Publications by authors named "Jinyang Li"

114 Publications

Dissecting phenotypic transitions in metastatic disease via photoconversion-based isolation.

Elife 2021 Feb 23;10. Epub 2021 Feb 23.

Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Cancer patients often harbor occult metastases, a potential source of relapse that is targetable only through systemic therapy. Studies of this occult fraction have been limited by a lack of tools with which to isolate discrete cells on spatial grounds. We developed PIC-IT, a photoconversion-based isolation technique allowing efficient recovery of cell clusters of any size - including single-metastatic cells - which are largely inaccessible otherwise. In a murine pancreatic cancer model, transcriptional profiling of spontaneously arising microcolonies revealed phenotypic heterogeneity, functionally reduced propensity to proliferate and enrichment for an inflammatory-response phenotype associated with NF-κB/AP-1 signaling. Pharmacological inhibition of NF-κB depleted microcolonies but had no effect on macrometastases, suggesting microcolonies are particularly dependent on this pathway. PIC-IT thus enables systematic investigation of metastatic heterogeneity. Moreover, the technique can be applied to other biological systems in which isolation and characterization of spatially distinct cell populations is not currently feasible.
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http://dx.doi.org/10.7554/eLife.63270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929558PMC
February 2021

PTHrP drives pancreatic cancer growth and metastasis and reveals a new therapeutic vulnerability.

Cancer Discov 2021 Feb 15. Epub 2021 Feb 15.

Columbia University Medical Center

Pancreatic cancer metastasis is a leading cause of cancer-related deaths, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Here, we report that the parathyroid hormone-related protein (PTHrP encoded by PTHLH) is frequently amplified as part of the KRAS amplicon in pancreatic cancer patients. PTHrP upregulation drives the growth of both primary and metastatic tumors in mice and is highly enriched in PDAC metastases. Loss of PTHrP - either genetically or pharmacologically - dramatically reduces tumor burden, eliminates metastasis, and enhances overall survival. These effects are mediated in part through a reduction in epithelial-to-mesenchymal transition, which reduces the tumor cells' ability to initiate the metastatic cascade. Spp1, which encodes Osteopontin, is revealed to be a downstream effector of PTHrP. Our results establish a new paradigm in pancreatic cancer whereby PTHrP is a driver of disease progression and emerges as a novel therapeutic vulnerability.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1098DOI Listing
February 2021

A pentapeptide enabled AL3810 liposome-based glioma-targeted therapy with immune opsonic effect attenuated.

Acta Pharm Sin B 2021 Jan 13;11(1):283-299. Epub 2020 Aug 13.

Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, China.

AL3810, a molecular dual inhibitor of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), has earned the permission of phase II clinical trial for tumor treatment by China FDA. As a reversible ATP-competitive inhibitor, AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR, whereas, AL3810 lacking interplay with extracellular region of receptors rendered deficient blood-brain tumor barrier (BBTB) recognition, poor brain penetration and unsatisfactory anti-glioma efficacy. Integrin v3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma. The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia, activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3b and C5b-9, and experienced complement-dependent opsonization. We newly proposed a pentapeptide mn with superb v3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation, targeting ability, and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly. Stemming from attenuated immunogenicity, peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.
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http://dx.doi.org/10.1016/j.apsb.2020.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838056PMC
January 2021

RCO-3 and COL-26 form an external-to-internal module that regulates the dual-affinity glucose transport system in Neurospora crassa.

Biotechnol Biofuels 2021 Jan 28;14(1):33. Epub 2021 Jan 28.

Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China.

Background: Low- and high-affinity glucose transport system is a conserved strategy of microorganism to cope with environmental glucose fluctuation for their growth and competitiveness. In Neurospora crassa, the dual-affinity glucose transport system consists of a low-affinity glucose transporter GLT-1 and two high-affinity glucose transporters HGT-1/HGT-2, which play diverse roles in glucose transport, carbon metabolism, and cellulase expression regulation. However, the regulation of this dual-transporter system in response to environmental glucose fluctuation is not yet clear.

Results: In this study, we report that a regulation module consisting of a downstream transcription factor COL-26 and an upstream non-transporting glucose sensor RCO-3 regulates the dual-affinity glucose transport system in N. crassa. COL-26 directly binds to the promoter regions of glt-1, hgt-1, and hgt-2, whereas RCO-3 is an upstream factor of the module whose deletion mutant resembles the Δcol-26 mutant phenotypically. Transcriptional profiling analysis revealed that Δcol-26 and Δrco-3 mutants had similar transcriptional profiles, and both mutants had impaired response to a glucose gradient. We also showed that the AMP-activated protein kinase (AMPK) complex is involved in regulation of the glucose transporters. AMPK is required for repression of glt-1 expression in starvation conditions by inhibiting the activity of RCO-3.

