Topical Agents
John Y. M. Koo, Ethan C. Levin, Argentina Leon, Jashin J. Wu, Alice B. Gottlieb in Moderate to Severe Psoriasis, 2014
Protein tyrosine kinase inhibitors, specifically in the Janus kinase (JAK) family, have shown efficacy in the treatment of psoriasis. Tofacitinib, the most studied in this class for psoriasis, is a selective Janus kinase 3 (Jak3) inhibitor, manufactured in oral and topical forms. Tofacitinib suppresses receptors for interleukin-2 (IL-2), IL-4, IL-9, IL-15, and IL-21 and disrupts activation of helper T and cytotoxic T cells [124]. Ports et al. randomized 71 subjects to tofacitinib 20 mg/g in two different ointment formulations, compared to respective ointment vehicle alone, applied twice daily for four weeks. The two ointment formulations differed by presence or absence of a proprietary penetration enhancer. Target plaque area and itch severity improved with statistical significance in the formulation of tofacitinib with a penetration enhancer but not the other formulations or vehicles. No significant safety or tolerability limitations were identified in the study population [125]. Another JAK inhibitor, ruxolitinib, was studied in 0.5%, 1.0%, and 1.5% concentrations in a blinded comparator trial against vehicle, calcitriol alone, or betamethasone alone over 28 days. Ruxolitinib in concentrations of 1.0% and 1.5% showed improved plaque scores when compared to vehicle. Comparison between ruxolitinib and calcipotriene or betamethasone showed similar improvement, although there were not enough patients to reach statistical significance. Adverse events included redness, stinging, dryness, and irritation at the site treated [126].
Biomarkers for the Immune Checkpoint Inhibitors
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
Antitumor T cells recognize not only tumor-specific mutant peptides like neoantigens, but also cancer germline antigens (CGAs), germline proteins whose expression is typically restricted to germline cells but is upregulated in tumor cells. Tumor types harboring higher numbers of nonsynonymous somatic variants have higher response rates to immunotherapy, due to greater numbers of neoantigens [28]. In some cases of MMR deficiency, whole-exome sequencing confirmed a 20-fold-higher level of nonsynonymous mutation-associated neoantigen load compared to MMR-proficient patients; this is consistent with other reports demonstrating an association between higher mutational load and response to anti-PD-1 in NSCLC [27]. In one example, a patient with metastatic lung adenocarcinoma showed an exceptional response to atezolizumab (anti-PD-L1). Whole-exome sequencing of the patient’s tumor and blood revealedgain-of-function somatic alterations in Janus kinase 3 (JAK3) as well as germline mutations in the same allele [78]. These studies demonstrate the impact of germline mutations that can influence neoantigen formation or immune signaling and may serve as future predictors of sensitivity to immunotherapy.
Station 1: Abdominal
Saira Ghafur, Parminder K Judge, Richard Kitchen, Samuel Blows, Fiona Moss in The MRCP PACES Handbook, 2017
Tell me about PRV. This is a primary polycythaemia, due to a fault in the bone marrow. It is the result of uncontrolled proliferation of mainly red blood cells, often due to a mutation in the Janus kinase 2 (JAK2) gene. Myeloid leucocytosis, thrombocytosis and splenomegaly can also occur.PRV may present with a raised haemoglobin level on a routine blood test. It can also present with thrombosis (or more rarely, bleeding), headache, sweating and pruritus.Investigation would initially be with a full blood count. Other (secondary) causes of polycythaemia should be excluded. If PRV is suspected, JAK2 mutation testing is carried out on a blood test. Imaging (CT/ultrasound) is used to visualise the spleen. Bone marrow biopsy is helpful for diagnosis.Diagnosis is by the World Health Organiz ation (WHO) diagnostic criteria 2008.Management is targeted at lowering the risk of thrombosis. This includes venesection, aspirin and myelosuppression. JAK2 inhibitors are being introduced/under clinical trial. Management of symptoms such as pruritus should also be considered.Alongside thrombosis, a major complication of PRV is transformation to acute myeloid leukaemia.
