• ANR-22-CE15-0038 Agence Nationale de la Recherche (French National Research Agency)
• ANR-24-CE18-2934 Agence Nationale de la Recherche (French National Research Agency)

• stevens-johnson syndrome
• toxic epidermal necrolysis
• necroptosis
• apoptosis

• Stevens-Johnson Syndrome/therapy
• Stevens-Johnson Syndrome/diagnosis
• Humans
• Fas Ligand Protein/metabolism
• Biomarkers/metabolism
• Allopurinol/therapeutic use
• Carbamazepine/therapeutic use
• Apoptosis

• Apoptosis
• Calcium
• Concatemer
• Stoichiometry
• TNF

• Humans
• Apoptosis/physiology
• Fas Ligand Protein
• fas Receptor
• Jurkat Cells

• PLBIO 2018-132 INCa PLBIO
• ANR-22-CE15-0038-02 ANR
• PCSI 2021 (CD95L-ProbInnov) ANR
• Price Jean Valade Fondation de France
• PCSI
• PLBIO 2018-132 Institut National Du Cancer

• ADAM
• CD95L
• MMP
• cancer
• cleavage
• inflammation

• Humans
• Fas Ligand Protein
• Ligands
• fas Receptor
• Metalloproteases/metabolism
• Signal Transduction
• Neoplasms
• Inflammation

• Institut National de la Santé et de la Recherche Médicale
• Institut National Du Cancer
• Agence Nationale de la Recherche

• Allografts/metabolism
• Animals
• Diabetes Mellitus, Type 1/therapy
• Islets of Langerhans Transplantation/methods
• Microgels
• Primates
• Sirolimus
• Streptavidin

• R01 DK128840 NIDDK NIH HHS
• U01 AI132817 NIAID NIH HHS
• National Science Foundation
• National Institute of Allergy and Infectious Diseases
• Juvenile Diabetes Research Foundation International

Blood disorders include a wide spectrum of blood-associated malignancies resulting from inherited or acquired defects. The ineffectiveness of existing therapies against blood disorders arises from different reasons, one of which is drug resistance, so different types of leukemia may show different responses to treatment. Leukemia occurs for a variety of genetic and acquired reasons, leading to uncontrolled proliferation in one or more cell lines. Regarding the genetic defects, oncogene signal transducer and activator of transcription (STAT) family transcription factor, especially STAT3, play an essential role in hematological disorders onset and progress upon mutations, dysfunction, or hyperactivity. Besides, microRNAs, as biological molecules, has been shown to play a dual role in either tumorigenesis and tumor suppression in various cancers. Besides, a strong association between STAT3 and miRNA has been reported. For example, miRNAs can regulate STAT3 via targeting its upstream mediators such as IL6, IL9, and JAKs or directly binding to the STAT3 gene. On the other hand, STAT3 can regulate miRNAs. In this review study, we aimed to determine the role of either microRNAs and STAT3 along with their effect on one another's activity and function in hematological malignancies.

Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular STAT3 mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.

• STAT3
• immunosuppressive therapy
• large granular lymphocytes
• neutropenia

• Bcl-2
• Primary Sjögren's syndrome
• apoptosis
• inflammation
• nitric oxide

• viral infection
• inflammation
• neutrophils
• translational immunology

• Burn
• Inflammation
• Organ damage
• Shock
• Soluble Fas ligand

• Adult
• Biomarkers/blood
• Burns/blood
• Burns/mortality
• Burns/therapy
• Case-Control Studies
• China/epidemiology
• Fas Ligand Protein/blood
• Female
• Humans
• Male
• Middle Aged
• Prospective Studies
• Resuscitation
• Severity of Illness Index
• Shock, Traumatic/blood
• Shock, Traumatic/mortality
• Shock, Traumatic/therapy

• hexosylceramides
• macrocytic anemia
• neutropenia
• sphingomyelins

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by detachment of the epidermis and mucous membrane. SJS/TEN are considered to be on the same spectrum of diseases with different severities. They are classified by the percentage of skin detachment area. SJS/TEN can also cause several complications in the liver, kidneys, and respiratory tract. The pathogenesis of SJS/TEN is still unclear. Although it is difficult to diagnose early stage SJS/TEN, biomarkers for diagnosis or severity prediction have not been well established. Furthermore, optimal therapeutic options for SJS/TEN are still controversial.

