-dependent mitochondria fission.

Toxicol Appl Pharmacol 2019 08 29;377:114601. Epub 2019 May 29.

Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131-0001, USA.

High concentration of zinc has been reported to act as a critical mediator of neuronal death in the ischemic brain. Our previous studies showed that labile zinc accumulates in cerebromicrovessels and contributes to blood-brain barrier (BBB) permeability increase after cerebral ischemia. However, the role of mitochondrial zinc in ischemia-induced BBB permeability alteration is still unclear. In this study, we showed that ischemia/reperfusion induced free zinc accumulation in endothelial cells (ECs), resulting in increased generation of reactive oxygen species (ROS) in both cultured ECs and in microvessels isolated from the brain of ischemic rats. Furthermore, we found that zinc was highly accumulated in mitochondria, leading to mitochondrial ROS generation under the ischemic condition. Moreover, zinc overload in mitochondria resulted in the collapse of the network of mitochondria, which was mediated through Dynamin-related protein-1 (Drp-1) dependent mitochondrial fission pathway. Finally, the zinc overload in mitochondria activated matrix metalloproteinase-2 and led to ischemia-induced BBB permeability increase. This study demonstrated that zinc-ROS pathway in mitochondria contributes to the ischemia-induced BBB disruption via Drp-1 dependent mitochondrial fission pathway.
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http://dx.doi.org/10.1016/j.taap.2019.114601DOI Listing
August 2019

Robustness of RNA sequencing on older formalin-fixed paraffin-embedded tissue from high-grade ovarian serous adenocarcinomas.

PLoS One 2019 6;14(5):e0216050. Epub 2019 May 6.

Division of Cancer Control and Population Sciences (DCCPS), National Cancer Institute, Rockville, MD, United States of America.

Formalin-fixed paraffin-embedded (FFPE) tissues are among the most widely available clinical specimens. Their potential utility as a source of RNA for transcriptome studies would greatly enhance population-based cancer studies. Although preliminary studies suggest FFPE tissue may be used for RNA sequencing, the effect of storage time on these specimens needs to be determined. We conducted this study to determine whether RNA in archived FFPE high-grade ovarian serous adenocarcinomas from Surveillance, Epidemiology and End Results (SEER) registries was present in sufficient quantity and quality for RNA-Seq analysis. FFPE tissues, stored from 7 to 32 years, were obtained from three SEER sites. RNA was extracted, quantified, quality assessed, and subjected to RNA-Seq (a whole transcriptome sequencing technology). FFPE specimens stored for longer periods of time had poorer RNA sample quality as indicated by negative correlations between specimen storage time and fragment distribution values (DV). In addition, sample contamination was a common issue among the RNA, with 41 of 67 samples having 5% to 48% bacterial contamination. However, regardless of specimen storage time and bacterial contamination, 60% of the samples yielded data that enabled gene expression quantification, identifying more than 10,000 genes, with the correlations among most biological replicates above 0.7. This study demonstrates that FFPE high-grade ovarian serous adenocarcinomas specimens stored in repositories for up to 32 years and under varying storage conditions are a promising source of RNA for RNA-Seq. We also describe certain caveats to be considered when designing RNA-Seq studies using archived FFPE tissues.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216050PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502345PMC
January 2020

A Decoupling Design with T-Shape Structure for the Aluminum Nitride Gyroscope.

Micromachines (Basel) 2019 Apr 12;10(4). Epub 2019 Apr 12.

Engineering Research Center for Semiconductor Integrated Technology, Institute of Semiconductors, Chinese Academy of Sciences, Beijing 100083, China.

