Publications by authors named "Meili Zhang"

71 Publications

Is preterm donor milk better than preterm formula for very-low-birth-weight infants?

Food Nutr Res 2021 24;65. Epub 2021 Sep 24.

Neonatal Intensive Care Unit, Quanzhou Women and Children's Hospital, Quanzhou, Fujian, China.

Background: Preterm human milk has advantages over preterm formula (PF), but it may compromise some functions after pasteurization.

Objective: To explore the effects of preterm donor milk (DM) on growth, feeding tolerance, and severe morbidity in very-low-birth-weight infants.

Method: This was a single-center, prospective cohort study that included 304 preterm infants weighing <1,500 g or of gestational age <32 weeks. If the mother's own milk was insufficient, the parents decided to use PF ( = 155) or DM ( = 149). The two groups were uniformly managed according to the standard NICU protocol. Growth parameters, feeding tolerance, and severe morbidity such as necrotizing enterocolitis, were compared between the two groups.

Results: The daily weight gain and weekly head growth in the DM group were not different from those in the PF group ( > 0.05). Feeding intolerance in the DM group was significantly lower than that in PF group ( < 0.05), and parenteral nutrition time and hospitalization time were also shorter than that in the PF group ( < 0.05). Moreover, the incidence of necrotizing enterocolitis and sepsis was also significantly lower in the DM group ( < 0.05).

Conclusion: The study indicated that preterm DM does not affect the growth of very-low-birth-weight infants. Further, it significantly reduces feeding intolerance, helps achieve full enteral feeding early, and has protective effects against necrotizing enterocolitis and sepsis. Thus, compared with formula, preterm DM can lower the rate of infection in preterm infants and is worthy of promotion.
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http://dx.doi.org/10.29219/fnr.v65.5346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494261PMC
September 2021

Adenosine A2A Receptor Activation Enhances Blood-Tumor Barrier Permeability in a Rodent Glioma Model.

Mol Cancer Res 2021 Sep 14. Epub 2021 Sep 14.

Neuro-Oncology Branch, NCI, NIH, Bethesda, Maryland.

The blood-tumor barrier (BTB) limits the entry of effective chemotherapeutic agents into the brain for treatment of malignant tumors like glioblastoma. Poor drug entry across the BTB allows infiltrative glioma stem cells to evade therapy and develop treatment resistance. Regadenoson, an FDA-approved adenosine A2A receptor (A2AR) agonist, has been shown to increase drug delivery across the blood-brain barrier in non-tumor-bearing rodents without a defined mechanism of enhancing BTB permeability. Here, we characterize the time-dependent impact of regadenoson on brain endothelial cell interactions and paracellular transport, using mouse and rat brain endothelial cells and tumor models. , A2AR activation leads to disorganization of cytoskeletal actin filaments by 30 minutes, downregulation of junctional protein expression by 4 hours, and reestablishment of endothelial cell integrity by 8 hours. In rats bearing intracranial gliomas, regadenoson treatment results in increase of intratumoral temozolomide concentrations, yet no increased survival noted with combined temozolomide therapy. These findings demonstrate regadenoson's ability to induce brain endothelial structural changes among glioma to increase BTB permeability. The use of vasoactive mediators, like regadenoson, which transiently influences paracellular transport, should further be explored to evaluate their potential to enhance central nervous system treatment delivery to aggressive brain tumors. IMPLICATIONS: This study provides insight on the use of a vasoactive agent to increase exposure of the BTB to chemotherapy with intention to improve glioma treatment efficacy.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0995DOI Listing
September 2021

How to design regional characteristics to improve green economic efficiency: a fuzzy-set qualitative comparative analysis approach.

Environ Sci Pollut Res Int 2021 Aug 26. Epub 2021 Aug 26.

School of Economics and Management, Harbin Engineering University, Nantong Street, Nangang District, Harbin, 150001, Heilongjiang Province, China.

Developing green economy has become the focus of governments, scholars, and entrepreneurs all over the world; however, the realization path of green economic efficiency for the regions under the interaction of multiple factors has still been uncertain. This study takes 30 provincial-level regions in China as the empirical object and applies a new method of fuzzy-set qualitative comparative analysis to explore the configuration of conditions for achieving green economic efficiency, which effectively improves the link between theory and practice. This study reveals that the improvement of green economy efficiency is the result of the joint action of multiple factors, and one factor in isolation is not enough for explaining it. Besides, there exist three equivalent paths to achieve high green economic efficiency; therefore, regions can design the most appropriate promotion strategy according to the determined paths. The result shows that high marketization is the core condition for achieving high green economy efficiency. Among the three paths, the combination of environmental regulation, urbanization, marketization, and technological innovation has the highest unique coverage, which alone explains how most regions have achieved high green economic efficiency. Third, four paths for achieving low green economy efficiency have been identified in this study, which provides lessons for regional governments to avoid the decline in green economy efficiency. And specially, the combination of high urbanization, high environment regulation, and high technological innovation can lead to low green economy efficiency because of low marketization. The conclusion improves the theory of green development and provides a practical reference for the regional government to develop green economy.
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http://dx.doi.org/10.1007/s11356-021-15963-3DOI Listing
August 2021

Anti-thrombogenic Surface Coatings for Extracorporeal Membrane Oxygenation: A Narrative Review.

ACS Biomater Sci Eng 2021 09 26;7(9):4402-4419. Epub 2021 Aug 26.

Innovative Cardiovascular Engineering and Technology Laboratory, Critical Care Research Group, The Prince Charles Hospital, Brisbane, Queensland 4032, Australia.

