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Article: Recent Advances in Cancer Drug Discovery Through the Use of Phenotypic Reporter Systems, Connectivity Mapping, and Pooled CRISPR Screening.

Salame, Natasha / Fooks, Katharine / El-Hachem, Nehme / Bikorimana, Jean-Pierre / Mercier, François E / Rafei, Moutih

2022 Volume 13, Page(s) 852143

Abstract: Multi-omic approaches offer an unprecedented overview of the development, plasticity, and resistance of cancer. However, the translation from anti-cancer compounds ... ...

Abstract	Multi-omic approaches offer an unprecedented overview of the development, plasticity, and resistance of cancer. However, the translation from anti-cancer compounds identified
Language	English
Publishing date	2022-06-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2022.852143
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Article ; Online: Humoral Immunity to Allogeneic Immunoproteasome-Expressing Mesenchymal Stromal Cells Requires Efferocytosis by Endogenous Phagocytes.

Bikorimana, Jean-Pierre / Abusarah, Jamilah / Salame, Natasha / El-Hachem, Nehme / Shammaa, Riam / Rafei, Moutih

Cells

2022 Volume 11, Issue 4

Abstract: The extensive use of mesenchymal stromal cells (MSCs) over the last decade has revolutionized modern medicine. From the delivery of pharmacological proteins to regenerative medicine and immune modulation, these cells have proven to be highly pleiotropic ... ...

Abstract	The extensive use of mesenchymal stromal cells (MSCs) over the last decade has revolutionized modern medicine. From the delivery of pharmacological proteins to regenerative medicine and immune modulation, these cells have proven to be highly pleiotropic and responsive to their surrounding environment. Nevertheless, their role in promoting inflammation has been fairly limited by the questionable use of interferon-gamma, as this approach has also been proven to enhance the cells' immune-suppressive abilities. Alternatively, we have previously shown that de novo expression of the immunoproteasome (IPr) complex instills potent antigen cross-presentation capabilities in MSCs. Interestingly, these cells were found to express the major histocompatibility class (MHC) II protein, which prompted us to investigate their ability to stimulate humoral immunity. Using a series of in vivo studies, we found that administration of allogeneic ovalbumin (OVA)-pulsed MSC-IPr cells elicits a moderate antibody titer, which was further enhanced by the combined use of pro-inflammatory cytokines. The generated antibodies were functional as they blocked CD4 T-cell activation following their co-culture with OVA-pulsed MSC-IPr and mitigated E.G7 tumor growth in vivo. The therapeutic potency of MSC-IPr was, however, dependent on efferocytosis, as phagocyte depletion prior to vaccination abrogated MSC-IPr-induced humoral responses while promoting their survival in the host. In contrast, antibody-mediated neutralization of CD47, a potent "do not eat me signal", enhanced antibody titer levels. These observations highlight the major role played by myeloid cells in supporting antibody production by MSC-IPr and suggest that the immune outcome is dictated by a net balance between efferocytosis-stimulating and -inhibiting signals.
MeSH term(s)	Antigen Presentation ; Hematopoietic Stem Cell Transplantation ; Immunity, Humoral ; Mesenchymal Stem Cells/metabolism ; Ovalbumin ; Phagocytes
Chemical Substances	Ovalbumin (9006-59-1)
Language	English
Publishing date	2022-02-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11040596
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Article ; Online: A1-reprogrammed mesenchymal stromal cells prime potent antitumoral responses.

Gonçalves, Marina Pereira / Farah, Roudy / Bikorimana, Jean-Pierre / Abusarah, Jamilah / El-Hachem, Nehme / Saad, Wael / Talbot, Sebastien / Stanga, Daniela / Beaudoin, Simon / Plouffe, Sebastien / Rafei, Moutih

iScience

2024 Volume 27, Issue 3, Page(s) 109248

Abstract: Mesenchymal stromal cells (MSCs) have been modified via genetic or pharmacological engineering into potent antigen-presenting cells-like capable of priming responding CD8 T cells. In this study, our screening of a variant library of Accum molecule ... ...