This paper reports a novel design for the decoupling of microelectromechanical systems (MEMS) gyroscopes. The MEMS gyroscope is based on piezoelectric aluminum nitride (AlN) film, and the main structure is a mass hung by T-shape beams. A pair of parallel drive electrodes are symmetrically placed on the surface of the vertical bar for driving the oscillating mass. A serpentine sense electrode is placed on the lateral bar. When the gyroscope is oscillating in drive mode, charges with equal quantity and opposite sign will be polarized and distributed symmetrically along the lateral bar. These charges neutralize each other at the sense electrode. Therefore, no coupling signals can be detected from the sense electrode. This design can realize the decoupling between the drive mode and sense mode. In this work, the T-shape decoupled structure was designed as the key component of an AlN piezoelectric gyroscope and the whole structure was simulated by COMSOL Multiphysics 5.2a. The working principle of the decoupling is described in detail. Electrical properties were characterized by the dynamic signal analyzer. According to the test results, the drive mode and the sense mode are decoupled. The coefficient of orthogonal coupling is 1.55%.
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http://dx.doi.org/10.3390/mi10040244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523559PMC
April 2019

Salinomycin-Loaded Gold Nanoparticles for Treating Cancer Stem Cells by Ferroptosis-Induced Cell Death.

Mol Pharm 2019 06 30;16(6):2532-2539. Epub 2019 Apr 30.

QIMR Berghofer Medical Research Institute , Brisbane , QLD 1006 , Australia.

Cancer stem cells (CSCs) are a subpopulation of tumor cells that exhibit self-renewal, differentiation, and tumorigenicity. CSCs are highly resistant to the conventional cancer treatment and have been associated with metastasis. Several studies have been shown that salinomycin (Sal) has the potential to target cancer stem cells evidenced by in vitro and in vivo tumor models. Here, salinomycin was conjugated with biocompatible gold nanoparticles (AuNPs) coated with poly(ethylene glycol) to improve its specificity in targeting breast cancer stem cells (BCSCs). BCSCs derived from CD24/CD44 subpopulation showed high sensitivity to Sal-AuNP treatment. An in-depth analysis on the mechanism of action of Sal-AuNPs indicated ferroptosis, an iron-dependent cell death, was achieved as a result of iron accumulation and inhibition of antioxidant properties. This also led to the induction of oxidative stress, mitochondrial dysfunction, and lipid oxidation. Our findings suggest Sal-AuNP treatment is an efficient therapeutic avenue in eliminating cancer stem cells.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00132DOI Listing
June 2019

Bis(2-pyridylmethyl)amine-functionalized alizarin: an efficient and simple colorimetric sensor for fluoride and a fluorescence turn-on sensor for Al in an organic solution.

Dalton Trans 2019 Apr;48(15):5035-5047

Department of Chemistry, Shanghai University, Shanghai 200444, China.

A complexone analog chemosensor, H2L, bearing chelating bis(2-pyridylmethyl) amine and alizarin groups was synthesized via the Mannich reaction. H2L chromically responds to OH-, F-, CH3COO-, and H2PO4- in DMF, CH3CN, and acetone, but not in CH3OH or H2O. The addition of F- ions to H2L selectively induces a significant and visible color change in acetonitrile and shifts both methylene proton signals upfield. H2L also exhibits visible responses to Mg2+, Sr2+, Ba2+, Tb3+, Cu2+, Co2+, Ni2+, Zn2+, Mn2+, Cd2+, and Fe3+ in solution. AlCl3 can form an Al : L = 2 : 3 complex that not only changes the color of the DMF solution, but also significantly increases its fluorescence intensity. The limit of fluorescence turn-on detection for AlCl3 in DMF is 2.7 × 10-8 M, which is an order higher than those of other anthraquinone sensors reported in the literature. NMR spectroscopy shows that hydroxyl is not deprotonated upon interacting with Al3+, but will be partially deprotonated in the presence of Zn2+. Contrary to the complexone, the H2L-Ce(iii) complex does not react chromically to F-. However, the H2L-NiCl2 complex responds chromically to F-, with higher sensitivity (LOD = 1.3 × 10-6 M F- in acetonitrile) than free H2L. The spectral changes in the presence of F- are similar to that of OH-; however, the spectrum shifts slightly to a longer wavelength and is more sensitive to both H2L and the H2L-NiCl2 complex. Moreover, 4% or less H2O in the solvent essentially has no influence on the F- sensitivity; however, high water content significantly decreases the F- sensitivity. The spectral changes of the Zn2+, Cu2+, Fe3+, Ce3+, and Ni2+ complexes in the presence of different NaOH concentrations were also investigated.
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http://dx.doi.org/10.1039/c9dt00859dDOI Listing
April 2019

Highly Responsive and Ultrasensitive Glucose Sensor Based on Au Foam.