Extracorporeal membrane oxygenation (ECMO) is used in critical care to manage patients with severe respiratory and cardiac failure. ECMO brings blood from a critically ill patient into contact with a non-endothelialized circuit which can cause clotting and bleeding simultaneously in this population. Continuous systemic anticoagulation is needed during ECMO. The membrane oxygenator, which is a critical component of the extracorporeal circuit, is prone to significant thrombus formation due to its large surface area and areas of low, turbulent, and stagnant flow. Various surface coatings, including but not limited to heparin, albumin, poly(ethylene glycol), phosphorylcholine, and poly(2-methoxyethyl acrylate), have been developed to reduce thrombus formation during ECMO. The present work provides an up-to-date overview of anti-thrombogenic surface coatings for ECMO, including both commercial coatings and those under development. The focus is placed on the coatings being developed for oxygenators. Overall, zwitterionic polymer coatings, nitric oxide (NO)-releasing coatings, and lubricant-infused coatings have attracted more attention than other coatings and showed some improvement in and anti-thrombogenic effects. However, most studies lacked standard hemocompatibility assessment and comparison studies with current clinically used coatings, either heparin coatings or nonheparin coatings. Moreover, this review identifies that further investigation on the thrombo-resistance, stability and durability of coatings under rated flow conditions and the effects of coatings on the function of oxygenators (pressure drop and gas transfer) are needed. Therefore, extensive further development is required before these new coatings can be used in the clinic.
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http://dx.doi.org/10.1021/acsbiomaterials.1c00758DOI Listing
September 2021

Reversing Epigenetic Gene Silencing to Overcome Immune Evasion in CNS Malignancies.

Front Oncol 2021 15;11:719091. Epub 2021 Jul 15.

Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, United States.

Glioblastoma (GBM) is an aggressive brain malignancy with a dismal prognosis. With emerging evidence to disprove brain-immune privilege, there has been much interest in examining immunotherapy strategies to treat central nervous system (CNS) cancers. Unfortunately, the limited success of clinical studies investigating immunotherapy regimens, has led to questions about the suitability of immunotherapy for these cancers. Inadequate inherent populations of tumor infiltrating lymphocytes (TILs) and limited trafficking of systemic, circulating T cells into the CNS likely contribute to the poor response to immunotherapy. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier (BBB) permeable small molecule inhibitor of EZH2, to reverse GBM immune evasion by epigenetic suppression of T cell chemotaxis. We also evaluated the efficacy of this drug in combination with anti-PD-1 treatment on tumor growth, survival and T cell infiltration in syngeneic mouse models. GSK126 reversed H3K27me in murine and human GBM cell lines. When combined with anti-PD-1 treatment, a significant increase in activated T cell infiltration into the tumor was observed. This resulted in decreased tumor growth and enhanced survival both in sub-cutaneous and intracranial tumors of immunocompetent, syngeneic murine models of GBM. Additionally, a significant increase in CXCR3 T cells was also seen in the draining lymph nodes, suggesting their readiness to migrate to the tumor. Closer examination of the mechanism of action of GSK126 revealed its ability to promote the expression of IFN-γ driven chemokines CXCL9 and CXCL10 from the tumor cells, that work to traffic T cells without directly affecting T maturation and/or proliferation. The loss of survival benefit either with single agent or combination in immunocompromised SCID mice, suggest that the therapeutic efficacy of GSK126 in GBM is primarily driven by lymphocytes. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor.
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http://dx.doi.org/10.3389/fonc.2021.719091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320893PMC
July 2021

Surface Coatings for Rotary Ventricular Assist Devices: A Systematic Review.

ASAIO J 2021 Jul 27. Epub 2021 Jul 27.

From the Innovative Cardiovascular Engineering and Technology Laboratory, Critical Care Research Group, The Prince Charles Hospital, Brisbane, Queensland, Australia School of Mechanical and Mining Engineering, University of Queensland, Brisbane, Queensland, Australia School of Engineering and Built Environment, Griffith University, Brisbane, Queensland, Australia School of Medicine, University of Queensland, Brisbane, Queensland, Australia School of Medicine, Griffith University, Brisbane, Queensland, Australia.

Rotary ventricular assist devices (VADs) are frequently used to provide mechanical circulatory support to patients suffering from end-stage heart failure. Therefore, these devices and especially their pump impeller and housing components have stringent requirements on wear resistance and hemocompatibility. Various surface coatings have been investigated to improve the wear resistance or hemocompatibility of these devices. The aim of the present systematic review was to build a comprehensive understanding of these coatings and provide potential future research directions. A Boolean search for peer-reviewed studies was conducted in online databases (Web of Science, Scopus, PubMed, and ScienceDirect), and a preferred reporting items for systematic reviews and meta-analyses (PRISMA) process was followed for selecting relevant papers for analysis. A total of 45 of 527 publications were included for analysis. Eighteen coatings were reported to improve wear resistance or hemocompatibility of rotary VADs with the most common coatings being diamond-like carbon (DLC), 2-methacryloyloxyethyl phosphorylcholine (MPC), and heparin. Ninety-three percent of studies focused on hemocompatibility, whereas only 4% of studies focused on wear properties. Thirteen percent of studies investigated durability. This review provides readers with a systematic catalogue and critical review of surface coatings for rotary VADs. The review has identified that more comprehensive studies especially investigations on wear properties and durability are needed in future work.
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http://dx.doi.org/10.1097/MAT.0000000000001534DOI Listing
July 2021

Clinical effect of combined western medicine and traditional Chinese medicine on children with Henoch-Schönlein purpura nephritis.

Am J Transl Res 2021 15;13(4):3323-3329. Epub 2021 Apr 15.

Department of Function, Jiaozhou People's Hospital Jiaozhou 266300, Shandong Province, China.

Objective: To investigate the efficacy of combined Chinese and western medicine in the treatment of children with Henoch-Schönlein purpura nephritis (HSPN) and its effects on immune function, interleukin (IL)-16, and IL-18 expressione.

