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1.
ACS Nano ; 15(9): 14149-14161, 2021 09 28.
Article in English | MEDLINE | ID: mdl-34478262

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) cells are surrounded by a dense extracellular matrix (ECM), which greatly restricts the access of therapeutic agents, resulting in poor clinical response to chemotherapy. Transforming growth factor-ß1 (TGF-ß1) signaling plays a crucial role in construction of the desmoplastic stroma and provides potential targets for PDAC therapy. To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG-PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-ß1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). By surface modification of the liposomes with a peptide, APTEDB, the nanosystem can be anchored to abundant tumor-associated fibronectin in PDAC stroma and decreases its size by releasing encapsulated TAX-loaded nanospheres, as well as VAC after collapse of the liposomes. The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Adenocarcinoma , Carcinoma, Pancreatic Ductal/drug therapy , Cell Transformation, Neoplastic , Humans , Pancreatic Neoplasms/drug therapy , Transforming Growth Factor beta/antagonists & inhibitors
2.
Methods ; 173: 69-74, 2020 02 15.
Article in English | MEDLINE | ID: mdl-31252060

ABSTRACT

Biomedical text mining is becoming increasingly important as the number of biomedical documents grow rapidly. Deep learning has boosted the development of biomedical text mining models. However, as deep learning models require a large amount of training data, a hierarchical attention based transfer learning model is proposed in this paper for the question answering task in biomedical field which lacks of sufficient training data. We adopt BERT (Bidirectional Encoder Representation Transformers), which has the ability to learn from large-scale unsupervised data, to enrich the semantic representation in our model. Especially, the scaled dot-product attention mechanism captures the question interaction clues for passage encoding. The domain adaptation technique of fine-tuning is used to reinforce the performance, which penalizes the deviations from the source model's parameters and remembers the knowledge of source domain. We evaluate the system performance on the open data set of BioASQ-Task B. The results show that our system achieves the state-of-the-art performance without any handcrafted features and outperforms the best solution for factoid questions in 2016 and 2017 BioASQ-Task B.


Subject(s)
Biomedical Research/methods , Data Mining/methods , Semantics , Algorithms , Humans
3.
Mol Cell ; 73(6): 1115-1126.e6, 2019 03 21.
Article in English | MEDLINE | ID: mdl-30772176

ABSTRACT

Dysregulation of chromatin methylation is associated with defects in cellular differentiation as well as a variety of cancers. How cells regulate the opposing activities of histone methyltransferase and demethylase enzymes to set the methylation status of the epigenome for proper control of gene expression and metabolism remains poorly understood. Here, we show that loss of methylation of the major phosphatase PP2A in response to methionine starvation activates the demethylation of histones through hyperphosphorylation of specific demethylase enzymes. In parallel, this regulatory mechanism enables cells to preserve SAM by increasing SAH to limit SAM consumption by methyltransferase enzymes. Mutants lacking the PP2A methyltransferase or the effector H3K36 demethylase Rph1 exhibit elevated SAM levels and are dependent on cysteine due to reduced capacity to sink the methyl groups of SAM. Therefore, PP2A directs the methylation status of histones by regulating the phosphorylation status of histone demethylase enzymes in response to SAM levels.


Subject(s)
Chromatin/metabolism , DNA Methylation , Histones/metabolism , Protein Phosphatase 2/metabolism , Protein Processing, Post-Translational , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/enzymology , Chromatin/genetics , Dealkylation , Gene Expression Regulation, Fungal , Histone Demethylases/genetics , Histone Demethylases/metabolism , Methylation , Mutation , Protein Binding , Protein Phosphatase 2/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , S-Adenosylmethionine/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics
4.
Cell Rep ; 23(7): 1907-1914, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29768191