Sensors (Basel) 2019 Mar 9;19(5). Epub 2019 Mar 9.

Beijing Bioprocess Key Laboratory, Beijing University of Chemical Technology, Beijing 100029, China.

Glucose concentration is an important physiological index, therefore methods for sensitive detection of glucose are important. In this study, Au foam was prepared by electrodeposition with a dynamic gas template on an Au nanoparticle/Si substrate. The Au foam showed ultrasensitivity, high selectivity, and long-term stability in the quantitative detection of glucose. The foam was used as an electrode, and the amperometric response indicated excellent catalytic activity in glucose oxidation, with a linear response across the concentration range 0.5 μM to 12 mM, and a limit of detection of 0.14 μM. High selectivity for interfering molecules at six times the normal level and long-term stability for 30 days were obtained. The results for electrochemical detection with Au foam of glucose in human serum were consistent with those obtained with a sensor based on surface-enhanced Raman spectroscopy and a commercial sensor. This proves that this method can be used with real samples. These results show that Au foam has great potential for use as a non-enzymatic glucose sensor.
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http://dx.doi.org/10.3390/s19051203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427456PMC
March 2019

Application of Audio Education in Respiratory Medicine Wards.

Clin Nurs Res 2020 07 17;29(6):392-397. Epub 2019 Feb 17.

Shanghai University of Traditional Chinese Medicine, China.

Improving the efficiency of patient education can help improve patient's satisfaction and alleviate the pressure of nurse shortage. This study aimed to develop and pilot an educational audio to improve the effectiveness of inpatient education. A primary literature review was conducted and educational materials were written and recorded by MP3. A pilot study was conducted in 713 adult patients in the department of respiratory medicine at a large urban Shanghai teaching hospital. Patients in the experimental group showed greater satisfaction with their health education. For the education to be effective during the admission, the asthma patients in the experimental group spent less time in face-to-face communication. The feedback rate for disease education among asthma patients in the experimental group was significantly higher. Wider applications of audio in patient education may be valuable to better adjust to nurse reduction and to improve nursing service quality.
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http://dx.doi.org/10.1177/1054773819829622DOI Listing
July 2020

Genome Assembly and Annotation of the Trichoplusia ni Tni-FNL Insect Cell Line Enabled by Long-Read Technologies.

Genes (Basel) 2019 01 23;10(2). Epub 2019 Jan 23.

NCI RAS Initiative, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD 21701, USA.

Background: derived cell lines are commonly used to enable recombinant protein expression via baculovirus infection to generate materials approved for clinical use and in clinical trials. In order to develop systems biology and genome engineering tools to improve protein expression in this host, we performed de novo genome assembly of the -derived cell line Tni-FNL.

Methods: By integration of PacBio single-molecule sequencing, Bionano optical mapping, and 10X Genomics linked-reads data, we have produced a draft genome assembly of Tni-FNL.

Results: Our assembly contains 280 scaffolds, with a N50 scaffold size of 2.3 Mb and a total length of 359 Mb. Annotation of the Tni-FNL genome resulted in 14,101 predicted genes and 93.2% of the predicted proteome contained recognizable protein domains. Ortholog searches within the superorder provided further evidence of high accuracy and completeness of the Tni-FNL genome assembly.

Conclusions: This first draft Tni-FNL genome assembly was enabled by complementary long-read technologies and represents a high-quality, well-annotated genome that provides novel insight into the complexity of this insect cell line and can serve as a reference for future large-scale genome engineering work in this and other similar recombinant protein production hosts.
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http://dx.doi.org/10.3390/genes10020079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409714PMC
January 2019