Methods: The clinical data of 91 children with HSPN were retrospectively collected and divided into two groups according to the treatment regimen. Group A (n=45) was treated only with western medicine, while group B (n=46) was treated with combined Chinese and western medicine. The clinical efficacy, traditional Chinese medicine (TCM) syndrome points before and after treatment, immune function indices, urinary indices, levels of IL-16 and IL-18, and the recurrence rate were compared between the two groups.

Results: The total effective rate was 95.65% in group B, higher than 75.56% in group A (<0.05). The TCM scores after treatment in group B was lower than that in group A (<0.05). The levels of immunoglobulin IgA and IgM after treatment were lower while IgG levels were higher in group B than those in group A (<0.05); Urinary microalbumin, urinary beta microglobulin, 24 h urine protein elimination, and red blood cells (RBC) in the urine were lower in group B after treatment than in group A (<0.05). The serum levels of IL-16 and IL-18 in group B were lower than those in group A after treatment (<0.05). The recurrence rate was 4.35% in group B, lower than 26.67% in group A (<0.05).

Conclusion: Combined regimen of western and Chinese medicine in children showed significant efficacy on improving immune function and reducing recurrence rate and IL-16 and IL-18 levels in patients with HSPN.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129211PMC
April 2021

Extracorporeal Membrane Oxygenation-Induced Hemolysis: An In Vitro Study to Appraise Causative Factors.

Membranes (Basel) 2021 04 25;11(5). Epub 2021 Apr 25.

Critical Care Research Group, The Prince Charles Hospital, Brisbane 4032, Australia.

In vitro hemolysis testing is commonly used to determine hemocompatibility of ExtraCorporeal Membrane Oxygenation (ECMO). However, poor reproducibility remains a challenging problem, due to several unidentified influencing factors. The present study investigated potential factors, such as flow rates, the use of anticoagulants, and gender of blood donors, which could play a role in hemolysis. Fresh human whole blood was anticoagulated with either citrate (n = 6) or heparin (n = 12; 6 female and 6 male blood donors). Blood was then circulated for 360 min at 4 L/min or 1.5 L/min. Regardless of flow rate conditions, hemolysis remained unchanged over time in citrated blood, but significantly increased after 240 min circulation in heparinized blood ( ≤ 0.01). The ratio of the normalized index of hemolysis () of heparinized blood to citrated blood was 11.7-fold higher at 4 L/min and 16.5-fold higher at 1.5 L/min. The difference in hemolysis between 1.5 L/min and 4 L/min concurred with findings of previous literature. In addition, the ratio of of male heparinized blood to female was 1.7-fold higher at 4 L/min and 2.2-fold higher at 1.5 L/min. Our preliminary results suggested that the choice of anticoagulant and blood donor gender could be critical factors in hemolysis studies, and should be taken into account to improve testing reliability during ECMO.
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http://dx.doi.org/10.3390/membranes11050313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145168PMC
April 2021

Long noncoding RNA affects the proliferative and invasive ability of colorectal cancer cells.

J Cancer 2021 1;12(2):428-437. Epub 2021 Jan 1.

Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.

Emerging evidence indicates that long noncoding RNAs (lncRNAs) are closely associated with colorectal cancer (CRC) tumorigenesis. One example is lncRNA Deleted in Lymphocytic Leukemia 2 (). However, how contributes to CRC is still poorly understood. This study sought to investigate the effects of on CRC pathogenesis, and the underlying mechanism involved. Using a quantitative real-time polymerase chain reaction (qRT-PCR) assay, we demonstrated that the expression levels of in 45 pairs of CRC tissues were higher than those in the corresponding normal colon mucosal tissues. In addition, CRC patients with high expression levels exhibited poor overall survival (OS) and recurrence-free survival (RFS), as determined by analyses and measurements from the GEO and GEPIA databases. When was silenced using short interfering RNA (siRNA) in CRC cell line, the results demonstrated that silencing suppressed CRC cell tumorigenesis which was associated with decreased expression of cyclin dependent kinase 6(CDK6), ZEB1, and ZEB2 as well as enhancing the expression of Cyclin-dependent kinase inhibitor 1A (CDKN1A). Taken together, the results of this study suggested that may play critical roles in the progression of CRC and may serve as a prognostic biomarker for CRC.
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http://dx.doi.org/10.7150/jca.48423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738996PMC
January 2021

hnRNPLL controls pluripotency exit of embryonic stem cells by modulating alternative splicing of Tbx3 and Bptf.

EMBO J 2021 02 22;40(4):e104729. Epub 2020 Dec 22.

State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.

The regulatory circuitry underlying embryonic stem (ES) cell self-renewal is well defined, but how this circuitry is disintegrated to enable lineage specification is unclear. RNA-binding proteins (RBPs) have essential roles in RNA-mediated gene regulation, and preliminary data suggest that they might regulate ES cell fate. By combining bioinformatic analyses with functional screening, we identified seven RBPs played important roles for the exit from pluripotency of ES cells. We characterized hnRNPLL, which mainly functions as a global regulator of alternative splicing in ES cells. Specifically, hnRNPLL promotes multiple ES cell-preferred exon skipping events during the onset of ES cell differentiation. hnRNPLL depletion thus leads to sustained expression of ES cell-preferred isoforms, resulting in a differentiation deficiency that causes developmental defects and growth impairment in hnRNPLL-KO mice. In particular, hnRNPLL-mediated alternative splicing of two transcription factors, Bptf and Tbx3, is important for pluripotency exit. These data uncover the critical role of RBPs in pluripotency exit and suggest the application of targeting RBPs in controlling ES cell fate.
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http://dx.doi.org/10.15252/embj.2020104729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883296PMC
February 2021

Modeling cancer progression using human pluripotent stem cell-derived cells and organoids.

Stem Cell Res 2020 12 27;49:102063. Epub 2020 Oct 27.