Conclusions: RCO-3 and COL-26 form an external-to-internal module that regulates the glucose dual-affinity transport system. Transcription factor COL-26 was identified as the key regulator. AMPK was also involved in the regulation of the dual-transporter system. Our findings provide novel insight into the molecular basis of glucose uptake and signaling in filamentous fungi, which may aid in the rational design of fungal strains for industrial purposes.
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http://dx.doi.org/10.1186/s13068-021-01877-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841889PMC
January 2021

Dynamic transcriptional and epigenetic changes drive cellular plasticity in the liver.

Hepatology 2021 Jan 10. Epub 2021 Jan 10.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Background And Aims: Following liver injury, a fraction of hepatocytes adopt features of biliary epithelial cells (BECs) in a process known as biliary reprogramming. The aim of this study was to elucidate the molecular events accompanying this dramatic shift in cellular identity. Approach and Results We applied the techniques of bulk RNA-sequencing (RNA-seq), single cell RNA-sequencing (scRNA-seq), and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to define the epigenetic and transcriptional changes associated with biliary reprogramming. In addition, we examined the role of TGFβ signaling by profiling cells undergoing reprogramming in mice with hepatocyte-specific deletion in the downstream TGFβ signaling component Smad4. Biliary reprogramming followed a stereotyped pattern of altered gene expression consisting of robust induction of biliary genes and weaker repression of hepatocyte genes. These changes in gene expression were accompanied by corresponding modifications at the chromatin level. While some reprogrammed cells had molecular features of "fully differentiated" BECs, most lacked some biliary characteristics and retained some hepatocyte characteristics. Surprisingly, single cell analysis of Smad4 mutant mice revealed a dramatic increase in reprogramming.

Conclusion: Hepatocytes undergo widespread chromatin and transcriptional changes during biliary reprogramming, resulting in epigenetic and gene expression profiles that are similar to, but distinct from, native BECs. Reprogramming involves a progressive accumulation of biliary molecular features without discrete intermediates. Paradoxically, canonical TGFβ signaling through Smad4 appears to constrain biliary reprogramming, indicating that TGFβ can either promote or inhibit biliary differentiation depending on which downstream components of the pathway are engaged. This work has implications for the formation of new BECs and bile ducts in the adult liver.
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http://dx.doi.org/10.1002/hep.31704DOI Listing
January 2021

Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19CD24CD27 Breg Cells.

Front Immunol 2020 4;11:603288. Epub 2020 Dec 4.

Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

CD19CD24CD27 memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them , in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells . Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases.
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http://dx.doi.org/10.3389/fimmu.2020.603288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746849PMC
December 2020

Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer.

Cell Rep Med 2020 Nov 17;1(8):100131. Epub 2020 Nov 17.

Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.

Activating KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs), yet KRAS has remained a difficult target to inhibit pharmacologically. Here, we demonstrate, using several human and mouse models of PDACs, rapid acquisition of tumor resistance in response to targeting KRAS or MEK, associated with integrin-linked kinase (ILK)-mediated increased phosphorylation of the mTORC2 component Rictor, and AKT. Although inhibition of mTORC1/2 results in a compensatory increase in ERK phosphorylation, combinatorial treatment of PDAC cells with either KRAS (G12C) or MEK inhibitors, together with mTORC1/2 inhibitors, results in synergistic cytotoxicity and cell death reflected by inhibition of pERK and pRictor/pAKT and of downstream regulators of protein synthesis and cell survival. Relative to single agents alone, this combination leads to durable inhibition of tumor growth and metastatic progression and increased survival. We have identified an effective combinatorial treatment strategy using clinically viable inhibitors, which can be applied to PDAC tumors with different KRAS mutations.
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http://dx.doi.org/10.1016/j.xcrm.2020.100131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691443PMC
November 2020

The vascular landscape of human cancer.

J Clin Invest 2021 Jan;131(2)

Department of Medicine.

Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anticancer target. However, only a fraction of patients with cancer benefit from angiogenesis inhibitors. Whether antiangiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric - the endothelial index (EI) - to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypovascular tumors, enabling the classification of human tumors into 6 vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular "hub" genes. The EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Thus, we believe our studies provide an unbiased picture of human tumor vasculature that may enable more precise deployment of antiangiogenesis therapy.
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http://dx.doi.org/10.1172/JCI136655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810485PMC
January 2021

Epigenetic and Transcriptional Control of the Epidermal Growth Factor Receptor Regulates the Tumor Immune Microenvironment in Pancreatic Cancer.

Cancer Discov 2021 Mar 6;11(3):736-753. Epub 2020 Nov 6.