Abstract	Mesenchymal stromal cells (MSCs) have been modified via genetic or pharmacological engineering into potent antigen-presenting cells-like capable of priming responding CD8 T cells. In this study, our screening of a variant library of Accum molecule revealed a molecule (A1) capable of eliciting antigen cross-presentation properties in MSCs. A1-reprogrammed MSCs (ARM) exhibited improved soluble antigen uptake and processing. Our comprehensive analysis, encompassing cross-presentation assays and molecular profiling, among other cellular investigations, elucidated A1's impact on endosomal escape, reactive oxygen species production, and cytokine secretion. By evaluating ARM-based cellular vaccine in mouse models of lymphoma and melanoma, we observe significant therapeutic potency, particularly in allogeneic setting and in combination with anti-PD-1 immune checkpoint inhibitor. Overall, this study introduces a strong target for developing an antigen-adaptable vaccination platform, capable of synergizing with immune checkpoint blockers to trigger tumor regression, supporting further investigation of ARMs as an effective and versatile anti-cancer vaccine.
Language	English
Publishing date	2024-02-17
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109248
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Article: Attitude des psychiatres et internes en psychiatrie au Liban vis-à-vis de la contention et du consentement éclairé.

Daou, M / El-Hachem, C / Nehme, K / Dagher, R / Richa, S

L'Encephale

2020 Volume 47, Issue 1, Page(s) 21–25

Abstract: Objectives: Psychiatry differs from the rest of medical specialties by the unique character of its pathologies, which makes ethical reflection difficult, including the collection of informed consent and the use of restraint and the seclusion-room. This ... ...

Title translation	Attitude of psychiatrists and psychiatry residents in Lebanon towards restraint and informed consent.
Abstract	Objectives: Psychiatry differs from the rest of medical specialties by the unique character of its pathologies, which makes ethical reflection difficult, including the collection of informed consent and the use of restraint and the seclusion-room. This reflection can be affected by subjectivity and a variety of influences, hence the interest of studying the attitude of psychiatrists and residents in psychiatry in Lebanon with regard to restraint and informed consent. Methods: We collected data using an anonymous questionnaire that we sent as a Google form to Lebanese psychiatrists and psychiatry residents by email and phone messages. The descriptive analysis was done using Microsoft Excel software, and the analytical analysis was done using the SPSS software and the following statistical tests: independent-sample test and the Mann Whitney U test. Results: Forty people responded, including 19 men and 21 women (16 psychiatric interns, 15 university psychiatrists and 9 non-university psychiatrists). Concerning the questions related to the use of restraint, 70% did not find that it is being commonly used in hospital practice. However, 92.5% would use it to counter the patient's dangerousness and 60% to help deliver treatment. 57.5% did not find the repeated usage of restraint as a dehumanization of care, but the majority (70%) agreed with the need for temporal limitation of any form of restraint. As for the ability to consent, 90% considered a patient in a psychotic state as unfit to consent. Conclusions: Restraint is considered uncommon by psychiatrists and psychiatric residents in Lebanon and must remain an option of last resort with efforts being made upstream in order to avoid situations where the use of restraint becomes mandatory. Post critical thinking is paramount, and restraint should never respond to a lack of manpower or a security goal. Informed consent is one of the most important guarantors of the principle of autonomy, and must be sought in each patient, individually. Finally, no significant difference was found between the subgroups, which would therefore become a single population. Ethical reflection would therefore be directly linked to the population. Mental illnesses are becoming more common and an important source of morbidity worldwide. It is our role to ensure the dignity of the mentally ill. The introduction of the Psychiatric Nurse Diploma, an increase in the relational approach to the training of psychiatrists in Lebanon, and an increase in the number of health care teams may help to maximize the ability of capacity.
MeSH term(s)	Attitude of Health Personnel ; Female ; Humans ; Informed Consent ; Lebanon ; Male ; Mentally Ill Persons ; Psychiatry ; Restraint, Physical
Language	French
Publishing date	2020-05-27
Publishing country	France
Document type	Journal Article
ZDB-ID	214431-1
ISSN	0013-7006
ISSN	0013-7006
DOI	10.1016/j.encep.2020.03.005
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Article ; Online: The

Bikorimana, Jean-Pierre / El-Hachem, Nehme / Abusarah, Jamilah / Eliopoulos, Nicoletta / Talbot, Sebastien / Shammaa, Riam / Rafei, Moutih

iScience

2022 Volume 25, Issue 12, Page(s) 105537

Abstract: Immunoproteasome-reprogrammed mesenchymal stromal cells (IRMs) can surpass dendritic cells at eliciting tumor-specific immunity. However, the current IRM vaccination regimen remains clinically unsuitable due to the relatively high dose of IRMs needed. ... ...