Department of Surgery, Weill Cornell Medicine, 1300 York Ave, New York, NY 10065, USA. Electronic address:

Conventional cancer cell lines and animal models have been mainstays of cancer research. More recently, human pluripotent stem cells (hPSCs) and hPSC-derived organoid technologies, together with genome engineering approaches, have provided a complementary platform to model cancer progression. Here, we review the application of these technologies in cancer modeling with respect to the cell-of-origin, cancer propagation, and metastasis. We further discuss the benefits and challenges accompanying the use of hPSC models for cancer research and discuss their broad applicability in drug discovery, biomarker identification, decoding molecular mechanisms, and the deconstruction of clonal and intra-tumoral heterogeneity. In summary, hPSC-derived organoids provide powerful models to recapitulate the pathogenic states in cancer and to perform drug discovery.
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http://dx.doi.org/10.1016/j.scr.2020.102063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849931PMC
December 2020

Enhanced efficacy of JAK1 inhibitor with mTORC1/C2 targeting in smoldering/chronic adult T cell leukemia.

Transl Oncol 2021 Jan 22;14(1):100913. Epub 2020 Oct 22.

Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1374, Bethesda, MD 20892, USA. Electronic address:

Adult T-cell leukemia (ATL) is an aggressive T-cell lymphoproliferative malignancy of regulatory T lymphocytes (Tregs), caused by human T-cell lymphotropic virus 1 (HTLV-1). Interleukin 2 receptor alpha (IL-2Rα) is expressed in the leukemic cells of smoldering/chronic ATL patients, leading to constitutive activation of the JAK/STAT pathway and spontaneous proliferation. The PI3K/AKT/mTOR pathway also plays a critical role in ATL cell survival and proliferation. We previously performed a high-throughput screen that demonstrated additive/synergistic activity of Ruxolitinib, a JAK1/2 inhibitor, with AZD8055, an mTORC1/C2 inhibitor. However, effects of unintended JAK2 inhibition with Ruxolitinib limits it therapeutic potential for ATL patients, which lead us to evaluate a JAK1-specific inhibitor. Here, we demonstrated that Upadacitinib, a JAK-1 inhibitor, inhibited the proliferation of cytokine-dependent ATL cell lines and the expression of p-STAT5. Combinations of Upadacitinib with either AZD8055 or Sapanisertib, mTORC1/C2 inhibitors, showed anti-proliferative effects against cytokine-dependent ATL cell lines and synergistic effect with reducing tumor growth in NSG mice bearing IL-2 transgenic tumors. Importantly, the combination of these two agents inhibited ex vivo spontaneous proliferation of ATL cells from patients with smoldering/chronic ATL. Combined targeting of JAK/STAT and PI3K/AKT/mTOR pathways represents a promising therapeutic intervention for patients with smoldering/chronic ATL.
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http://dx.doi.org/10.1016/j.tranon.2020.100913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585144PMC
January 2021

Metabolic plasticity of IDH1 glioma cell lines is responsible for low sensitivity to glutaminase inhibition.

Cancer Metab 2020 21;8:23. Epub 2020 Oct 21.

Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, 37 Convent Drive, Building 37, Room 1136A, Bethesda, Maryland USA.

Background: Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1 ) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG).

Methods: We have employed a combination of C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1 glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity.

Results: We report the adaptability of IDH1 cells' metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1 cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition.

Conclusions: Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1 gliomas.
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http://dx.doi.org/10.1186/s40170-020-00229-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579920PMC
October 2020

Structural characterization of calcium-binding sunflower seed and peanut peptides and enhanced calcium transport by calcium complexes in Caco-2 cells.

J Sci Food Agric 2021 Jan 29;101(2):794-804. Epub 2020 Sep 29.

Department of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot, China.

Background: Peptide-Ca complexes can promote Ca absorption. The present study aimed to determine the transport mechanism and structural characteristics of sunflower seed and peanut peptides with high Ca binding capacity with respect to developing third-generation Ca supplements and functional food ingredients.

Results: High Ca-binding fractions of 1-3 kDa sunflower seed peptide (SSP ) and ≥ 10 kDa peanut peptide (PP ) had higher amount of Ca transported than CaCl and two hydrolyzed proteins in Caco-2 cells. SSP and PP were separated by Ca ion metal chelate affinity chromatography, and high Ca-binding fractions were observed for SSP -P and PP -P . The amino acid sequences of SSP -P and PP -P were characterized by high-performance liquid chromatography-electrospray ionization-time of flight mass spectrometry. Seven and eight peptides were identified from SSP -P and PP -P , respectively. These peptides had molecular weights ranging from 1500 Da to 2500 Da and a large number of characteristic amino acid sequences, such as EEEQQQ, EQ-QQQ-QQ, QQ-QQQQQ, E-EEE, EE-EEQ, RR, Q-QQ-QQQ, EE-EQ-EE-Q, QQ-QQQQ, and Q-QQQQ, where 'E' is glutamic acid and 'Q' is glutamine.

Conclusion: SSP and PP can promote Ca transport in Caco-2 cells without affecting cell permeability. The amino acid sequences of SSP -P and PP -P with high Ca-binding abilities contain characteristic sequences, such as continuous glutamic acid and glutamine, and have low molecular weights. © 2020 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.10800DOI Listing
January 2021

MerTK inhibition decreases immune suppressive glioblastoma-associated macrophages and neoangiogenesis in glioblastoma microenvironment.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa065. Epub 2020 Jun 3.

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

Background: Glioblastoma-associated macrophages and microglia (GAMs) are the predominant immune cells in the tumor microenvironment. Activation of MerTK, a receptor tyrosine kinase, polarizes GAMs to an immunosuppressive phenotype, promoting tumor growth. Here, the role of MerTK inhibition in the glioblastoma microenvironment is investigated in vitro and in vivo.