Several drugs, such as carbamazepine and allopurinol, are reported to have a strong relationship with a specific human leukocyte antigen (HLA) type. This relationship differs between different ethnicities. Recently, the usefulness of HLA screening before administering specific drugs to decrease the incidence of SJS/TEN has been investigated.

Skin detachment in SJS/TEN skin lesions is caused by extensive epidermal cell death, which has been considered to be apoptosis via the Fas-FasL pathway or perforin/granzyme pathway. We reported that necroptosis, i.e. programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, and its interaction with the formyl peptide receptor 1 induce necroptosis. Several diagnostic or prognostic biomarkers for SJS/TEN have been reported, such as CCL-27, IL-15, galectin-7, and RIP3.

Supportive care is recommended for the treatment of SJS/TEN. However, optimal therapeutic options such as systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-α antagonists are still controversial. Recently, the beneficial effects of cyclosporine and TNF-α antagonists have been explored. In this review, we discuss recent advances in the pathophysiology and management of SJS/TEN.

• Stevens-Johnson syndrome
• drug reaction
• erythema multiforme
• necroptosis
• toxic epidermal necrolysis

CD95 is a pre-ligand-associated transmembrane (TM) receptor. The interaction with its ligand CD95L brings to a next level its aggregation and triggers different signaling pathways, leading to cell motility, differentiation or cell death. This diversity of biological responses associated with a unique receptor devoid of enzymatic property raises the question of whether different ligands exist, or whether the fine-tuned control of CD95 aggregation and conformation, its distribution within certain plasma membrane sub-domains or the pattern of post-translational modifications account for this such broad-range of cell signaling. Herein, we review how the different domains of CD95 and their post-translational modifications or the different forms of CD95L can participate in the receptor aggregation and induction of cell signaling. Understanding how CD95 response goes from cell death to cell proliferation, differentiation and motility is a prerequisite to reveal novel therapeutic options to treat chronic inflammatory disorders and cancers.

• Fas
• aggregation
• apoptosis
• inflammation
• migration
• stoichiometry

• CD95
• ER stress
• IRE1
• PERK
• TNFR1
• TRAIL-R1/2
• cell death
• death receptor
• post-translational modifications
• unfolded protein response

• PDF20171206671 Fondation ARC pour la Recherche sur le Cancer

MicroRNAs or miRNAs are a component of the non-coding RNAs family which is engaged in many cellular functions such as cell proliferation, apoptosis, gene expression, signaling pathways, angiogenesis, and etc. Endometriosis is a malignant gynecologic disorder occurring in women before menopausal age. Pathogenesis of this illness is still a discussion subject between the scientists but in our knowledge, microRNAs can be one of the possible involved factors. The purpose of this paper is to investigate the role of apoptotic activities of miRNAs in endometriosis. Accumulative evidence has demonstrated the role of cell proliferation, apoptosis, and invasion in the progression of these diseases. In this review, we looked into the specific role of apoptosis and its related genes and pathways in endometriosis and tied to present an explanation of how miRNAs can affect endometriosis by their apoptotic activities. What we found is that a great extent of miRNAs is involved in this illness and they are responsible for repressing apoptosis and progression of the disease. As a result, miRNAs have two different usages in endometriosis: biomarkers and potential therapeutic targets. In this review we gathered a great amount of evidence to inquire into the role of micro RNAs in inducing apoptosis and how this mechanism can be exerted for therapeutic purposes for endometriosis.