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Although immunotherapy has revolutionized cancer care, patients with pancreatic ductal adenocarcinoma (PDA) rarely respond to these treatments, a failure that is attributed to poor infiltration and activation of T cells in the tumor microenvironment (TME). We performed an CRISPR screen and identified lysine demethylase 3A (KDM3A) as a potent epigenetic regulator of immunotherapy response in PDA. Mechanistically, KDM3A acts through Krueppel-like factor 5 (KLF5) and SMAD family member 4 (SMAD4) to regulate the expression of the epidermal growth factor receptor (EGFR). Ablation of KDM3A, KLF5, SMAD4, or EGFR in tumor cells altered the immune TME and sensitized tumors to combination immunotherapy, whereas treatment of established tumors with an EGFR inhibitor, erlotinib, prompted a dose-dependent increase in intratumoral T cells. This study defines an epigenetic-transcriptional mechanism by which tumor cells modulate their immune microenvironment and highlights the potential of EGFR inhibitors as immunotherapy sensitizers in PDA. SIGNIFICANCE: PDA remains refractory to immunotherapies. Here, we performed an CRISPR screen and identified an epigenetic-transcriptional network that regulates antitumor immunity by converging on EGFR. Pharmacologic inhibition of EGFR is sufficient to rewire the immune microenvironment. These results offer a readily accessible immunotherapy-sensitizing strategy for PDA..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933070PMC
March 2021

An updated incidence trends of soft-tissue sarcoma and cancer-specific survival of patients with primary soft-tissue sarcoma of liver: a population-based study.

Expert Rev Gastroenterol Hepatol 2020 Nov 13:1-10. Epub 2020 Nov 13.

Key Laboratory on Living Donor Transplantation, Ministry of Health, Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, China.

: This study aimed to evaluate and update incidence trends of soft-tissue sarcoma (STS) and to develop a nomogram to predict cancer-specific survival (CSS) in patients diagnosed with primary STS of the liver. : Patients with hepatic STS were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Joinpoint regression analyses were performed to assess the incidence trends of STS. A nomogram was developed based on the independent risk factors chosen by Cox regression models. The calibration curve, area under the receiver operating characteristic curve (AUC), C-index, and decision curve analysis (DCA) were used to assess the predictive performance of the nomogram. : The incidence of STS increased between 1994 and 2012. There was a sudden decline in the incidence of STS from 2013. The incidence of STS was different in distinct races and genders. The nomogram for predicting the CSS of hepatic STS according to the independent factors was well calibrated and it displayed optimal discrimination power. : This study highlights that age, sex, tumor size, quality of surgery, and histologic subtypes may contribute to the prognosis of hepatic STS, and STS may be etiologically distinct and should be considered separately in different races and genders.
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http://dx.doi.org/10.1080/17474124.2021.1842193DOI Listing
November 2020

Deep anterior lamellar keratoplasty with cross-linked acellular porcine corneal stroma to manage fungal keratitis.

Xenotransplantation 2020 Oct 26:e12655. Epub 2020 Oct 26.

School of Ophthalmology and Optometry, Wenzhou Medical University, Zhejiang, China.

Purpose: To evaluate the effects of deep anterior lamellar keratoplasty (DALK) with cross-linked acellular porcine corneal stroma (APCS) and post-operative topical tacrolimus treatment in patients with fungal keratitis.

Methods: This multicenter prospective study involved 25 cases of fungal keratitis that were treated by DALK with cross-linked APCSs and post-operative topical tacrolimus from December 2013 to November 2014 at the Wenzhou Eye Hospital and the Henan provincial Eye Hospital. Signs of post-operative inflammation, corneal reepithelialization, corneal neovascularization, and graft rejection were assessed, and best corrected visual acuity (BCVA), intraocular pressure (IOP), and APCS graft transparency were monitored for the 12-month follow-up period.

Results: All 25 patients underwent DALK without Descemet's membrane perforation. Corneal epithelium recovered completely in 17 patients in the first week, and APCS grafts maintained transparency in 18 patients at 1-year follow-up. The mean BCVA significantly improved from 2.16 ± 0.32 (LogMAR) at baseline to 1.56 ± 0.70 at 1-week (P < .001), 0.95 ± 0.57 at 1-month (P < .001), and 0.70 ± 0.51 at 3-month follow-ups (P < .001). The BCVA kept stable at 6-month and 12-month follow-ups. Post-operative topical tacrolimus alleviated the ciliary injection, except in one case which acute stromal rejection occurred. One patient developed fungal reinfection and underwent penetrating keratoplasty. Graft rejection occurred in three patients. No case was noted with graft splitting, elevated IOP or tacrolimus intolerance.

Conclusions: DALK using cross-linked APCS combining topical tacrolimus treatment is safe and effective in managing fungal keratitis. It may ameliorate the shortage of corneal donation globally.
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http://dx.doi.org/10.1111/xen.12655DOI Listing
October 2020

Pb(OF)Cu(SeO)(NO): a selenite fluoride nitrate with a breathing kagomé lattice.

Chem Commun (Camb) 2020 Oct 7;56(80):11965-11968. Epub 2020 Sep 7.

State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China.

The Cu-based breathing kagomé material Pb(OF)Cu(SeO)(NO) with both corner-sharing and edge-sharing has been synthesized. Magnetic measurements suggest ferromagnetic interactions inside the layers and antiferromagnetic interactions between the neighboring layers, leading to an antiferromagnetic ground state with a field-induced spin-flip transition at low temperature.
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http://dx.doi.org/10.1039/d0cc03684fDOI Listing
October 2020

Platelet membrane-functionalized nanoparticles with improved targeting ability and lower hemorrhagic risk for thrombolysis therapy.