Methods: Effects of MRX-2843 in glioblastoma microenvironment regulation were determined in vitro by cell viability, cytokine array, in vitro tube formation, Western blotting, and wound healing assays. A syngeneic GL261 orthotopic glioblastoma mouse model was used to evaluate the survival benefit of MRX-2843 treatment. Multiplex fluorescent immunohistochemistry was used to evaluate the expression of CD206, an anti-inflammatory marker on GAMs, and angiogenesis in murine brain tumor tissues.

Results: MRX-2843 inhibited cell growth and induced apoptosis in human glioblastoma cells and decreased protein expression of phosphorylated MerTK, AKT, and ERK, which are essential for cell survival signaling. Interleukin-8 and C-C motif chemokine ligand 2, the pro-glioma and pro-angiogenic cytokines, were decreased by MRX-2843. Decreased vascular formation and numbers of immunosuppressive (CD206+) GAMs were observed following MRX-2843 treatment in vivo, suggesting that in addition to alleviating immunosuppression, MRX-2843 also inhibits neoangiogenesis in the glioma microenvironment. These results were supported by a prolonged survival in the syngeneic mouse orthotopic GL261 glioblastoma model following MRX-2843 treatment.

Conclusion: Our findings suggest that MRX-2843 has a therapeutic benefit via promoting GAM polarization away from immunosuppressive condition, inhibiting neoangiogenesis in the glioblastoma microenvironment and inducing tumor cell death.
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http://dx.doi.org/10.1093/noajnl/vdaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324055PMC
June 2020

Metabolic Landscape of a Genetically Engineered Mouse Model of IDH1 Mutant Glioma.

Cancers (Basel) 2020 Jun 19;12(6). Epub 2020 Jun 19.

Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institute of Health, Bethesda, MD 20814, USA.

Understanding the metabolic reprogramming of aggressive brain tumors has potential applications for therapeutics as well as imaging biomarkers. However, little is known about the nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate from α-ketoglutarate. In order to gain insight into the metabolism of these malignant brain tumors, we conducted metabolic profiling of the orthotopic tumor and the contralateral regions for the mouse model of IDH1 mutant glioma; as well as to examine the utilization of glucose and glutamine in supplying major metabolic pathways such as glycolysis and tricarboxylic acid (TCA). We also revealed that the main substrate of 2-hydroxyglutarate is glutamine in this model, and how this re-routing impairs its utilization in the TCA. Our C tracing analysis, along with hyperpolarized magnetic resonance experiments, revealed an active glycolytic pathway similar in both regions (tumor and contralateral) of the brain. Therefore, we describe the reprogramming of the central carbon metabolism associated with the IDH1 mutation in a genetically engineered mouse model which reflects the tumor biology encountered in glioma patients.
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http://dx.doi.org/10.3390/cancers12061633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352932PMC
June 2020

Determination and comparison of agarwood from different origins by comprehensive two-dimensional gas chromatography-quadrupole time-of-flight mass spectrometry.

J Sep Sci 2020 Apr 21;43(7):1284-1296. Epub 2020 Jan 21.

Department of Applied Chemistry, Zhengzhou University of Light Industry, Zhengzhou, P. R. China.

Agarwood, a species of resinous heartwood, is a precious medicinal plant and a type of rare natural spice, which is widely used in medicine, cosmetics, religious activities, and other fields. In this study, agarwood samples from eight different regions across four countries were analyzed by comprehensive two-dimensional gas chromatography-quadrupole time-of-flight mass spectrometry. A total of 232 species were identified (the match factors of these compounds were above 750). The main compounds of agarwood are oxygenated sesquiterpenes and chromones. The compositions of India1 and Malaysia2 were significantly different from those of other samples, which might be attributed to the different production processes of agarwood. For further investigation, factor analysis was conducted for six agarwood samples. The results showed that the data classification possessed a regional characteristic; according to the retention time and relative content, characteristic compositions were determined by factor scores. Finally, the differences of characteristic compositions were simply analyzed, and the reasons were speculated.
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http://dx.doi.org/10.1002/jssc.201901008DOI Listing
April 2020

In vitro dentine tubule occlusion by a novel toothpaste containing calcium silicate and sodium phosphate.

J Dent 2020 6;103S:100024. Epub 2020 Aug 6.

Unilever Oral Care, Quarry Road East, Bebington, Wirral CH63 3JW, United Kingdom. Electronic address:

Objectives: To investigate the deposition, formation of hydroxyapatite (HAP) and acid resistance of dentine surfaces following brushing with a toothpaste containing calcium silicate and sodium phosphate (CSSP) and fluoride in vitro.

Methods: Human dentine specimens were brushed with a slurry of CSSP toothpaste followed by exposure to simulated oral fluid (SOF) in two in vitro studies, with a silica-based non-occluding toothpaste as control. The surface and tubule deposits were analysed after 14 cycles with scanning electron microscopy (SEM), energy dispersive x-ray spectroscopy (EDX), transmission electron microscopy (TEM) and selected area electron diffraction (SAED). In a third study, dentine specimens were additionally exposed to citric acid erosive challenges for 30, 300 or 600 s after 2, 6, 10 and 14 cycles of SOF and either the CSSP toothpaste or a positive control toothpaste containing calcium sodium phosphosilicate and fluoride. The level of tubule occlusion was evaluated using SEM.

Results: The SEM analyses indicated complete coverage of the dentine surface following 14 cycles of brushing with CSSP toothpaste with no observable patent tubules, in contrast to the non-occluding control toothpaste. The TEM and SAED analyses confirmed the deposited material on the surface and within tubules was HAP. The deposited material from CSSP toothpaste was more acid resistant than the deposited material from the positive control toothpaste at all time points and acid exposure levels (p < 0.05).

Conclusions: The CSSP toothpaste fully occluded dentine tubules and formed the mineral HAP. The dentine deposition on and within dentine tubules was resilient to acid erosive challenges.

