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Clinical and Experimental Rheumatology Jul 2022Patients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis (UC), have an increased risk of herpes... (Review)
Review
Patients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis (UC), have an increased risk of herpes zoster (HZ) infection, compared with the general population. This risk is further increased by the use of immunomodulatory therapies, with a higher incidence of HZ reported in patients receiving Janus kinase (JAK) inhibitors, compared with those receiving other immunomodulatory or biological therapies. Tofacitinib is an oral JAK inhibitor for the treatment of RA, PsA and UC. In this narrative review, we discuss the effects of tofacitinib and other JAK inhibitors on HZ risk in patients with RA, PsA and UC, and strategies for risk management. We also discuss current UK guidelines for HZ vaccination in healthy individuals and patients with chronic inflammatory diseases, consider selected international guidelines, and review current HZ vaccination strategies.
Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Colitis, Ulcerative; Gastroenterology; Herpes Zoster; Humans; Janus Kinase Inhibitors; Janus Kinases; Pyrroles; Rheumatology; Vaccination
PubMed: 34874825
DOI: 10.55563/clinexprheumatol/0jdyse -
International Journal of Molecular... Feb 2023The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and... (Review)
Review
The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin-proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin-proteasome system but also act directly on JAKs to suppress the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor-vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.
Topics: Humans; Cell Differentiation; Cullin Proteins; Elongin; Janus Kinases; Proteasome Endopeptidase Complex; Ubiquitin; Ubiquitin-Protein Ligases; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein; Neurogenesis; Suppressor of Cytokine Signaling Proteins
PubMed: 36835292
DOI: 10.3390/ijms24043880 -
American Journal of Hematology Dec 2020
Topics: Animals; COVID-19; Humans; Janus Kinases; Lymphohistiocytosis, Hemophagocytic; Macrophages; Mice; Monocytes; Pandemics; Protein Kinase Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32918336
DOI: 10.1002/ajh.25985 -
Frontiers in Immunology 2020Many immune cells and effector molecules (e.g. cytokines, Interferons, growth factors) utilize different combinations of Janus kinase (JAK) and signal transducer and... (Review)
Review
Many immune cells and effector molecules (e.g. cytokines, Interferons, growth factors) utilize different combinations of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules to transduce signals from the cell surface to the nucleus, where they regulate transcription. This pathway is basically involved in almost all inflammatory diseases and also in the interleukin (IL)-23/IL-17 cascade, which is an essential part of the pathogenesis of spondyloarthropathies (SpA). Upon evidence from and experiments indicating disease-modifying effects of JAK inhibition in inflammatory joint disease, numerous inhibitors of the JAK/STAT pathway (= JAKinibs) with different selectivity against the four members of the JAK family [JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)] were developed. Trials in rheumatoid arthritis were successful with respect to efficacy and safety, and currently, three JAKinibs are approved for the treatment of rheumatoid arthritis in the European Union. Although new treatment options (anti-IL-23, anti-IL-17, and phosphodiesterase 4 inhibitors) have become available for spondyloarthritis and especially psoriatic arthritis (PsA) within the last years, most of them are biologics and do not address all disease manifestations equally. Therefore, multiple trials were initiated to evaluate JAKinibs in PsA and axial spondyloarthritis (axSpA). A trial of Tofacitinib (OPAL) was successful in PsA and has led to the inclusion of JAKinibs into the treatment algorithm. Currently many trials with JAKinibs are ongoing for PsA and axSpA, with one phase III trial of upadacitinib (selective JAK1 inhibitor) showing good therapeutic response in active radiographic axSpA.
Topics: Animals; Biomarkers; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Janus Kinase Inhibitors; Janus Kinases; Molecular Targeted Therapy; STAT Transcription Factors; Signal Transduction; Spondylarthropathies; Treatment Outcome
PubMed: 33193430
DOI: 10.3389/fimmu.2020.591176 -
Hematology. American Society of... Dec 2020The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) are a heterogenous group of hematopoietic stem cell diseases characterized by activated... (Review)
Review
The Philadelphia chromosome-negative (Ph-) myeloproliferative neoplasms (MPNs) are a heterogenous group of hematopoietic stem cell diseases characterized by activated JAK/STAT signaling and a variable propensity toward myelofibrotic and leukemic transformation. Acquisition of somatic mutations in addition to the canonical JAK2, MPL, and CALR mutations found in MPNs is an important catalyst in the clonal evolution and progression of these disorders. In recent years, our increasing understanding of the molecular landscape of Ph- MPNs has generated important prognostic information that informs our approach to risk stratification and therapeutic decision-making. This review will focus on the critical impact of genomics on our approach to management of advanced Ph- MPNs.
