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  1. Article ; Online: TREM1 activation of myeloid cells promotes antitumor immunity.

    Juric, Vladislava / Mayes, Erin / Binnewies, Mikhail / Lee, Tian / Canaday, Pamela / Pollack, Joshua L / Rudolph, Joshua / Du, Xiaoyan / Liu, Victoria M / Dash, Subhadra / Palmer, Rachael / Jahchan, Nadine S / Ramoth, Åsa Johanna / Lacayo, Sergio / Mankikar, Shilpa / Norng, Manith / Brassell, Chris / Pal, Aritra / Chan, Christopher /
    Lu, Erick / Sriram, Venkataraman / Streuli, Michel / Krummel, Matthew F / Baker, Kevin P / Liang, Linda

    Science translational medicine

    2023  Volume 15, Issue 711, Page(s) eadd9990

    Abstract: Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor ...

    Abstract Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses. TREM1 is expressed on neutrophils, subsets of monocytes and tissue macrophages, and suppressive myeloid populations in the TME, including tumor-associated neutrophils, monocytes, and tumor-associated macrophages. Depletion or inhibition of immunosuppressive myeloid cells, or stimulation by TREM1-mediated inflammatory signaling, could be used to promote an immunostimulatory TME. We developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody with enhanced FcγR binding. PY159 is a TREM1 agonist that induces signaling, leading to up-regulation of costimulatory molecules on monocytes and macrophages, production of proinflammatory cytokines and chemokines, and enhancement of T cell activation in vitro. An antibody against mouse TREM1, PY159m, promoted antitumor efficacy in syngeneic mouse tumor models. These results suggest that PY159-mediated agonism of TREM1 on tumoral myeloid cells can promote a proinflammatory TME and offer a promising strategy for immunotherapy.
    MeSH term(s) Animals ; Mice ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Disease Models, Animal ; Immunosuppressive Agents ; Macrophages ; Monocytes ; Myeloid Cells ; Triggering Receptor Expressed on Myeloid Cells-1
    Chemical Substances Antibodies, Monoclonal ; Immunosuppressive Agents ; Triggering Receptor Expressed on Myeloid Cells-1 ; TREM1 protein, mouse
    Language English
    Publishing date 2023-08-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.add9990
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  2. Article ; Online: Targeting TREM2 on tumor-associated macrophages enhances immunotherapy.

    Binnewies, Mikhail / Pollack, Joshua L / Rudolph, Joshua / Dash, Subhadra / Abushawish, Marwan / Lee, Tian / Jahchan, Nadine S / Canaday, Pamela / Lu, Erick / Norng, Manith / Mankikar, Shilpa / Liu, Victoria M / Du, Xiaoyan / Chen, Amanda / Mehta, Ranna / Palmer, Rachael / Juric, Vladislava / Liang, Linda / Baker, Kevin P /
    Reyno, Leonard / Krummel, Matthew F / Streuli, Michel / Sriram, Venkataraman

    Cell reports

    2021  Volume 37, Issue 3, Page(s) 109844

    Abstract: Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify ... ...

    Abstract Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2
    MeSH term(s) Animals ; Antineoplastic Agents, Immunological/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cell Line, Tumor ; Coculture Techniques ; Drug Resistance, Neoplasm ; Female ; HEK293 Cells ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Lymphocyte Activation/drug effects ; Lymphocytes, Tumor-Infiltrating/drug effects ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Membrane Glycoproteins/antagonists & inhibitors ; Membrane Glycoproteins/metabolism ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/immunology ; Programmed Cell Death 1 Receptor/metabolism ; Receptors, Immunologic/antagonists & inhibitors ; Receptors, Immunologic/metabolism ; Signal Transduction ; Tumor Cells, Cultured ; Tumor Microenvironment ; Tumor-Associated Macrophages/drug effects ; Tumor-Associated Macrophages/immunology ; Tumor-Associated Macrophages/metabolism ; Mice
    Chemical Substances Antineoplastic Agents, Immunological ; Immune Checkpoint Inhibitors ; Membrane Glycoproteins ; PDCD1 protein, human ; Pdcd1 protein, mouse ; Programmed Cell Death 1 Receptor ; Receptors, Immunologic ; TREM2 protein, human ; Trem2 protein, mouse
    Language English
    Publishing date 2021-10-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2021.109844
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: TRPV6 mediates capsaicin-induced apoptosis in gastric cancer cells--Mechanisms behind a possible new "hot" cancer treatment.