Clinical Significance: A novel toothpaste containing CSSP can form HAP on dentine surfaces and within tubules. The potential of this technology is for a novel approach for the protection of dentine surfaces to acid challenges and the reduction of dentine hypersensitivity.
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http://dx.doi.org/10.1016/j.jjodo.2020.100024DOI Listing
June 2021

Genotoxins exaggerate the stressed state of aneuploid embryonic stem cells via activation of autophagy.

Sci China Life Sci 2020 Jul 20;63(7):1026-1036. Epub 2019 Dec 20.

State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.

The cellular consequences of aneuploidy are largely dependent on the cell types examined. Aneuploid yeasts and mouse embryonic fibroblasts exhibit cell proliferation defects and can be selectively inhibited by compounds that cause proteotoxic or energy stress. By contrast, most aneuploid pluripotent stem cells proliferate rapidly and reach higher saturation densities. The responses of aneuploid pluripotent stem cells to the stress-inducing compounds remain uncharacterized. Here, we tested the response of aneuploid embryonic stem cells to several compounds that caused proteotoxic, energy and genotoxic stress using previously established mouse embryonic stem cell lines trisomic for chromosome 6, 8, 11, or 15. Not all trisomic embryonic stem cells were selectively inhibited by compounds that cause proteotoxic or energy stress. However, most of these cells exhibited increased sensitivity to genotoxins. They displayed elevated DNA damage response as characterized by increased γH2A.X foci under genotoxic stress. Further investigations indicated that elevated autophagy levels might contribute to the increased cytotoxic effects of genotoxins on trisomic embryonic stem cells. Our study laid the foundation for eliminating aneuploidy that might be an effective approach for controlling cancer progression.
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http://dx.doi.org/10.1007/s11427-019-9666-yDOI Listing
July 2020

Up-regulation of promotes the tumourigenesis in colorectal cancer.

J Cancer 2019 19;10(25):6405-6413. Epub 2019 Oct 19.

Department of Hematology, Xiangya hospital, Central South University, Changsha, Hunan 410008, China.

Recent studies have reported that long non-coding RNAs (lncRNAs) are associated with the tumourigenesis of colorectal cancer (CRC); however, several of these are yet to be identified and characterised. In this study, we report a novel lncRNA, , which was significantly up-regulated in CRC; we investigated its function and mechanism in CRC. Our study demonstrated that LINC00467 levels in 45 pairs of CRC tissues were higher than those in the corresponding normal colon mucosal tissues. We used the Gene Expression Omnibus (GEO) and Gene Expression Profiling Interactive Analysis (GEPIA) databases for the analysis and measurement of clinical samples, and observed that the CRC patients with high expression levels showed poor overall survival (OS) and recurrent-free survival (RFS) rates. Furthermore, following the short interfering RNA (siRNA) knockdown of in the CRC cell line, the results demonstrated that suppresses the proliferation, invasion and metastasis of CRC cells . Moreover, its molecular mechanism of decreased the expression of Cyclin D1, Cyclin A1, CDK2, CDK4 and Twist1 as well as enhanced the expression of E‑cadherin. Collectively, these findings suggest that may be crucial in the progression and development of CRC, and may serve as a potential therapeutic target for CRC patients.
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http://dx.doi.org/10.7150/jca.32216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856745PMC
October 2019

IL-2 receptors preassemble and signal in the ER/Golgi causing resistance to antiproliferative anti-IL-2Rα therapies.

Proc Natl Acad Sci U S A 2019 10 30;116(42):21120-21130. Epub 2019 Sep 30.

Department of Biophysics and Cell Biology, Doctoral School of Molecular Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary;

Interleukin-2 (IL-2) and IL-15 play pivotal roles in T cell activation, apoptosis, and survival, and are implicated in leukemias and autoimmune diseases. Their heterotrimeric receptors share their β- and γ-chains, but have distinct α-chains. Anti-IL-2Rα (daclizumab) therapy targeting cell surface-expressed receptor subunits to inhibit T cell proliferation has only brought limited success in adult T cell leukemia/lymphoma (ATL) and in multiple sclerosis. We asked whether IL-2R subunits could already preassemble and signal efficiently in the endoplasmic reticulum (ER) and the Golgi. A combination of daclizumab and anti-IL-2 efficiently blocked IL-2-induced proliferation of IL-2-dependent wild-type (WT) ATL cells but not cells transfected with IL-2, suggesting that in IL-2-producing cells signaling may already take place before receptors reach the cell surface. In the Golgi fraction isolated from IL-2-producing ATL cells, we detected by Western blot phosphorylated Jak1, Jak3, and a phosphotyrosine signal attributed to the γ-chain, which occurred at much lower levels in the Golgi of WT ATL cells. We expressed EGFP- and mCherry-tagged receptor chains in HeLa cells to study their assembly along the secretory pathway. Confocal microscopy, Förster resonance energy transfer, and imaging fluorescence cross-correlation spectroscopy analysis revealed partial colocalization and molecular association of IL-2 (and IL-15) receptor chains in the ER/Golgi, which became more complete in the plasma membrane, further confirming our hypothesis. Our results define a paradigm of intracellular autocrine signaling and may explain resistance to antagonistic antibody therapies targeting receptors at the cell surface.
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http://dx.doi.org/10.1073/pnas.1901382116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800387PMC
October 2019

miR-18a reactivates the Epstein-Barr virus through defective DNA damage response and promotes genomic instability in EBV-associated lymphomas.

BMC Cancer 2018 Dec 29;18(1):1293. Epub 2018 Dec 29.

Key Laboratory of Carcinogenesis of Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410078, Hunan, China.

Background: The Epstein-Barr virus (EBV) is closely associated with several types of malignancies. EBV is normally present in the latent state in the peripheral blood B cell compartment. The EBV latent-to-lytic switch is required for virus spread and virus-induced carinogenesis. Immunosuppression or DNA damage can induce the reactivation of EBV replication. EBV alone is rarely sufficient to cause cancer. In this study, we investigated the roles of host microRNAs and environmental factors, such as DNA-damage agents, in EBV reactivation and its association with lymphomagenesis.