Abstract	Immunoproteasome-reprogrammed mesenchymal stromal cells (IRMs) can surpass dendritic cells at eliciting tumor-specific immunity. However, the current IRM vaccination regimen remains clinically unsuitable due to the relatively high dose of IRMs needed. Since the administration of a lower IRM dose triggers a feeble anti-tumoral response, we aimed to combine this vaccination regimen with different modalities to fine-tune the potency of the vaccine. In a nutshell, we found that the co-administration of IRMs and interleukin-12 accentuates the anti-tumoral response, whereas the cross-presentation potency of IRMs is enhanced via intracellular succinate build-up, delayed endosomal maturation, and increased endosome-to-cytosol plasticity. Stimulating phagocyte-mediated cancer efferocytosis by blocking the CD47-SIRPα axis was also found to enhance IRM vaccine outcomes. Upon designing a single protocol combining the abovementioned strategies, 60% of treated animals exhibited a complete response. Altogether, this is the first IRM-based vaccination study, optimized to simultaneously target three vaccine-related pitfalls: T-cell response, antigen cross-presentation, and cancer phagocytosis.
Language	English
Publishing date	2022-11-09
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.105537
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Article ; Online: LSD1 Inhibition Enhances the Immunogenicity of Mesenchymal Stromal Cells by Eliciting a dsRNA Stress Response.

Mardani, Fatemeh / Saad, Wael / El-Hachem, Nehme / Bikorimana, Jean-Pierre / Kurdi, Mazen / Shammaa, Riam / Talbot, Sebastien / Rafei, Moutih

Cells

2022 Volume 11, Issue 11

Abstract: Mesenchymal stromal cells (MSCs) are commonly known for their immune-suppressive abilities. However, our group provided evidence that it is possible to convert MSCs into potent antigen presenting cells (APCs) using either genetic engineering or ... ...

Abstract	Mesenchymal stromal cells (MSCs) are commonly known for their immune-suppressive abilities. However, our group provided evidence that it is possible to convert MSCs into potent antigen presenting cells (APCs) using either genetic engineering or pharmacological means. Given the capacity of UM171a to trigger APC-like function in MSCs, and the recent finding that this drug may modulate the epigenome by inhibiting the lysine-specific demethylase 1 (LSD1), we explored whether the direct pharmacological inhibition of LSD1 could instill APC-like functions in MSCs akin to UM171a. The treatment of MSCs with the LSD1 inhibitor tranylcypromine (TC) elicits a double-stranded (ds)RNA stress response along with its associated responsive elements, including pattern recognition receptors (PRRs), Type-I interferon (IFN), and IFN-stimulated genes (ISGs). The net outcome culminates in the enhanced expression of H2-K
MeSH term(s)	CD8-Positive T-Lymphocytes ; Histone Demethylases/metabolism ; Mesenchymal Stem Cells/metabolism ; RNA, Double-Stranded ; Tranylcypromine/pharmacology
Chemical Substances	RNA, Double-Stranded ; Tranylcypromine (3E3V44J4Z9) ; Histone Demethylases (EC 1.14.11.-)
Language	English
Publishing date	2022-06-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11111816
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Article ; Online: UM171A-induced ROS promote antigen cross-presentation of immunogenic peptides by bone marrow-derived mesenchymal stromal cells.

Salame, Natasha / Bikorimana, Jean-Pierre / El-Hachem, Nehme / Saad, Wael / Kurdi, Mazen / Zhao, Jing / Eliopoulos, Nicoletta / Shammaa, Riam / Rafei, Moutih

Stem cell research & therapy

2022 Volume 13, Issue 1, Page(s) 16

Abstract: Background: Mesenchymal stromal cells (MSCs) have been extensively used in the clinic due to their exquisite tissue repair capacity. However, they also hold promise in the field of cellular vaccination as they can behave as conditional antigen ... ...