Topics: Animals; Clonal Evolution; Disease Management; Disease Progression; Genomics; Hematopoietic Stem Cell Transplantation; Humans; Janus Kinases; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Protein Kinase Inhibitors; Signal Transduction
PubMed: 33275731
DOI: 10.1182/hematology.2020000129 -
Drug Design, Development and Therapy 2022Interstitial lung disease (ILD) refers to a heterogeneous group of diseases characterized by lung fibroblast proliferation, interstitial inflammation, and... (Review)
Review
Interstitial lung disease (ILD) refers to a heterogeneous group of diseases characterized by lung fibroblast proliferation, interstitial inflammation, and fibrosis-induced lung damage. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is known to be activated by pro-fibrotic/pro-inflammatory cytokines such as IL-6 and IL-13, whose levels are elevated in ILD. The overexpression of growth factors such as transforming growth factor β1 in ILD activates the JAK/STAT pathway through classical or non-classical pathways, promotes macrophage activation, increases the release of pro-inflammatory and pro-fibrosis factors, and facilitates fibroblast differentiation into myofibroblasts. These findings implicate that the JAK/STAT pathway plays an important role in the course of ILD. Recent evidence also suggests that JAK inhibition alleviates excessive inflammation and pulmonary fibrosis. Accordingly, the JAK inhibitors may serve as promising drugs for the treatment of JAK/STAT-induced ILD.
Topics: Fibrosis; Humans; Inflammation; Janus Kinase 1; Janus Kinase 2; Janus Kinase Inhibitors; Janus Kinases; Lung Diseases, Interstitial; Pulmonary Fibrosis; STAT Transcription Factors; Signal Transduction
PubMed: 35400994
DOI: 10.2147/DDDT.S353494 -
Journal of Thrombosis and Haemostasis :... May 2023Vascular activation is characterized by increased proinflammatory, pro thrombotic, and proadhesive signaling. Several chronic and acute conditions, including...
BACKGROUND
Vascular activation is characterized by increased proinflammatory, pro thrombotic, and proadhesive signaling. Several chronic and acute conditions, including Bcr-abl-negative myeloproliferative neoplasms (MPNs), graft-vs-host disease, and COVID-19 have been noted to have increased activation of the janus kinase (JAK)-signal transducer and downstream activator of transcription (STAT) pathways. Two notable inhibitors of the JAK-STAT pathway are ruxolitinib (JAK1/2 inhibitor) and fedratinib (JAK2 inhibitor), which are currently used to treat MPN patients. However, in some conditions, it has been noted that JAK inhibitors can increase the risk of thromboembolic complications.
OBJECTIVES
We sought to define the anti-inflammatory and antithrombotic effects of JAK-STAT inhibitors in vascular endothelial cells.
METHODS
We assessed endothelial activation in the presence or absence of ruxolitinib or fedratinib by using immunoblots, immunofluorescence, qRT-PCR, and function coagulation assays. Finally, we used endothelialized microfluidics perfused with blood from normal and JAK2 individuals to evaluate whether ruxolitinib and fedratinib changed cell adhesion.
RESULTS
We found that both ruxolitinib and fedratinib reduced endothelial cell phospho-STAT1 and STAT3 signaling and attenuated nuclear phospho-NK-κB and phospho-c-Jun localization. JAK-STAT inhibition also limited secretion of proadhesive and procoagulant P-selectin and von Willebrand factor and proinflammatory IL-6. Likewise, we found that JAK-STAT inhibition reduced endothelial tissue factor and urokinase plasminogen activator expression and activity.
CONCLUSIONS
By using endothelialized microfluidics perfused with whole blood samples, we demonstrated that endothelial treatment with JAK-STAT inhibitors prevented rolling of both healthy control and JAK2 MPN leukocytes. Together, these findings demonstrate that JAK-STAT inhibitors reduce the upregulation of critical prothrombotic pathways and prevent increased leukocyte-endothelial adhesion.