ABSTRACT

The conserved GATOR1 complex consisting of NPRL2-NPRL3-DEPDC5 inhibits mammalian target of rapamycin complex 1 (mTORC1) in response to amino acid insufficiency. Here, we show that loss of NPRL2 and GATOR1 function in skeletal muscle causes constitutive activation of mTORC1 signaling in the fed and fasted states. Muscle fibers of NPRL2 knockout animals are significantly larger and show altered fiber-type composition, with more fast-twitch glycolytic and fewer slow-twitch oxidative fibers. NPRL2 muscle knockout mice also have altered running behavior and enhanced glucose tolerance. Furthermore, loss of NPRL2 induces aerobic glycolysis and suppresses glucose entry into the TCA cycle. Such chronic activation of mTORC1 leads to compensatory increases in anaplerotic pathways to replenish TCA intermediates that are consumed for biosynthetic purposes. These phenotypes reveal a fundamental role for the GATOR1 complex in the homeostatic regulation of mitochondrial functions (biosynthesis versus ATP) to mediate carbohydrate utilization in muscle.


Subject(s)
Glycolysis , Mechanistic Target of Rapamycin Complex 1/metabolism , Muscle Fibers, Skeletal/metabolism , Aerobiosis , Amino Acids/metabolism , Animals , Behavior, Animal , Carbohydrate Metabolism , Citric Acid Cycle , Mice, Inbred C57BL , Mice, Knockout , Tumor Suppressor Proteins/metabolism
5.
Biomaterials ; 175: 110-122, 2018 08.
Article in English | MEDLINE | ID: mdl-29803999

ABSTRACT

Nogo-B receptor (NgBR) plays fundamental roles in regulating angiogenesis, vascular development, and the epithelial-mesenchymal transition (EMT) of cancer cells. However, the therapeutic effect of NgBR blockade on tumor vasculature and malignancy is unknown, investigations on which requires an adequate delivery system for small interfering RNA against NgBR (NgBR siRNA). Here a surface charge switchable polymeric nanoparticle that was sensitive to the slightly acidic tumor microenvironment was developed for steady delivery of NgBR siRNA to tumor tissues. The nanoformulation was constructed by conjugating 2, 3-dimethylmaleic anhydride (DMMA) molecules to the surface amines of micelles formed by cationic co-polymer poly(lactic-co-glycolic acid)2-poly(ethylenimine) and subsequent absorption of NgBR siRNAs. The nanoparticles remained negatively charged in physiological condition and smartly converted to positive surface charge due to tumor-acidity-activated shedding of DMMA. The charge conversion facilitated cellular uptake of siRNAs and in turn efficiently depleted the expression of NgBR in tumor-bearing tissues. Silencing of NgBR suppressed endothelial cell migration and tubule formation, and reverted the EMT process of breast cancer cells. Delivery of the nanoformulation to mice bearing orthotopic breast carcinoma showed no effect on tumor growth, but led to remarkable decrease of distant metastasis by normalizing tumor vessels and suppressing the EMT of breast cancer cells. This study demonstrated that NgBR is a promising therapeutic target in abnormal tumor vasculature and aggressive cancer cells, and the tumor-responsive nanoparticle with the feature of charge transformation offers great potential for tumor-specific delivery of gene therapeutics.


Subject(s)
Mammary Neoplasms, Animal/blood supply , Mammary Neoplasms, Animal/pathology , Nanoparticles/chemistry , RNA, Small Interfering/administration & dosage , Receptors, Cell Surface/metabolism , Animals , Cell Line, Tumor , Cell Movement , Drug Carriers , Drug Liberation , Epithelial-Mesenchymal Transition , Female , Human Umbilical Vein Endothelial Cells/cytology , Humans , Maleic Anhydrides/chemistry , Mammary Neoplasms, Animal/therapy , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , Neoplasm Metastasis , Neovascularization, Pathologic/therapy , Polyethyleneimine/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Receptors, Cell Surface/genetics , Tumor Microenvironment
6.
J Am Soc Mass Spectrom ; 28(10): 2078-2089, 2017 10.
Article in English | MEDLINE | ID: mdl-28752479