J Control Release 2020 Dec 25;328:78-86. Epub 2020 Aug 25.

Department of Pharmaceutics, School of Pharmacy, Key Laboratory of Smart Drug Delivery (Ministry of Education and PLA), Fudan University, Shanghai 201203, China; State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China; Institute of Integrative Medicine of Fudan University, Shanghai 200041, China; Minhang Branch, Zhongshan Hospital and Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201199, China. Electronic address:

Intravenous injection of thrombolytic drugs is the most effective strategy for the treatment of thrombotic diseases. However, the clinical application of most thrombolytic drugs is limited by hemorrhagic risks and narrow therapeutic index. The targeted drug delivery systems may help to address these problems. Inspired by the crucial role of platelets in the process of thrombus, Platelet membrane-coated PLGA cores loading lumbrokinase (PNPs/LBK) were designed for effective thrombolysis with reduced hemorrhagic risk. Using a mouse carotid thrombosis model, the affinity of platelet membrane-coated nanoparticles to the thrombus was confirmed. Also, the PNPs/LBK exhibited excellent thrombolytic efficacy at a low dose, compared with free LBK. More importantly, PNPs/LBK showed less adverse effect on the function of the coagulation system, and thus reduced hemorrhagic risk. These results indicated that a promising thrombus-targeted drug delivery system was achieved by coating PLGA nanoparticles with platelet membrane. Such rationally designed drug delivery system will provide a broad platform for thrombus treatment.
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http://dx.doi.org/10.1016/j.jconrel.2020.08.030DOI Listing
December 2020

Effects of interaction of NOS1AP gene polymorphisms and childhood abuse on paranoid personality disorder features among male violent offenders in China.

J Psychiatr Res 2020 11 4;130:180-186. Epub 2020 Aug 4.

The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China; Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, China; Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, Jiangsu, China; School of Psychology, Nanjing Normal University, Nanjing, Jiangsu, China.

Background: Paranoid Personality Disorder (PPD) results from a complex synergy between genetic and environmental factors. Childhood abuse is one of risk factors. Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) is a candidate gene of schizophrenia, which has similar pathophysiology to PPD. This study investigated the role of NOS1AP gene polymorphisms and a history of childhood abuse in predicting PPD features among male violent offenders in the Chinese Han population.

Method: Four NOS1AP Single Nucleotide Polymorphisms (SNPs), rs4145621, rs3751284, rs348624 and rs6680461 were genotyped in a sample of 423 male prisoners. Participant evaluations included demographic information, measures of childhood abuse (Child Trauma Questionnaire, CTQ), and PPD features (Personality Diagnostic Questionnaire-4, PDQ-4). Participants were divided into a PPD group and non-PPD group assessed by PDQ-4.

Results: Regression analysis revealed that emotional abuse, NOS1AP SNPs rs348624 and rs4145621 predicted PPD features (P < 0.05) among prison samples. Significant interactions between childhood abuse history and NOS1AP SNPs rs3751284 and rs6680461 were also observed. Individuals carrying the C allele of rs3751284 were susceptible to PPD features when exposed to higher levels of emotional neglect (P < 0.05); Individuals with the G allele of rs6680461 were susceptible to PPD features when exposed to higher levels of emotional, physical and sexual abuse (P < 0.01).

Conclusions: These results suggest that the interaction between childhood abuse and NOS1AP gene polymorphisms may have an influence on PPD features, at least in male violent offenders.
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http://dx.doi.org/10.1016/j.jpsychires.2020.07.026DOI Listing
November 2020

Impacts of different sources of animal manures on dissemination of human pathogenic bacteria in agricultural soils.

Environ Pollut 2020 Nov 13;266(Pt 2):115399. Epub 2020 Aug 13.

School of Water Conservancy and Environment, University of Jinan, Jinan, 250022, China. Electronic address:

The human pathogenic bacteria (HPB) in animal feces may disseminate to agricultural soils with their land application as organic fertilizer. However, the knowledge about the impacts of different sources and rates of animal manures on the temporal changes of soil HPB remains limited, which hamper our ability to estimate the potential risks of their land application. Here, we constructed an HPB database including 565 bacterial strains. By blasting the 16 S rRNA gene sequences against the database we explored the occurrence and fate of HPB in soil microcosms treated with two rates of swine, poultry or cattle manures. A total of 30 HPB were detected in all of manure and soil samples. Poultry manure at the high level obviously improved the abundance of soil HPB. The application of swine manure could introduce concomitant HPB into the soils. Of which, Pseudomonas syringae pv. syringae B728a and Escherichia coli APEC O78 may deserve more attention because of their survival for a few days in manured soils and being possible hosts of diverse antibiotic resistance genes (ARGs) as revealed by co-occurrence pattern. Bayesian source tracking analysis showed that the HPB derived from swine manure had a higher contribution to soil pathogenic communities than those from poultry or cattle manures in early days of incubation. Mantel test together with variation partitioning analysis suggested that bacterial community and soil physicochemical properties were the dominant factors determining the profile of HPB and contributed 64.7% of the total variations. Overall, our results provided experimental evidence that application of animal manures could facilitate the potential dissemination of HPB in soil environment, which should arouse sufficient attention in agriculture practice and management to avoid the threat to human health.
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http://dx.doi.org/10.1016/j.envpol.2020.115399DOI Listing
November 2020

Cell Cycle Regulation Meets Tumor Immunosuppression.