• Apoptosis
• BAX
• BCL-2
• Endometriosis
• miRNA

• cell death
• lung myofibroblasts
• matrix metalloproteinase (MMP)
• pulmonary fibrosis
• soluble FasL (sFasL)

• Apoptosis
• Calcium
• Cytoskeleton
• Migration
• TNF

• Apoptosis
• Calcium/metabolism
• Cytoskeleton/metabolism
• Cytotoxicity, Immunologic
• Fas Ligand Protein/genetics
• Fas Ligand Protein/metabolism
• Homeostasis
• Humans
• Immunomodulation
• Neoplasm Metastasis
• Neoplasm Staging
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/therapy
• Neoplastic Stem Cells/immunology
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Protein Binding
• Signal Transduction
• fas Receptor/genetics
• fas Receptor/metabolism

• Aromatic
• CD95
• Cell migration
• Fas
• Lupus
• Mutagenesis
• Peptidomimetic
• Phospholipase
• Protein protein interaction

• Large granular lymphocyte leukemia
• hematological abnormality
• neutropenia
• targeted therapy

• Fas ligand
• Renal tubules
• captisol
• cisplatin
• nephrotoxicity
• oxidative damage

The contribution of Epstein-Barr virus (EBV) to the development of specific types of benign lymphoproliferations and malignant lymphomas has been extensively studied since the discovery of the virus over the last 50 years. The importance and better understanding of the EBV-associated lymphoproliferative disorders (LPD) of B, T or natural killer (NK) cell type has resulted in the recognition of new entities like EBV+ mucocutaneous ulcer or the addition of chronic active EBV (CAEBV) infection in the revised 2016 World Health Organization (WHO) lymphoma classification. In this article, we review the definitions, morphology, pathogenesis, and evolving concepts of the various EBV-associated disorders including EBV+ diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), EBV+ mucocutaneous ulcer, DLBCL associated with chronic inflammation, fibrin-associated DLBCL, lymphomatoid granulomatosis, the EBV+ T and NK-cell LPD of childhood, aggressive NK leukaemia, extranodal NK/T-cell lymphoma, nasal type, and the new provisional entity of primary EBV+ nodal T- or NK-cell lymphoma. The current knowledge regarding the pathogenesis of B-cell lymphomas that can be EBV-associated including Burkitt lymphoma, plasmablastic lymphoma and classic Hodgkin lymphoma will be also explored.

• Epstein-Barr virus
• clinical features
• epidemiology
• lymphoma
• lymphoproliferations
• morphology
• pathogenesis

Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30–40% of patients with large granular lymphocyte leukemia. Herein, we aimed to study whether these mutations can also be detected in Felty syndrome, which would imply the existence of a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3, which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of large granular lymphocytes was observed, and in the majority of cases the CD8⁺ T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that ten of the 92 assayed cytokines were elevated both in Felty syndrome and large granular lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as they are in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, a unified reclassification of these two syndromes is warranted.

• FLIP
• Fas
• PI3K
• T lymphocytes
• apoptosis
• caspase-8
• immune response
• inflammation
• lupus
• migration

• Fas ligand
• acute kidney injury
• cecal ligation and puncture
• neonates
• pigs
• sepsis

• Acute Kidney Injury/blood
• Animals
• Animals, Newborn
• Apoptosis
• Biomarkers/blood
• Biomarkers/urine
• Blood Urea Nitrogen
• C-Reactive Protein/analysis
• Disease Models, Animal
• Fas Ligand Protein/blood
• Fas Ligand Protein/urine
• Kidney/physiopathology
• Male
• Sepsis/complications
• Swine

• P30 DK079337 NIDDK NIH HHS
• R01 DK101668 NIDDK NIH HHS

• Fas
• FasL
• apoptosis
• endothelium
• lupus metastasis
• migration
• tyrosine kinase

• STAT3 mutation
• fas ligand
• immunophenotype
• large granular lymphocyte leukemia
• neutropenia