    Chow, Justine / Norng, Manith / Zhang, Jing / Chai, Jianyuan

    Biochimica et biophysica acta

    2007  Volume 1773, Issue 4, Page(s) 565–576

    Abstract: Unlabelled: Capsaicin is an organic compound in chili peppers which are consumed by over one quarter of the world's population daily. Studies have shown that capsaicin can induce apoptosis in some cancer cells by unknown mechanisms. In this study, both ... ...

    Abstract Unlabelled: Capsaicin is an organic compound in chili peppers which are consumed by over one quarter of the world's population daily. Studies have shown that capsaicin can induce apoptosis in some cancer cells by unknown mechanisms. In this study, both gastric cancer and normal epithelial cells were treated with capsaicin and examined for apoptosis by Annexin V binding. Our results showed that capsaicin induces apoptosis in both cells, although cancer cells are more susceptible. This susceptibility is dependent on the availability of TRPV6, a calcium-selective channel protein, as overexpression of TRPV6 in normal cells increased capsaicin-induced apoptosis and knockdown of TRPV6 in cancer cells suppressed this action. Our results further demonstrated that capsaicin increases mitochondrial permeability through activation of Bax and p53 in a JNK-dependent manner.
    Conclusions: (1) TRPV6, rather than TRPV1 (the well-known capsaicin receptor), mediates capsaicin-induced apoptosis in gastric cells; (2) abundance of TRPV6 in gastric cells determines their live or death under capsaicin treatment; and (3) capsaicin induces apoptosis by stabilization of p53 through JNK activation. Together, our data suggest that capsaicin may be a promising dietary candidate for cancer chemoprevention.
    MeSH term(s) Apoptosis/drug effects ; Calcium Channels/metabolism ; Capsaicin/pharmacology ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Epithelial Cells/cytology ; Epithelial Cells/drug effects ; Gene Expression/drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mitochondrial Membranes/drug effects ; Stomach Neoplasms/pathology ; Stomach Neoplasms/therapy ; TRPV Cation Channels/metabolism ; Thermodynamics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Calcium Channels ; TRPV Cation Channels ; TRPV6 protein, human ; Tumor Suppressor Protein p53 ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Capsaicin (S07O44R1ZM)
    Language English
    Publishing date 2007-04
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbamcr.2007.01.001
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  4. Article ; Online: The anti-apoptosis protein, survivin, mediates gastric epithelial cell cytoprotection against ethanol-induced injury via activation of the p34(cdc2) cyclin-dependent kinase.

    Jones, Michael K / Padilla, Oscar R / Webb, Nicole A / Norng, Manith

    Journal of cellular physiology

    2008  Volume 215, Issue 3, Page(s) 750–764

    Abstract: The anti-apoptosis protein, survivin, promotes cell survival and mitosis. Recent studies have demonstrated that survivin is expressed in normal gastric mucosa. Using an in vitro model, we examined whether survivin plays a role in the cytoprotection ... ...