Trends Immunol 2020 10 13;41(10):859-863. Epub 2020 Aug 13.

Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Reciprocal interactions between tumor cells and immune cells shape the tumor microenvironment. Recent studies indicate that enhanced cell cycle activity in cancer cells suppresses antitumor immunity. Herein we discuss potential mechanisms by which cell cycle programs intrinsic to tumor cells are coupled to immune behavior, with consequences for immunotherapy.
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http://dx.doi.org/10.1016/j.it.2020.07.010DOI Listing
October 2020

The presence of tetracyclines and sulfonamides in swine feeds and feces: dependence on the antibiotic type and swine growth stages.

Environ Sci Pollut Res Int 2020 Dec 29;27(34):43093-43102. Epub 2020 Jul 29.

Macau Environmental Research Institute, Macau University of Science and Technology, Taipa, Macau, 999078, China.

Swine farms are one of the important sources of antibiotics in the environment. In this study, 42 samples of compound feed and feces of swine collected at different growth stages from intensive farms were evaluated for the occurrence and concentrations of three tetracyclines (TCs, namely oxytetracycline, chlortetracycline, and doxycycline) and three sulfonamides (SAs, namely sulfadiazine, sulfadimidine, and sulfamethoxazole). To check for other additional sources of antibiotic administration, ratios (R) of the measured and the predicted levels of each antibiotic excreted via feces were also estimated. Our results showed that the maximum concentration of TCs was 376,210 μg kg and 541,020 μg kg in the feeds and feces, respectively, both for oxytetracycline. In contrast, the highest concentration of SAs were 16.98 μg kg for sulfadimidine in the feeds and 14.70 μg kg for sulfadiazine in the feces. The concentrations of ΣTCs (sum of the three tetracyclines) in swine feeds and feces were found to be 1-4 orders of magnitude higher than those of ΣSAs (sum of the three sulfonamides). Approximately 36% of the R values were found to be greater than one, indicating other sources of administration such as injection and/or oral administration (via drinking water) may also contribute to the presence of antibiotics in feces. Most of the higher R values were found in starter pigs, which were generally administrated with antibiotics by multiple routes to prevent disease and promote swine growth. Our study suggests that comprehensive measures may be undertaken to control antibiotic use in intensive swine farms.
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http://dx.doi.org/10.1007/s11356-020-10266-5DOI Listing
December 2020

Identification of Natural Resistance Mediated by Recognition of Effector Gene in Potato.

Front Plant Sci 2020 19;11:919. Epub 2020 Jun 19.

State Key Laboratory of Crop Stress Biology for Arid Areas and College of Agronomy, Northwest A&F University, Yangling, China.

Late blight is considered the most renowned devastating potato disease worldwide. Resistance gene ()-based resistance to late blight is the most effective method to inhibit infection by the causal agent . However, the limited availability of resistant potato varieties and the rapid loss of resistance, caused by virulence variability, make disease control rely on fungicide application. We employed an -mediated transient gene expression assay and effector biology approach to understand late blight resistance of Chinese varieties that showed years of promising field performance. We are particularly interested in , the most common virulent allele of that triggers a -mediated hypersensitive response (HR) and late blight resistance. Through our significantly improved -mediated transient gene expression assay in potato using cultured seedlings, we characterized two dominant potato varieties, Qingshu9 and Longshu7, in China by transient expression of effector genes. Transient expression of 10 known avirulence genes showed that and could induce HR in Qingshu9, and in Longshu7, respectively. Our study also indicated that is recognized by these two potato varieties, and is likely involved in their significant field performance of late blight resistance. The identification of natural resistance mediated by recognition in Qingshu9 and Longshu7 will facilitate breeding for improved potato resistance against .
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http://dx.doi.org/10.3389/fpls.2020.00919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318898PMC
June 2020

FDA Approved Drug Library Screening Identifies Robenidine as a Repositionable Antifungal.

Front Microbiol 2020 3;11:996. Epub 2020 Jun 3.

Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Due to the increasing prevalence of pathogenic fungal infections, the emergence of antifungal resistant clinical isolates worldwide, and the limited arsenal of available antifungals, developing new antifungal strategies is imperative. In this study, we screened a library of 1068 FDA-approved drugs to identify hits that exhibit broad-spectrum antifungal activity. Robenidine, an anticoccidial agent which has been widely used to treat coccidian infections of poultry and rabbits, was identified in this screen. Physiological concentration of robenidine (8 μM) was able to significantly inhibit yeast cell growth, filamentation and biofilm formation of - the most extensively studied human fungal pathogen. Moreover, we observed a broad-spectrum antifungal activity of this compound against fluconazole resistant clinical isolates of , a wide range of other clinically relevant fungal pathogens. Intriguingly, robenidine-treated cells were hypersensitive to diverse cell wall stressors, and analysis of the cell wall structure by transmission electron microscopy (TEM) showed that the cell wall was severely damaged by robenidine, implying that this compound may target the cell wall integrity signaling pathway. Indeed, upon robenidine treatment, we found a dose dependent increase in the phosphorylation of the cell wall integrity marker Mkc1, which was decreased after prolonged exposure. Finally, we provide evidence by RNA-seq and qPCR that Rlm1, the downstream transcription factor of Mkc1, may represent a potential target of robenidine. Therefore, our data suggest that robenidine, a FDA approved anti-coccidiosis drug, displays a promising and broadly effective antifungal strategy, and represents a potentially repositionable candidate for the treatment of fungal infections.
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http://dx.doi.org/10.3389/fmicb.2020.00996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283467PMC
June 2020

How Tumor Cell Dedifferentiation Drives Immune Evasion and Resistance to Immunotherapy.

Cancer Res 2020 10 18;80(19):4037-4041. Epub 2020 Jun 18.

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. While tumor antigens are needed for effective immunotherapy, a favorable tumor immune microenvironment is also critical. In this review, we discuss emerging evidence that tumor cells exploit cellular plasticity and dedifferentiation programs to avoid immune surveillance, which in turn drives metastatic dissemination and resistance to immunotherapy. A deeper understanding of these programs may provide novel opportunities to enhance the efficacy of existing immunotherapies.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541560PMC
October 2020

Alterations in the Ocular Surface Microbiome in Traumatic Corneal Ulcer Patients.

Invest Ophthalmol Vis Sci 2020 06;61(6):35

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Purpose: Corneal ulcers are a common eye inflammatory disease that can cause visual impairment or even blindness if not treated promptly. Ocular trauma is a major risk factor for corneal ulcers, and corneal trauma in agricultural work can rapidly progress to corneal ulcers. This study aims to evaluate the changes in the ocular surface (OS) microbiome of patients with traumatic corneal ulcer (TCU).

Methods: Among 20 healthy control (HC) subjects and 22 patients with TCU, 42 eyes were examined to investigate the OS microbial flora using metagenomic shotgun sequencing.

Results: At the taxonomic composition level, our findings showed that dysbiosis (alterations in richness and community structure) occurs in the OS microbiome of patients with TCU. Notably, Pseudomonas was present at a greater than 30% relative abundance in all individuals in the TCU group. At the species level, the abundance of Pseudomonas fluorescens and Pseudomonas aeruginosa was significantly elevated in the TCU group compared to the HC group. At the functional level, we identified significant differences in the HC and TCU groups. We observed that inflammation-related pathways involved in bacterial chemotaxis, flagellar assembly, and biofilm formation were significantly more abundant in the TCU group. Besides, the pathways related to biosynthesis, degradation, and metabolism were also increased significantly in the TCU group.

Conclusions: These findings indicate an altered OS microbiome in the affected eyes of patients with TCU. Further research is needed to determine whether these alterations contribute to the pathogenesis of TCU or impact disease progression.
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http://dx.doi.org/10.1167/iovs.61.6.35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415308PMC
June 2020

Ultrafast physical bacterial inactivation and photocatalytic self-cleaning of ZnO nanoarrays for rapid and sustainable bactericidal applications.

Sci Total Environ 2020 Oct 2;738:139714. Epub 2020 Jun 2.

School of Materials Science and Engineering, Key Laboratory of Advanced Technologies of Materials (Ministry of Education), Southwest Jiaotong University, Chengdu 610031, China. Electronic address:

Various nanostructured surfaces have been developed recently to physically inactivate bacteria, for reducing the rapidly spreading threat of pathogenic bacteria. However, it generally takes several hours for these surfaces to inactivate most of the bacteria, which greatly limits their application in the fields favoring rapid bactericidal performance. Besides, the accumulated bacteria debris left on these surfaces is rarely discussed in the previous reports. Herein we report the nanotip-engineered ZnO nanoarrays (NAs) with ultrafast physical bactericidal rate and the ability to photocatalytically remove the bacteria debris. Neither chemical (Zn or reactive oxygen species) nor photocatalytic effect leads to the ultrafast bactericidal rate, where 97.5% of E. coli and 94.9% of S. aureus are inactivated within only 1 min. The simulation analysis further supported our proposed mechanism attributing the ultrafast bactericidal activity to the great stress enabled by the uneven topography. Moreover, the re-exposure of the ZnO NAs nanotips can be achieved in only 10 min under a mild UV light source. This study not only presents an ultrafast physical bactericidal activity, but also demonstrates the potential of the recyclable and photocatalytic self-cleaning functions of theses surfaces for applications that desire rapid and sustainable bactericidal performance.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266591PMC
October 2020

Co(SeO)(SO)(OH): A Selenite-Sulfate Compound with a Distorted Kagomé Lattice.

Inorg Chem 2020 Jun 27;59(12):8054-8060. Epub 2020 May 27.