Fas-mediated apoptosis contributes to physiological and pathological cellular processes, such as differentiation and survival. In particular, the roles of Fas in immune cells are complex and critical for the maintenance of immune tolerance. The precise pathways and unique functions associated with Fas/FasL-mediated signaling in the immune system are known. The dual character of Fas/FasL-mediated immune regulation that induces beneficial or harmful effects is associated with the onset or development of immune disorders. Studies on mutations in genes encoding Fas and FasL gene of humans and mice contributed to our understanding of the pathogenesis of autoimmune diseases. Here, we review the opposing functions of Fas/FasL-mediated signaling, bilateral effects of Fas/FasL on in immune cells, and complex pathogenesis of autoimmunity mediated by Fas/FasL.

• B cell
• Fas
• FasL
• T cell
• activation-induced cell death
• apoptosis
• autoimmunity
• immune tolerance

Aging is associated with systemic inflammation and cellular apoptosis accelerating physiological dysfunctions. Whether physically active way of life affects these associations is unclear. This study measured the levels of serum inflammatory and apoptotic molecules, their change over 10 years, and their associations with physical performance in sprint-trained male athletes. HsCRP, cell counts, HGB, FasL, miR-21, and miR-146a were measured cross-sectionally (n = 67, 18–90 yrs) and serum FasL, miR-21, and miR-146a and their aging-related associations with physical performance were assessed over a 10-year follow-up (n = 49, 50–90 yrs). The cross-sectional study showed positive age correlations for neutrophils and negative for lymphocytes, red blood cells, HGB, FasL, and miR-146a. During the 10-year follow-up, FasL decreased (P = 0.017) and miR-21 (P < 0.001) and miR-146a (P = 0.005) levels increased. When combining the molecule levels, aging, and physical performance, FasL associated with countermovement jump and bench press (P < 0.001), miR-21 and miR-146a with knee flexion (P = 0.023; P < 0.001), and bench press (P = 0.004; P < 0.001) and miR-146a with sprint performance (P < 0.001). The studied serum molecules changed in an age-dependent manner and were associated with declining physical performance. They have potential as biomarkers of aging-related processes influencing the development of physiological dysfunctions. Further research is needed focusing on the origins and targets of circulating microRNAs to clarify their function in various tissues with aging.

• Intravenous immunoglobulin
• efficacy
• immunomodulatory
• sCD
• sCD8
• sFasL
• sHLA molecules

• ADAM proteases
• Fas Ligand
• Lipid rafts
• Proteolysis
• Secretory lysosomes
• T Lymphocytes

CD95 (Fas/APO-1) and its ligand, CD95L, have long been viewed as a death receptor/death ligand system that mediates apoptosis induction to maintain immune homeostasis. In addition, these molecules are important in the immune elimination of virus-infected cells and cancer cells. CD95L was, therefore, considered to be useful for cancer therapy. However, major side effects have precluded its systemic use. During the last 10 years, it has been recognized that CD95 and CD95L have multiple cancer-relevant nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to be critical survival factors for cancer cells, and were found to protect and promote cancer stem cells. We now discuss five different ways in which inhibiting or eliminating CD95L, rather than augmenting, may be beneficial for cancer therapy alone or in combination with standard chemotherapy or immune therapy.

Apoptosis is a fundamental process contributing to tissue homeostasis, immune response, and development. CD95, also called Fas, is a member of the tumor necrosis factor receptor (TNF-R) superfamily. Its ligand, CD95L, was initially detected at the plasma membrane of activated T lymphocytes and natural killer (NK) cells where it contributes to the elimination of transformed and infected cells. Given its implication in immune homeostasis and immune surveillance combined with the fact that various lineages of malignant cells exhibit loss-of-function mutations, CD95 was initially classified as a tumor suppressor gene. Nonetheless, in different pathophysiological contexts, this receptor is able to transmit non-apoptotic signals and promote inflammation and carcinogenesis. Although the different non-apoptotic signaling pathways (NF-κB, MAPK, and PI3K) triggered by CD95 are known, the initial molecular events leading to these signals, the mechanisms by which the receptor switches from an apoptotic function to an inflammatory role, and, more importantly, the biological functions of these signals remain elusive.