ABSTRACT

With recent advances in understanding the genomic underpinnings and oncogenic drivers of pathogenesis in different subtypes, it is increasingly clear that proper pretreatment diagnostics are essential for the choice of appropriate treatment options for non-small cell lung cancer (NSCLC). Tumor tissue preservation in optimal cutting temperature (OCT) compound is commonly used in the surgical suite. However, proteins recovered from OCT-embedded specimens pose a challenge for LC-MS/MS experiments, due to the large amounts of polymers present in OCT. Here we present a simple workflow for whole proteome analysis of OCT-embedded NSCLC tissue samples, which involves a simple trichloroacetic acid precipitation step. Comparisons of protein recovery between frozen versus OCT-embedded tissue showed excellent consistency with more than 9200 proteins identified. Using an isobaric labeling strategy, we quantified more than 5400 proteins in tumor versus normal OCT-embedded core needle biopsy samples. Gene ontology analysis indicated that a number of proliferative as well as squamous cell carcinoma (SqCC) marker proteins were overexpressed in the tumor, consistent with the patient's pathology based diagnosis of "poorly differentiated SqCC". Among the most downregulated proteins in the tumor sample, we noted a number of proteins with potential immunomodulatory functions. Finally, interrogation of the aberrantly expressed proteins using a candidate approach and cross-referencing with publicly available databases led to the identification of potential druggable targets in DNA replication and DNA damage repair pathways. We conclude that our approach allows LC-MS/MS proteomic analyses on OCT-embedded lung cancer specimens, opening the way to bring powerful proteomics into the clinic. Graphical Abstract ᅟ.


Subject(s)
Biopsy, Large-Core Needle , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Proteome/analysis , Tandem Mass Spectrometry/methods , Biomarkers, Tumor/analysis , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Proliferation , Chromatography, Liquid , Gene Expression Regulation, Neoplastic , Humans , Kinesins/analysis , Kinesins/genetics , Kinesins/metabolism , Proteome/genetics , Proteome/metabolism , Proteomics/methods , Reproducibility of Results , Signal-To-Noise Ratio , Temperature
7.
Nat Biomed Eng ; 1(8): 667-679, 2017 Aug.
Article in English | MEDLINE | ID: mdl-31015598

ABSTRACT

Limited intratumoural perfusion and nanoparticle retention remain major bottlenecks for the delivery of nanoparticle therapeutics into tumours. Here, we show that polymer-lipid-peptide nanoparticles delivering the antiplatelet antibody R300 and the chemotherapeutic agent doxorubicin can locally deplete tumour-associated platelets, thereby enhancing vascular permeability and augmenting the accumulation of the nanoparticles in tumours. R300 is specifically released in the tumour on cleavage of the lipid-peptide shell of the nanoparticles by matrix metalloprotease 2, which is commonly overexpressed in tumour vascular endothelia and stroma, thus facilitating vascular breaches that enhance tumour permeability. We also show that this strategy leads to substantial tumour regression and metastasis inhibition in mice.

8.
Nat Biomed Eng ; 1(8): 680, 2017 08.
Article in English | MEDLINE | ID: mdl-31015600

ABSTRACT

In the version of the Supplementary Information originally published, in Supplementary Fig. 8a, in the bottom row, the left-most image ('Control') was not the correct image; this has now been replaced.