    Abstract The anti-apoptosis protein, survivin, promotes cell survival and mitosis. Recent studies have demonstrated that survivin is expressed in normal gastric mucosa. Using an in vitro model, we examined whether survivin plays a role in the cytoprotection produced in gastric mucosa by mild irritant ethanol (ETOH) against subsequent exposure to concentrated ETOH. Pre-treatment of rat gastric epithelial cells with 1% ETOH reduced cell death, in response to subsequent incubation with 5% ETOH, by 94% (P < 0.005). This pre-treatment also resulted in increased total and phosphorylated survivin protein levels by 180% (P < 0.0001) and 540% (P < 0.0002), respectively, which required the p34(cdc2) cell cycle-dependent kinase. The cytoprotective effect was abrogated upon siRNA knockdown of survivin protein levels. Further, overexpression of exogenous survivin resulted in significant cytoprotection by 62% (P < 0.02) in the absence of any pre-treatment. We further examined the in vivo relevance of these findings. In fasted rats, administration of 20% ETOH, which we found to be 93% (P < 0.0001) cytoprotective against 50% ETOH challenge, resulted in increased total and phosphorylated survivin protein levels by 234% (P < 0.001) and 214% (P < 0.02), respectively. Administration of 20% ETOH resulted in increased gastric p34(cdc2) activity by 146% (P < 0.01). Inhibition of p34(cdc2) by the potent inhibitor, roscovitine, abolished the increased survivin levels in response to pre-administration of 20% ETOH and reduced the cytoprotection against 50% ETOH challenge by 59% (P < 0.01). These results indicate that survivin is a key mediator of cytoprotection against ETOH-induced gastric injury, acting at the epithelial cell level, by a mechanism that is dependent, in part, on p34(cdc2).
    MeSH term(s) Animals ; Apoptosis/drug effects ; CDC2 Protein Kinase/antagonists & inhibitors ; CDC2 Protein Kinase/metabolism ; Cytoprotection/physiology ; Enzyme Activation/drug effects ; Epithelial Cells/cytology ; Epithelial Cells/drug effects ; Epithelial Cells/enzymology ; Epithelial Cells/pathology ; Ethanol/administration & dosage ; Ethanol/toxicity ; Gastric Mucosa/drug effects ; Gastric Mucosa/enzymology ; Gastric Mucosa/pathology ; Male ; Microtubule-Associated Proteins/metabolism ; Phosphoproteins/metabolism ; Protein Biosynthesis/drug effects ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Stomach/cytology ; Stomach/pathology ; Threonine
    Chemical Substances Birc5 protein, rat ; Microtubule-Associated Proteins ; Phosphoproteins ; RNA, Messenger ; Threonine (2ZD004190S) ; Ethanol (3K9958V90M) ; CDC2 Protein Kinase (EC 2.7.11.22)
    Language English
    Publishing date 2008-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3116-1
    ISSN 1097-4652 ; 0021-9541
    ISSN (online) 1097-4652
    ISSN 0021-9541
    DOI 10.1002/jcp.21358
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  5. Article: Cys254 and Cys49/Cys87of simian virus 40 Vp1 are essential in formation of infectious virions.

    Gharakhanian, Editte / Mana, Wafa / Norng, Manith

    Virus research

    2005  Volume 107, Issue 1, Page(s) 21–25

    Abstract: The SV40 capsid is composed of pentameric capsomeres of Vp1. We have previously shown that disulfide linkages at Vp1 Cys9, Cys104, and Cys207 are essential in formation of infectious virions. Here, the role of the remaining four cysteines was explored. ... ...