• lipid raft
• apoptotic signal
• death domain
• disc formation
• pi3k signaling pathway

• Adjuvant chemotherapy
• Apoptosis
• Breast cancer
• Cytochrome c
• Fas ligand
• Granzyme B

• Apoptosis
• Carcinogenesis
• Cytokine
• Fas
• Inflammation

• Animals
• Carcinogenesis/genetics
• Fas Ligand Protein/physiology
• Humans
• Receptors, Tumor Necrosis Factor/physiology
• Signal Transduction/physiology
• fas Receptor/physiology

• Animals
• Apoptosis/drug effects
• CD4-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/immunology
• Cell Line
• Cyclohexanones/pharmacology
• Cyclohexanones/toxicity
• Cytoplasmic Granules
• Cytotoxicity, Immunologic/drug effects
• DNA Fragmentation/drug effects
• Epoxy Compounds
• Exocytosis/drug effects
• Fas Ligand Protein
• Membrane Glycoproteins/analysis
• Membrane Glycoproteins/drug effects
• Membrane Glycoproteins/physiology
• Mice
• Perforin
• Pore Forming Cytotoxic Proteins
• T-Lymphocytes, Cytotoxic/immunology
• Tumor Necrosis Factors/analysis
• Tumor Necrosis Factors/physiology

• Acute liver injury
• Biomarker
• Cell death
• Chronic liver injury

• Acute coronary syndrome
• Apoptosis
• Coronary artery disease
• Immune system
• Leukocytes
• Natural killer cells

• Aged
• Aged, 80 and over
• Apoptosis
• Cohort Studies
• Convalescence
• Coronary Artery Disease/blood
• Coronary Artery Disease/immunology
• Coronary Artery Disease/therapy
• Cross-Sectional Studies
• Fas Ligand Protein/blood
• Female
• Follow-Up Studies
• Humans
• Interleukin-12/pharmacology
• Interleukin-15/pharmacology
• Interleukin-6/blood
• Killer Cells, Natural/drug effects
• Killer Cells, Natural/metabolism
• Killer Cells, Natural/pathology
• Lymphocyte Count
• Male
• Middle Aged
• Sweden
• T-Lymphocytes/drug effects
• T-Lymphocytes/metabolism
• T-Lymphocytes/pathology
• fas Receptor/blood

• Cancer Vaccines/immunology
• Cancer Vaccines/therapeutic use
• Dendritic Cells/immunology
• Dendritic Cells/transplantation
• Humans
• Leukemia, Myeloid, Acute/immunology
• Leukemia, Myeloid, Acute/therapy
• T-Lymphocytes/immunology
• T-Lymphocytes/transplantation

• Adult
• Aged
• Apoptosis
• Diabetes Mellitus, Type 2/blood
• Diabetes Mellitus, Type 2/diagnosis
• Diabetes Mellitus, Type 2/physiopathology
• Fas Ligand Protein/blood
• Female
• Glucose Tolerance Test
• Humans
• Insulin/metabolism
• Insulin Resistance
• Insulin-Secreting Cells/cytology
• Insulin-Secreting Cells/metabolism
• Male
• Middle Aged
• fas Receptor/blood

The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective induction of cell death in potentially dangerous and superfluous cells to providing costimulatory signals that help mount an effective immune response. This diverse and important regulatory role in immunity has sparked great interest in the development of TNFL/TNFR-targeted cancer immunotherapeutics. In this review, I will discuss the biology of the most prominent proapoptotic and co-stimulatory TNF ligands and review their current status in cancer immunotherapy.