Abstract	Background: Mesenchymal stromal cells (MSCs) have been extensively used in the clinic due to their exquisite tissue repair capacity. However, they also hold promise in the field of cellular vaccination as they can behave as conditional antigen presenting cells in response to interferon (IFN)-gamma treatment under a specific treatment regimen. This suggests that the immune function of MSCs can be pharmacologically modulated. Given the capacity of the agonist pyrimido-indole derivative UM171a to trigger the expression of various antigen presentation-related genes in human hematopoietic progenitor cells, we explored the potential use of UM171a as a means to pharmacologically instill and/or promote antigen presentation by MSCs. Methods: Besides completing a series of flow-cytometry-based phenotypic analyses, several functional antigen presentation assays were conducted using the SIINFEKL-specific T-cell clone B3Z. Anti-oxidants and electron transport chain inhibitors were also used to decipher UM171a's mode of action in MSCs. Finally, the potency of UM171a-treated MSCs was evaluated in the context of therapeutic vaccination using immunocompetent C57BL/6 mice with pre-established syngeneic EG.7T-cell lymphoma. Results: Treatment of MSCs with UM171a triggered potent increase in H2-K Conclusions: Altogether, our findings reveal a new immune-related function for UM171a and clearly allude to a direct link between UM171a-mediated ROS induction and antigen cross-presentation by MSCs. The fact that UM171a treatment modulates MSCs to become antigen-presenting cells without the use of IFN-gamma opens-up a new line of investigation to search for additional agents capable of converting immune-suppressive MSCs to a cellular tool easily adaptable to vaccination.
MeSH term(s)	Animals ; Antigen Presentation/drug effects ; Bone Marrow Cells/cytology ; Bone Marrow Cells/drug effects ; Bone Marrow Cells/immunology ; Cross-Priming ; Indoles/pharmacology ; Interferon-gamma/pharmacology ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/drug effects ; Mesenchymal Stem Cells/immunology ; Mice ; Mice, Inbred C57BL ; Pyrimidines/pharmacology ; Reactive Oxygen Species/metabolism
Chemical Substances	Indoles ; Pyrimidines ; Reactive Oxygen Species ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2022-01-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-021-02693-z
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Article ; Online: Intratumoral administration of unconjugated Accum™ impairs the growth of pre-established solid lymphoma tumors.

Bikorimana, Jean-Pierre / El-Hachem, Nehme / Moreau, Mathilde / Lawson, Christine / Tai, Lee-Hwa / Gonçalves, Marina / Abusarah, Jamilah / Beaudoin, Simon / Stanga, Daniela / Plouffe, Sebastien / Rafei, Moutih

Cancer science

2023 Volume 114, Issue 12, Page(s) 4499–4510

Abstract: The Accum™ technology was initially designed to enhance the bioaccumulation of a given molecule in target cells. It does so by triggering endosomal membrane damages allowing endocytosed products to enter the cytosol, escaping the harsh environmental cues ...

Abstract	The Accum™ technology was initially designed to enhance the bioaccumulation of a given molecule in target cells. It does so by triggering endosomal membrane damages allowing endocytosed products to enter the cytosol, escaping the harsh environmental cues of the endosomal lumen. In an attempt to minimize manufacturing hurdles associated with Accum™ conjugation, we tested whether free Accum™ admixed with antigens could lead to outcomes similar to those obtained with conjugated products. Surprisingly, unconjugated Accum™ was found to promote cell death in vitro, an observation further confirmed on various murine tumor cell lines (EL4, CT-26, B16, and 4 T1). At the molecular level, unconjugated Accum™ triggers the production of reactive oxygen species and elicits immunogenic cell death while retaining its innate ability to cause endosomal damages. When administered as a monotherapy to animals with pre-established EL4 T-cell lymphoma, Accum™ controlled tumor growth in a dose-dependent manner, and its therapeutic effect relies on CD4 and CD8 T cells. Although unconjugated Accum™ synergizes with various immune checkpoint inhibitors (anti-CTLA4, anti-PD-1, or anti-CD47) at controlling tumor growth, its therapeutic potency could not be further enhanced when combined with all three tested immune checkpoint inhibitors at once due to its dependency on a specific dosing regimen. In sum, we report in this study an unprecedented new function for unconjugated Accum™ as a novel anticancer molecule. These results could pave the path for a new line of investigation aimed at exploring the pro-killing properties of additional Accum™ variants as a mean to develop second-generation anticancer therapeutics.
MeSH term(s)	Animals ; Mice ; Immune Checkpoint Inhibitors ; CD8-Positive T-Lymphocytes ; Cell Line, Tumor ; Lymphoma, T-Cell
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2023-09-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2115647-5
ISSN	1349-7006 ; 1349-7006
ISSN (online)	1349-7006
ISSN	1349-7006
DOI	10.1111/cas.15985
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Article ; Online: Repurposing Cilostazol for Raynaud's Phenomenon.