Topics: Humans; Janus Kinases; Signal Transduction; Endothelial Cells; STAT Transcription Factors; COVID-19; Janus Kinase 2; Leukocytes
PubMed: 36738826
DOI: 10.1016/j.jtha.2023.01.027 -
Developmental Cell Apr 2020Epithelial-repair-dependent mucosal healing (MH) is associated with a more favorable prognosis for patients with inflammatory bowel disease (IBD). MH is accomplished via...
Epithelial-repair-dependent mucosal healing (MH) is associated with a more favorable prognosis for patients with inflammatory bowel disease (IBD). MH is accomplished via repair and regeneration of the intestinal epithelium. However, the mechanism underlying MH is ill defined. We found a striking upregulation of peroxisomes in the injured crypts of IBD patients. By increasing peroxisome levels in Drosophila midguts, we found that peroxisome elevation enhanced RAB7-dependent late endosome maturation, which then promoted stem and/or progenitor-cell differentiation via modulation of Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT)-SOX21A signaling. This in turn enhanced ISC-mediated regeneration. Importantly, RAB7 and SOX21 were upregulated in the crypts of IBD patients. Moreover, administration of drugs that increased peroxisome levels reversed the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice. This study demonstrates a peroxisome-mediated epithelial repair mechanism, which opens a therapeutic avenue for the enhancement of MH in IBD patients.
Topics: Adolescent; Adult; Animals; Cell Differentiation; Colorectal Neoplasms; Drosophila melanogaster; Female; Gene Expression Regulation; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Janus Kinases; Male; Mice; Mice, Inbred C57BL; Middle Aged; Peroxisomes; SOXB2 Transcription Factors; STAT Transcription Factors; Stem Cells; Young Adult; rab GTP-Binding Proteins; rab7 GTP-Binding Proteins
PubMed: 32243783
DOI: 10.1016/j.devcel.2020.03.002 -
Genes May 2021Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with... (Review)
Review
Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with Philadelphia-positive ALL although lacking the pathognomonic BCR-ABL1 oncoprotein. Its prevalence increases with age and similar to -positive ALL, Ph-like ALL is characterized by or other B-lymphoid transcription factor gene deletions and by poor outcome to conventional therapeutic approaches. Genetic alterations are highly heterogenous across patients and include gene fusions, sequence mutations, DNA copy number changes and cryptic rearrangements. These lesions drive constitutively active cytokine receptor and kinase signaling pathways which deregulate ABL1 or JAK signaling and more rarely other kinase-driven pathways. The presence of activated kinase alterations and cytokine receptors has led to the incorporation of targeted therapy to the chemotherapy backbone which has improved treatment outcome for this high-risk subtype. More recently, retrospective studies have shown the efficacy of immunotherapies including both antibody drug-conjugates and chimeric antigen receptor T cell therapy and as they are not dependent on a specific genetic alteration, it is likely their use will increase in prospective clinical trials. This review summarizes the genomic landscape, clinical features, diagnostic assays, and novel therapeutic approaches for patients with Ph-like ALL.
Topics: Genetic Heterogeneity; Humans; Immunotherapy; Janus Kinases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl
PubMed: 34062932
DOI: 10.3390/genes12050687 -
Hematology/oncology Clinics of North... Apr 2021Design features of phase I, II, and III clinical trials of pharmaceutical interventions in myelofibrosis (MF) are discussed. Model-assisted and model-based designs for... (Review)
Review
Design features of phase I, II, and III clinical trials of pharmaceutical interventions in myelofibrosis (MF) are discussed. Model-assisted and model-based designs for phase I trials are useful for maximizing therapeutic benefit and include novel approaches to dose escalation. Trials in MF have shifted to accommodate new challenges following approval of JAK inhibitor therapies. Standardized response criteria exist; however, alternative measures of response when evaluating newer agents may be needed. Noninferiority and other adaptive designs can be used to incorporate design changes over time. Patient-reported outcomes, including quality-of-life and symptom assessment, should be included as outcome measures.
Topics: Clinical Trials as Topic; Humans; Janus Kinases; Patient Reported Outcome Measures; Primary Myelofibrosis; Quality of Life; Research Design
PubMed: 33641878
DOI: 10.1016/j.hoc.2020.12.009