    Abstract The SV40 capsid is composed of pentameric capsomeres of Vp1. We have previously shown that disulfide linkages at Vp1 Cys9, Cys104, and Cys207 are essential in formation of infectious virions. Here, the role of the remaining four cysteines was explored. Single, double, and quadruple cys --> ser mutant genomes at Vp1 Cys49, Cys87, Cys254, and Cys267 codons were generated and transfected into CV-1 cells. The quadruple mutant Vp1 continued to localize to the nucleus and to bind DNA, but resulted in no plaques. SV40Vp1.Cys254 was the only single mutant with complete defect in plaque formation. The double mutant at Vp1.Cys49.Cys87 showed complete defect in plaque formation, while single mutants at the two residues resulted in plaques, suggesting a cumulative effect. All mutants defective in plaque formation continued to localize viral proteins in the nucleus. Taken together, our results suggest that Cys254 and the Cys49/Cys87 combination are essential in late stages of infectious virion formation.
    MeSH term(s) Animals ; Antigens, Polyomavirus Transforming/genetics ; Antigens, Polyomavirus Transforming/metabolism ; Capsid Proteins/chemistry ; Capsid Proteins/genetics ; Capsid Proteins/physiology ; Cell Line ; Cell Nucleus/virology ; Cercopithecus aethiops ; Cysteine/chemistry ; Mutagenesis, Site-Directed ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Simian virus 40/genetics ; Simian virus 40/physiology ; Transfection ; Viral Plaque Assay ; Virion/genetics ; Virion/physiology ; Virus Assembly/genetics ; Virus Assembly/physiology
    Chemical Substances Antigens, Polyomavirus Transforming ; Capsid Proteins ; Recombinant Fusion Proteins ; VP1 protein, polyomavirus ; Cysteine (K848JZ4886)
    Language English
    Publishing date 2005-01
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 605780-9
    ISSN 1872-7492 ; 0168-1702
    ISSN (online) 1872-7492
    ISSN 0168-1702
    DOI 10.1016/j.virusres.2004.06.006
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  6. Article: A critical role of serum response factor in myofibroblast differentiation during experimental oesophageal ulcer healing in rats.

    Chai, Jianyuan / Norng, Manith / Tarnawski, Andrzej S / Chow, Justine

    Gut

    2007  Volume 56, Issue 5, Page(s) 621–630

    Abstract: Background: Myofibroblast differentiation is a key event during wound healing and is triggered primarily by transforming growth factor beta (TGFbeta). Serum response factor (SRF) is a TGFbeta-inducible transcription factor that is important for wound ... ...

    Abstract Background: Myofibroblast differentiation is a key event during wound healing and is triggered primarily by transforming growth factor beta (TGFbeta). Serum response factor (SRF) is a TGFbeta-inducible transcription factor that is important for wound healing. Injection of SRF expression plasmid into rat gastric ulcers significantly accelerated restoration of epithelium and smooth muscle structures.
    Aim: To determine the role of SRF in oesophageal ulcer healing, especially in myofibroblast differentiation.
    Subjects: Rats (in vivo), oesophageal epithelial cells (Het1A) and fibroblasts (Rat1-R12) (in vitro) were used.
    Methods: Oesophageal ulcers were induced in rats with acetic acid and subsequently treated by local injection of plasmids expressing either SRF or SRF antisense sequence. Rats were killed at 1, 3, 6, 9 and 14 days after treatment and tissues collected. For in vitro studies, both Het1A and Rat1-R12 cells were transfected with the plasmids used in ulcer treatment.
    Results: Upregulation of SRF increased the myofibroblast population in ulcer granulation tissue; knockdown of SRF suppressed this event. In addition, ulceration induced SRF and TGFbeta expression coordinately. In vitro studies showed that overexpression of SRF in either oesophageal epithelial cells or fibroblasts was sufficient to induce myofibroblast phenotype. Furthermore, the TGFbeta-induced myofibroblast phenotype required integrin-linked kinase (ILK)-mediated SRF activation, as either knockdown of SRF or inactivation of ILK prevented this action.
    Conclusions: SRF is indispensable for myofibroblast differentiation during oesophageal ulcer healing and is required for TGFbeta-induced myofibroblast transition from either epithelial cells or fibroblasts. ILK is a mediator in TGFbeta-induced SRF activation and subsequent myofibroblast differentiation. ILK is associated with SRF, and TGFbeta enhances this association.
    MeSH term(s) Acetic Acid ; Animals ; Cell Differentiation ; Cells, Cultured ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Esophageal Diseases/chemically induced ; Esophageal Diseases/metabolism ; Esophageal Diseases/pathology ; Esophageal Diseases/therapy ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Genetic Therapy/methods ; Male ; Protein-Serine-Threonine Kinases/metabolism ; Protein-Serine-Threonine Kinases/physiology ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/pharmacology ; Serum Response Factor/genetics ; Serum Response Factor/physiology ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta/pharmacology ; Transforming Growth Factor beta/physiology ; Ulcer/chemically induced ; Ulcer/metabolism ; Ulcer/pathology ; Ulcer/therapy ; Wound Healing
    Chemical Substances Recombinant Proteins ; Serum Response Factor ; Transforming Growth Factor beta ; integrin-linked kinase (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Acetic Acid (Q40Q9N063P)
    Language English
    Publishing date 2007-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 80128-8
    ISSN 1468-3288 ; 0017-5749
    ISSN (online) 1468-3288
    ISSN 0017-5749
    DOI 10.1136/gut.2006.106674
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  7. Article ; Online: CCN1 induces a reversible epithelial-mesenchymal transition in gastric epithelial cells.