El-Hachem, Nehme / Fardoun, Manal M / Slika, Hasan / Baydoun, Elias / Eid, Ali H

Current medicinal chemistry

2020 Volume 28, Issue 12, Page(s) 2409–2417

Abstract: Raynaud 's Phenomenon (RP) results from exaggerated cold-induced vasoconstriction. RP patients suffer from vasospastic attacks and compromised digital blood perfusion leading to a triple color change at the level the fingers. Severe RP may cause ulcers ... ...

Abstract	Raynaud 's Phenomenon (RP) results from exaggerated cold-induced vasoconstriction. RP patients suffer from vasospastic attacks and compromised digital blood perfusion leading to a triple color change at the level the fingers. Severe RP may cause ulcers and threaten tissue viability. Many drugs have been used to alleviate the symptoms of RP. These include calcium-channel blockers, cGMP-specific phosphodiesterase type 5 inhibitors, prostacyclin analogs, and angiotensin receptor blockers. Despite their variety, these drugs do not treat RP but rather alleviate its symptoms. To date, no drug for RP has been yet approved by the U.S Food and Drugs Administration. Cilostazol is a selective inhibitor of phosphodiesterase-III, originally prescribed to treat intermittent claudication. Owing to its antiplatelet and vasodilating properties, cilostazol is being repurposed as a potential drug for RP. This review focuses on the different lines of action of cilostazol serving to enhance blood perfusion in RP patients.
MeSH term(s)	Calcium Channel Blockers/therapeutic use ; Cilostazol/therapeutic use ; Drug Repositioning ; Fingers ; Humans ; Raynaud Disease/drug therapy
Chemical Substances	Calcium Channel Blockers ; Cilostazol (N7Z035406B)
Language	English
Publishing date	2020-09-16
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	1319315-6
ISSN	1875-533X ; 0929-8673
ISSN (online)	1875-533X
ISSN	0929-8673
DOI	10.2174/0929867327666200903114154
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Zs.A 4432: Show issues

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Article ; Online: Thymoproteasome-Expressing Mesenchymal Stromal Cells Confer Protective Anti-Tumor Immunity

Bikorimana, Jean-Pierre / El-Hachem, Nehme / El-Kadiry, Abed El-Hakim / Abusarah, Jamilah / Salame, Natasha / Shammaa, Riam / Rafei, Moutih

Frontiers in immunology

2021 Volume 11, Page(s) 596303

Abstract: Proteasomes are complex macromolecular structures existing in various forms to regulate a myriad of cellular processes. Besides degrading unwanted or misfolded proteins (proteostasis), distinct immune functions were ascribed for the immunoproteasome and ... ...

Abstract	Proteasomes are complex macromolecular structures existing in various forms to regulate a myriad of cellular processes. Besides degrading unwanted or misfolded proteins (proteostasis), distinct immune functions were ascribed for the immunoproteasome and thymoproteasome (TPr) complexes. For instance, antigen degradation during ongoing immune responses mainly relies on immunoproteasome activity, whereas intrathymic CD8 T-cell development requires peptide generation by the TPr complex. Despite these substantial differences, the functional contribution of the TPr to peripheral T-cell immunity remains ill-defined. We herein explored whether the use of mesenchymal stromal cells (MSCs) engineered to exhibit altered proteasomal activity through
MeSH term(s)	Animals ; Antigen Presentation/immunology ; Antigens, Neoplasm/immunology ; Cell Line, Tumor ; Cross-Priming/immunology ; Cytokines/metabolism ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Epitope Mapping ; Female ; Genetic Engineering ; Humans ; Immunomodulation ; Mesenchymal Stem Cells/immunology ; Mesenchymal Stem Cells/metabolism ; Mice ; Models, Biological ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; Proteasome Endopeptidase Complex/immunology ; Proteasome Endopeptidase Complex/metabolism
Chemical Substances	Antigens, Neoplasm ; Cytokines ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2021-01-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.596303
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