Methods: We first analyzed the publicly available microRNA array data containing 45 diffuse large B-cell lymphoma patients and 10 control lymph nodes or B cells with or without EBV infection. In situ hybridization for miR-18a and immunohistochemitry were performed to evaluate the correlation between the expression of miR-18a and nuclear EBV protein EBNA1 in lymphoid neoplasm. The proliferative effects of miR-18a were investigated in EBV-positive or -negative lymphoid neoplasm cell lines. EBV viral load was measured by a quantitative real-time EBV PCR and FISH assay. The genomic instability was evaluated by CGH-array.

Results: In this study, we analyzed the publicly available microRNA array data and observed that the expression of the miR-17-92 cluster was associated with EBV status. In situ hybridization for miR-18a, which is a member of the miR-17-92 cluster, showed a significant upregulation in lymphoma samples. miR-18a, which shares the homolog sequence with EBV-encoded BART-5, promoted the proliferation of lymphoma cells in an EBV status-dependent manner. The DNA-damaging agent UV or hypoxia stress induced EBV activation, and miR-18a contributed to DNA damaging-induced EBV reactivation. In contrast to the promoting effect of ATM on the lytic EBV reactivation in normoxia, ATM inhibited lytic EBV gene expression and decreased the EBV viral load in the prescence of hypoxia-induced DNA damage. miR-18a reactivated EBV through inhibiting the ATM-mediated DNA damage response (DDR) and caused genomic instability.

Conclusions: Taken together, these results indicate that DNA-damaging agents and host microRNAs play roles in EBV reactivation. Our study supported the interplay between host cell DDR, environmental genotoxic stress and EBV.
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http://dx.doi.org/10.1186/s12885-018-5205-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311029PMC
December 2018

IL-15 enhanced antibody-dependent cellular cytotoxicity mediated by NK cells and macrophages.

Proc Natl Acad Sci U S A 2018 11 29;115(46):E10915-E10924. Epub 2018 Oct 29.

Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

The goal of cancer immunotherapy is to stimulate the host immune system to attack malignant cells. Antibody-dependent cellular cytotoxicity (ADCC) is a pivotal mechanism of antitumor action of clinically employed antitumor antibodies. IL-15 administered to patients with metastatic malignancy by continuous i.v. infusion at 2 μg/kg/d for 10 days was associated with a 38-fold increase in the number and activation status of circulating natural killer (NK) cells and activation of macrophages which together are ADCC effectors. We investigated combination therapy of IL-15 with rituximab in a syngeneic mouse model of lymphoma transfected with human CD20 and with alemtuzumab (Campath-1H) in a xenograft model of human adult T cell leukemia (ATL). IL-15 greatly enhanced the therapeutic efficacy of both rituximab and alemtuzumab in tumor models. The additivity/synergy was shown to be associated with augmented ADCC. Both NK cells and macrophages were critical elements in the chain of interacting effectors involved in optimal therapeutic responses mediated by rituximab with IL-15. We provide evidence supporting the hypothesis that NK cells interact with macrophages to augment the NK-cell activation and expression of FcγRIV and the capacity of these cells to become effectors of ADCC. The present study supports clinical trials of IL-15 combined with tumor-directed monoclonal antibodies.
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http://dx.doi.org/10.1073/pnas.1811615115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243244PMC
November 2018

IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability.

Leukemia 2019 05 23;33(5):1243-1255. Epub 2018 Oct 23.

University of Virginia Cancer Center and Department of Medicine, Division of Hematology & Oncology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.

Interleukin-15 (IL-15) and IL-2 drive T-cell malignancies including T-cell large granular lymphocyte leukemia (T-LGLL) and HTLV-1 driven adult T-cell leukemia (ATL). Both cytokines share common γ-chain receptors and downstream signaling pathways. T-LGLL is characterized by clonal expansion of cytotoxic T cells and is associated with abnormal JAK/STAT signaling. ATL is an aggressive CD4+ T-cell neoplasm associated with HTLV-1. T-LGLL and ATL share dependence on IL-2 and IL-15 for survival and both diseases lack effective therapies. BNZ-1 is a pegylated peptide designed to specifically bind the γc receptor to selectively block IL-2, IL-15, and IL-9 signaling. We hypothesized that treatment with BNZ-1 would reduce cytokine-mediated proliferation and viability. Our results demonstrated that in vitro treatment of a T-LGLL cell line and ex vivo treatment of T-LGLL patient cells with BNZ-1 inhibited cytokine-mediated viability. Furthermore, BNZ-1 blocked downstream signaling and increased apoptosis. These results were mirrored in an ATL cell line and in ex vivo ATL patient cells. Lastly, BNZ-1 drastically reduced leukemic burden in an IL-15-driven human ATL mouse xenograft model. Thus, BNZ-1 shows great promise as a novel therapy for T-LGLL, ATL, and other IL-2 or IL-15 driven hematopoietic malignancies.
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http://dx.doi.org/10.1038/s41375-018-0290-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478569PMC
May 2019

Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma.

Cancer Cell 2018 08 26;34(2):286-297.e10. Epub 2018 Jul 26.

Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

Adult T cell leukemia/lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). RNAi screening of ATLL lines revealed that their proliferation depends on BATF3 and IRF4, which cooperatively drive ATLL-specific gene expression. HBZ, the only HTLV-I encoded transcription factor that is expressed in all ATLL cases, binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including MYC. Inhibitors of bromodomain-and-extra-terminal-domain (BET) chromatin proteins collapsed the transcriptional network directed by HBZ and BATF3, and were consequently toxic for ATLL cell lines, patient samples, and xenografts. Our study demonstrates that the HTLV-I oncogenic retrovirus exploits a regulatory module that can be attacked therapeutically with BET inhibitors.
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http://dx.doi.org/10.1016/j.ccell.2018.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078141PMC
August 2018

Iron Oxide Nanoparticles Synergize with Erlotinib to Suppress Refractory Non-Small Cell Lung Cancer Cell Proliferation Through the Inhibition of ErbB/PI3K/AKT and PTEN Activation.