    Chai, Jianyuan / Norng, Manith / Modak, Cristina / Reavis, Kevin M / Mouazzen, Wasim / Pham, Jennifer

    Laboratory investigation; a journal of technical methods and pathology

    2010  Volume 90, Issue 8, Page(s) 1140–1151

    Abstract: CCN1 is a matricellular protein that activates many genes related to wound healing and tissue remodeling in fibroblasts, but its effect on epithelial cells remains unclear. This study examined the role of CCN1 in epithelial wound healing using rat ... ...

    Abstract CCN1 is a matricellular protein that activates many genes related to wound healing and tissue remodeling in fibroblasts, but its effect on epithelial cells remains unclear. This study examined the role of CCN1 in epithelial wound healing using rat gastric epithelial cells and rat stomach ulcer as in vitro and in vivo models, respectively. We found that CCN1 expression is highly upregulated in the epithelial cells adjacent to a wound and remains high until the wound is healed. Upregulation of CCN1 activates a transient epithelial-mesenchymal transition in the epithelial cells at the migrating front and drives wound closure. Once the wound is healed, these epithelial cells and their progeny can resume their original epithelial phenotype. We also found that CCN1-induced E-cadherin loss is not due to transcriptional regulation but rather protein degradation due to the collapse of adherens junctions, which is contributed by beta-catenin translocation. CCN1-activated integrin-linked kinase mediates this process. Finally, our in vivo study showed that locally neutralizing CCN1 drastically impairs wound closure, whereas local injection of recombinant CCN1 protein induces expression of vimentin and smooth muscle alpha-actin in normal gastric mucosal epithelial cells and accelerates re-epithelialization during ulcer healing. In conclusion, our study indicates that CCN1 can induce reversible epithelial-mesenchymal transition, and this feature may have great value for clinical wound healing.
    MeSH term(s) Actins/metabolism ; Adherens Junctions/metabolism ; Animals ; Cadherins/biosynthesis ; Cadherins/metabolism ; Cell Movement ; Cysteine-Rich Protein 61/genetics ; Epithelial Cells/metabolism ; Fibroblasts/metabolism ; Protein Serine-Threonine Kinases ; Rats ; Stomach Ulcer/metabolism ; Up-Regulation ; Vimentin/biosynthesis ; Vimentin/metabolism ; Wound Healing/physiology ; beta Catenin/metabolism
    Chemical Substances Actins ; Cadherins ; Cysteine-Rich Protein 61 ; Vimentin ; beta Catenin ; integrin-linked kinase (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2010-05-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 80178-1
    ISSN 1530-0307 ; 0023-6837
    ISSN (online) 1530-0307
    ISSN 0023-6837
    DOI 10.1038/labinvest.2010.101
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