9.
Biochem Pharmacol ; 108: 11-21, 2016 May 15.
Article in English | MEDLINE | ID: mdl-26944193

ABSTRACT

Amifostine, an organic thiophosphate prodrug, has been clinically utilized for selective protection of normal tissues with high expression of alkaline phosphatase from oxidative damage elicited by chemotherapy or radiotherapy. However, the patients receiving amifostine suffer from severe dose-dependent adverse effects. Strategies for improvement of the protective efficacy and toxicity profile of amifostine are urgently required. Here we constructed a PEGylated amifostine (PEG-amifostine) through conjugation of amifostine to the 4-arm PEG (5000 Da) by a mild one-step reaction. The relatively large PEG-amifostine molecules clustered into spherical nanoparticles, resulting in distinct hydrolysis properties, cell uptake profile and antioxidative activity compared with the free small molecules. PEGylation prolonged the hydrolysis time of amifostine, providing sustained transformation to its functional metabolites. PEG-amifostine could be internalized into cells and translocated to acidic organelles in a time-dependent manner. The intrinsic cytotoxicity of amifostine, which is related to the reductive reactivity of its metabolites and their ability to diffuse readily, was attenuated after PEGylation. This modification impeded the interaction between free sulfhydryls and functional biomolecules, providing PEG-amifostine with an improved safety profile in vitro. Moreover, PEG-amifostine showed higher efficiency in the elimination of reactive oxygen species and prevention of cisplatin-induced cytotoxicity compared with free amifostine. Overall, our study for the first time developed a PEGylated form of amifostine which significantly improved the efficacy and decreased the adverse effects of this antioxidant in vitro with great promise for clinical translation. In vivo study is urgently needed to confirm and redeem the cytoprotective effects of the PEG-amifostine in chemotherapy.


Subject(s)
Amifostine/pharmacology , Antioxidants/pharmacology , Polyethylene Glycols/chemistry , Alkaline Phosphatase/chemistry , Amifostine/chemistry , Amifostine/toxicity , Animals , Antineoplastic Agents/toxicity , Antioxidants/chemistry , Antioxidants/toxicity , Cell Line, Tumor , Cells, Cultured , Cisplatin/toxicity , Cytoprotection , Humans , Hydrolysis , Male , Mice, Inbred BALB C , Reactive Oxygen Species/metabolism
10.
Mol Cancer Ther ; 14(10): 2390-400, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26269603

ABSTRACT

Peptide therapeutics hold great promise for the treatment of cancer due to low toxicity, high specificity, and ease of synthesis and modification. However, the unfavorable pharmacokinetic parameters strictly limit their therapeutic efficacy and clinical translation. Here, we tailor-designed an amphiphilic chimeric peptide through conjugation of functional 3-diethylaminopropyl isothiocyanate (DEAP) molecules to a short antitumor peptide, C16Y. The ultimate DEAP-C16Y peptides self-assembled into spherical nanostructures at physiologic conditions, which dissociated to release individual peptide molecules in weakly acidic tumors. DEAP-C16Y peptides showed negligible cytotoxicity but impaired vascular endothelial cell migration and tubule formation by inactivation of the focal adhesion kinase and PI3K-Akt pathways, as well as tumor cell invasion by decreasing invadopodia formation. Compared with C16Y, the systemically administered DEAP-C16Y nanostructures exhibited superior stability, thereby allowing prolonged treatment interval and resulting in significant decreases in microvessel density, tumor growth, and distant metastasis formation in orthotopic mammary tumor models. Through encapsulation of hydrophobic doxorubicin, DEAP-C16Y nanostructure served as a smart carrier to achieve targeted drug delivery and combination therapy. Our study, for the first time, demonstrates that a simple nanoformulation using a functional antitumor peptide as the building block can show innate antitumor activity and also provide a nanoplatform for combination therapy, opening a new avenue for the design of antitumor nanotherapeutics.


Subject(s)
Angiogenesis Inhibitors/administration & dosage , Doxorubicin/administration & dosage , Drug Carriers/administration & dosage , Peptides/administration & dosage , Amino Acid Sequence , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacokinetics , Animals , Cell Line, Tumor , Cell Survival/drug effects , Chemistry, Pharmaceutical , Doxorubicin/chemistry , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Stability , Female , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/physiology , Mice, Inbred BALB C , Mice, Nude , Molecular Sequence Data , Nanoparticles/chemistry , Peptides/chemistry , Peptides/pharmacokinetics , Tumor Microenvironment/drug effects , Xenograft Model Antitumor Assays
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