J Biomed Nanotechnol 2017 Apr;13(4):458-68

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib and gefitinib, are currently approved for the management of NSCLC. However, primary and acquired resistances to EGFR-TKIs are the major obstacles in the treatment of NSCLC. These resistances have been associated with the development of secondary mutations in EGFR or continued oncogenic signaling despite TKI treatment. In this study, NSCLC cells with wild-type EGFR, A549, H460, H358, H157 which do not respond to EGFR-TKIs, were used. We investigated whether a combination therapy of erlotinib plus iron oxide nanoparticles (IONPs) could sensitize NSCLC cells to erlotinib-induced cancer inhibition. In the 4 NSCLC cells investigated, erlotinib and IONPs combination therapy obviously inhibited NSCLC proliferation in vitro and in vivo, compared with erlotinib treatment alone. This effect was not dependent on erlotinib dose. Activation of ErbB3 was observed in these refractory NSCLC cells. Combined with IONPs, erlotinib could block ErbB3 activity and induce the expression of PTEN, which in turn inhibited the downstream PI3KAKT signaling pathway. These data demonstrate the therapeutic potential of biocompatible IONPs in combination with EGFR-TKIs in NSCLC, thus expanding and repurposing the current therapy for NSCLC.
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http://dx.doi.org/10.1166/jbn.2017.2358DOI Listing
April 2017

Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma.

Proc Natl Acad Sci U S A 2018 01 2;115(3):E498-E505. Epub 2018 Jan 2.

Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792;

STAT3 is constitutively activated in many cancers and regulates gene expression to promote cancer cell survival, proliferation, invasion, and migration. In diffuse large B cell lymphoma (DLBCL), activation of STAT3 and its kinase JAK1 is caused by autocrine production of IL-6 and IL-10 in the activated B cell-like subtype (ABC). However, the gene regulatory mechanisms underlying the pathogenesis of this aggressive lymphoma by STAT3 are not well characterized. Here we performed genome-wide analysis and identified 2,251 STAT3 direct target genes, which involve B cell activation, survival, proliferation, differentiation, and migration. Whole-transcriptome profiling revealed that STAT3 acts as both a transcriptional activator and a suppressor, with a comparable number of up- and down-regulated genes. STAT3 regulates multiple oncogenic signaling pathways, including NF-κB, a cell-cycle checkpoint, PI3K/AKT/mTORC1, and STAT3 itself. In addition, STAT3 negatively regulates the lethal type I IFN signaling pathway by inhibiting expression of , , , and Inhibition of STAT3 activity by ruxolitinib synergizes with the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL cells in vitro and in a xenograft mouse model. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate ruxolitinib or a specific JAK1 inhibitor combined with lenalidomide in ABC DLBCL.
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http://dx.doi.org/10.1073/pnas.1715118115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776985PMC
January 2018

Arrayed mutant haploid embryonic stem cell libraries facilitate phenotype-driven genetic screens.

Nucleic Acids Res 2017 Dec;45(22):e180

State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.

Forward genetic screens using mammalian embryonic stem (ES) cells have identified genes required for numerous cellular processes. However, loss-of-function screens are more difficult to conduct in diploid cells because, in most cases, both alleles of a gene must be mutated to exhibit a phenotype. Recently, mammalian haploid ES cell lines were successfully established and applied to several recessive genetic screens. However, all these screens were performed in mixed pools of mutant cells and were mainly based on positive selection. In general, negative screening is not easy to apply to these mixed pools, although quantitative deep sequencing of mutagen insertions can help to identify some 'missing' mutants. Moreover, the interplay between different mutant cells in the mixed pools would interfere with the readout of the screens. Here, we developed a method for rapidly generating arrayed haploid mutant libraries in which the proportion of homozygous mutant clones can reach 85%. After screening thousands of individual mutant clones, we identified a number of novel factors required for the onset of differentiation in ES cells. A negative screen was also conducted to discover mutations conferring cells with increased sensitivity to DNA double-strand breaks induced by the drug doxorubicin. Both of these screens illustrate the value of this system.
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http://dx.doi.org/10.1093/nar/gkx857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727442PMC
December 2017

Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies.

Am J Hematol 2017 Sep 5;92(9):892-901. Epub 2017 Jun 5.

Veterans Affairs Medical Center, Washington D.C., 20422, USA.

With the emerging success of treating CD19 expressing B cell malignancies with ex vivo modified, autologous T cells that express CD19-directed chimeric antigen receptors (CAR), there is intense interest in expanding this evolving technology to develop effective modalities to treat other malignancies including solid tumors. Exploiting this approach to develop a therapeutic modality for T cell malignancies for which the available regimens are neither curative, nor confer long term survival we generated a lentivirus-based CAR gene transfer system to target the chemokine receptor CCR4 that is over-expressed in a spectrum of T cell malignancies as well as in CD4 CD25 Foxp3 T regulatory cells that accumulate in the tumor microenvironment constituting a barrier against anti-tumor immunity. Ex vivo modified, donor-derived T cells that expressed CCR4 directed CAR displayed antigen-dependent potent cytotoxicity against patient-derived cell lines representing ATL, CTCL, ALCL and a subset of HDL. Furthermore, these CAR T cells also eradicated leukemia in a mouse xenograft model of ATL illustrating the potential utility of this modality in the treatment of a wide spectrum of T cell malignancies.
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http://dx.doi.org/10.1002/ajh.24794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546946PMC
September 2017
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