State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, P. R. China.

A new selenite-sulfate compound Co(SeO)(SO)(OH) was prepared using a typical hydrothermal reaction. This compound is found to crystallize in an orthorhombic space group of , featuring a 2D distorted kagomé structure composed of linear and zigzag Co-chains, in which the magnetic ions construct different isosceles-triangles. Our results of magnetic and specific heat measurements confirm a canted antiferromagnetic order at ∼ 29 K. Further, the successive field-induced metamagnetic transitions can be observed at ∼ 1 T, ∼ 23 T, and ∼ 27 T, respectively. A clear magnetic hysteresis loop with a coercive field () of ∼1.4 T is also observed.
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http://dx.doi.org/10.1021/acs.inorgchem.0c00316DOI Listing
June 2020

The Efficacy of Intense Pulsed Light Combined With Meibomian Gland Expression for the Treatment of Dry Eye Disease Due to Meibomian Gland Dysfunction: A Multicenter, Randomized Controlled Trial.

Eye Contact Lens 2021 Jan;47(1):45-53

Department of Ophthalmology (X.Y., B.R., W.S., Y.C.), Peking University First Hospital, Beijing, China; Department of Ophthalmology (J.H., Y.F.), Peking University Third Hospital. Beijing, China; Eye Center (X.J., X.H., L.L.), Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China; and The School of Ophthalmology and Optometry and Eye Hospital (W.C., J.L.), Wenzhou Medical University, Wenzhou, China.

Objectives: To compare the efficacy of intense pulsed light (IPL) combined with Meibomian gland expression (MGX), and instant warm compresses combined with MGX, for treatment of dry eye disease (DED) due to meibomian gland dysfunction (MGD).

Methods: In a prospective, multicenter, interventional study, 120 subjects with DED due to MGD were randomized 1:1 to an IPL arm or a control arm. Each subject was treated 3 times at 3-week intervals. The primary outcome measure was the tear break up time (TBUT). Tear break up time and a few additional outcome measures were evaluated at the baseline and at 3 weeks after the last treatment.

Results: All outcome measures improved in both arms, but in general, the improvement was significantly larger in the IPL arm. Tear break up time increased by 2.3±1.9 and 0.5±1.4 sec, in the IPL and control arms respectively (P<0.001). SPEED was reduced by 38% and 22% in the IPL and control arms, respectively (P<0.01). Meibomian Gland Yielding Secretion Score was improved by 197% in the IPL arm and 96% in the control arm. Corneal fluorescein staining also decreased by 51% and 24% in the IPL and control arms respectively, but the differences between the two arms were not statistically significant (P=0.61). A composite score of lid margin abnormalities improved in both arms, but more in the IPL arm (P<0.05).

Conclusions: Intense pulsed light combined with MGX therapy was significantly more effective than instant warm compresses followed with MGX. This suggests that the IPL component has a genuine contribution to the improvement of signs and symptoms of DED.
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http://dx.doi.org/10.1097/ICL.0000000000000711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752242PMC
January 2021

Pharmacologic Activation of the G Protein-Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma.

Cell Mol Gastroenterol Hepatol 2020 4;10(4):868-880.e1. Epub 2020 May 4.

Perelman School of Medicine, Department of Dermatology, University of Pennsylvania, Philadelphia. Electronic address:

Background & Aims: Female sex is associated with lower incidence and improved clinical outcomes for most cancer types including pancreatic ductal adenocarcinoma (PDAC). The mechanistic basis for this sex difference is unknown. We hypothesized that estrogen signaling may be responsible, despite the fact that PDAC lacks classic nuclear estrogen receptors.

Methods: Here we used murine syngeneic tumor models and human xenografts to determine that signaling through the nonclassic estrogen receptor G protein-coupled estrogen receptor (GPER) on tumor cells inhibits PDAC.

Results: Activation of GPER with the specific, small molecule, synthetic agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically administered G-1 was well-tolerated in PDAC bearing mice, induced tumor regression, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors, independent of tumor stage.

Conclusions: These data, coupled with the wide tissue distribution of GPER and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against a range of cancers that are not classically considered sex hormone responsive and that arise in tissues outside of the reproductive system.
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http://dx.doi.org/10.1016/j.jcmgh.2020.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578406PMC
May 2020

ɑβ-targeted liposomal drug delivery system with attenuated immunogenicity enabled by linear pentapeptide for glioma therapy.

J Control Release 2020 06 8;322:542-554. Epub 2020 Apr 8.

Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China; Zhongshan Hospital and Institute of Fudan-Minghang Academic Health System, Minghang Hospital, Fudan University, Shanghai 201199, China; The Institutes of Integrative Medicine of Fudan University, Shanghai 200041, China. Electronic address:

Owing to the binding capacity to ɑβ integrin overexpressed on glioma, vasculogenic mimicry and neovasculature, the peptide c(RGDyK) has been exploited pervasively to functionalize nanocarriers for targeted delivery of bioactives. The former study in our group substantiated the immunotoxicity of c(RGDyK)-modified liposome, and this unfavorable immunogenicity is known to compromise blood circulation, targeting efficacy and therapeutic outcome. Therefore, we need to find a superior alternative ligand in order to evade the exquisite immuno-sensitization. We developed mn by structure-guided peptide design and retro-inverso isomerization technique, which was experimentally substantiated to have exceptional binding affinity to ɑβ integrin. Besides mn does not have affinity toward normal liver cells and kidney cells, which c(RGDyK) possesses in a certain degree. Warranting that mn and c(RGDyK) anchored ɑβ, we formulated peptide-tethered liposomes and investigated in vivo bio-fate. Compared with c(RGDyK)-modified liposome, mn-modified liposome presented longer blood circulation and reduced ingestion by Kupffer cells with decreased retention in liver accordingly, benefitting from attenuated anti-liposome IgG and IgM response elicited by multiple sequential doses. Those merits strengthened the anti-glioma efficacy of ɑβ-targeted doxorubicin-loaded liposomes, proving the importance of immunocompatibility in process of targeted drug delivery.
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http://dx.doi.org/10.1016/j.jconrel.2020.04.009DOI Listing
June 2020

Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer.

Cell 2020 04 31;181(2):424-441.e21. Epub 2020 Mar 31.

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address:

KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8 T cells into otherwise immunologically "cold" tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.
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http://dx.doi.org/10.1016/j.cell.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278897PMC
April 2020

All-stage precisional glioma targeted therapy enabled by a well-designed D-peptide.

Theranostics 2020 4;10(9):4073-4087. Epub 2020 Mar 4.

Department of Pharmaceutics, School of Pharmacy, Fudan University, and Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, & State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.

Uncontrollable cell proliferation and irreversible neurological damage make glioma one of the most deadly diseases in clinic. Besides the multiple biological barriers, glioma stem cells (GSCs) that are responsible for the maintenance and recurrence of tumor tissues also hinder the therapeutic efficacy of chemotherapy. Therefore, all-stage precisional glioma targeted therapy regimens that could efficiently deliver drugs to glioma cells and GSCs after overcoming multiple barriers have received increasing scrutiny. : A polymeric micelle-based drug delivery system was developed by modifying a "Y-shaped" well-designed ligand of both GRP78 protein and quorum sensing receptor to achieve all-stage precisional glioma targeting, then we evaluated the targeting ability and barrier penetration ability both and . In order to achieve all-stage precisional therapy, we need kill both GSCs and glioma related cells. Parthenolide (PTL) has been investigated for its selective toxicity to glioma stem cells while Paclitaxel (PTX) and Temozolomide (TMZ) are widely used in experimental and clinical therapy of glioma respectively. So the anti-glioma effect of combination therapy was evaluated by Kaplan-Meier survival analysis and immunohistochemical (IHC) examination of tumor tissues. : The "Y-shaped" well-designed peptide, termed WVAP, exhibited excellent glioma (and GSCs) homing and barrier penetration ability. When modified on micelle surface, WVAP peptide significantly enhanced accumulation of micelles in brain and glioma. In addition, WVAP micelles showed no immunogenicity and cytotoxicity, which could guarantee their safety when used . Treatment of glioma-bearing mice with PTL loaded WVAP modified PEG-PLA micelles plus PTX loaded WVAP modified PEG-PLA micelles or PTL loaded WVAP modified PEG-PLA micelles plus TMZ showed improved anti-tumor efficacy in comparison to PTL and PTX loaded unmodified micelles or PTL loaded unmodified micelles plus TMZ. : Combination of all-stage targeting strategy and concomitant use of chemotherapeutics and stem cell inhibitors could achieve precise targeted therapy for glioma.
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http://dx.doi.org/10.7150/thno.41382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086363PMC
March 2020

Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression.

Cancer Discov 2020 Jun 18;10(6):854-871. Epub 2020 Mar 18.

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Epithelial plasticity, reversible modulation of a cell's epithelial and mesenchymal features, is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. Although different master transcription factors and epigenetic modifiers have been implicated in this process in various contexts, the extent to which a unifying, generalized mechanism of transcriptional regulation underlies epithelial plasticity remains largely unknown. Here, through targeted CRISPR/Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-to-mesenchymal identity, tumor differentiation, and metastasis. Using a lysine-to-methionine histone mutant to directly inhibit H3K36me2, we found that global modulation of the mark is a conserved mechanism underlying the mesenchymal state in various contexts. Mechanistically, regulation of H3K36me2 reprograms enhancers associated with master regulators of epithelial-to-mesenchymal state. Our results thus outline a unifying epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity and metastasis in cancer. SIGNIFICANCE: Although epithelial plasticity contributes to cancer metastasis and chemoresistance, no strategies exist for pharmacologically inhibiting the process. Here, we show that global regulation of a specific histone mark, H3K36me2, is a universal epigenome-wide mechanism that underlies epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition in carcinoma cells. These results offer a new strategy for targeting epithelial plasticity in cancer..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269857PMC
June 2020