Safety of systemic therapy for noninfectious uveitis
Published in Expert Opinion on Drug Safety, 2019
Maria Soledad Ormaechea, Muhammad Hassan, Neil Onghanseng, Jung Hyun Park, Sarakshi Mahajan, Khalid Yusuf Al-Kirwi, Gunay Uludag, Muhammad Sohail Halim, Ariel Schlaen, Yasir J Sepah, Diana V Do, Quan Dong Nguyen
Janus Kinases (JAK) are a group of tyrosine kinases involved in signal transductions of various inflammatory cytokines. They act via phosphorylation of the signal transducers and activators of transcription (STATs) [257]. Therefore, JAK inhibition can have a wide variety of anti-inflammatory effect and serves as potential therapeutic option of multiple inflammatory conditions. Filgotinib is a selective JAK-1 inhibitor that is administered orally and is converted to its active metabolite. Both the parent molecule and the metabolite contribute to the drug’s pharmacodynamics properties giving it a long half-life [257]. Filgotinib has shown efficacy in multiple systemic inflammatory disorders such as inflammatory bowel disease, ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis [258–262]. A phase 2 multicenter, randomized, placebo-controlled has recently been launched to study the role of filgotinib in patients with NIU (NCT03207815).
Therapeutic potential of JAK inhibitors in juvenile idiopathic arthritis-associated uveitis
Published in Expert Review of Clinical Immunology, 2023
Ilaria Maccora, Preston Land, Virginia Miraldi Utz, Sheila T Angeles-Han
In uveitis, dysregulated activation of the immune system leads to hyper-activation of T Cells (Th1 and Th17) and B cell subsets [7]. Studies in models of experimental autoimmune uveitis and in biospecimens such as aqueous humor and tears highlight the crucial role of Th1 and Th17 as in the development of uveitis, triggering the inflammatory cascade [7,9]. The secretion of inflammatory mediators such as cytokines (IL-6, TNF-α, interferon-gamma [IFN-γ], IL-2, and IL-17), and chemokines amplify the inflammatory cascade. Recruitment of additional inflammatory cells and increased cytokines and chemokines locally leads to a consequent breakdown of the blood retina barrier [7,8]. Cytokines and chemokines interact with their receptors resulting in receptor oligomerization with subsequent activation and phosphorylation of JAK. Subsequently, JAK phosphorylates the signal transducer and activator of transcription (STATs), a superfamily of DNA binding proteins (STAT1, 2, 3, 4, 5A, 5B, and 6) [7,8]. After phosphorylation, STAT will then dimerize and translocate to the nucleus, where it regulates the expression of specific genes critical for enhancing inflammation [7]. Different ligand and receptors activate different subtypes of JAK, which then influence inflammatory cell proliferation, development, differentiation, migration, and apoptosis [7]. In this context, Janus Kinase acts as a signaling pathway mediator for cytokines and chemokines by transducing the signals affecting and regulating the immune response6.
Micro RNA facilitated chemoresistance in gastric cancer: a novel biomarkers and potential therapeutics
Published in Alexandria Journal of Medicine, 2020
Henu Kumar Verma, Yashwant Kumar Ratre, Pellegrino Mazzone, Simona Laurino, L. V. K. S. Bhaskar
The JAK/STAT signaling cascade is one of the principal molecular signaling mechanisms such as cell growth, proliferation, differentiation, cell migration, apoptosis, inflammation, and survival of immune cells [137]. The JAK/STAT interaction is specifically concerned for a wide array of growth factors and cytokines such as IFNα, IFN-γ and IL-6 mediated signaling [138]. Janus kinase family consists of four members coding as JAK1, JAK2, JAK3, and TYK2. JAK1, JAK2, and TYK2 are ubiquitously expressed cytoplasmic non-receptor. The expression of JAK3 is only restricted to the hematopoietic cells and responsible for hematopoietic differentiation. The miRNA-375 reduced GC cell proliferation and metastasis by targeting the JAK2 gene [139]. The miRNA-135a represses p-STAT3 by targeting JAK2 thus resulting in reduced expression of cyclin D1 and Bcl-xL and suppressed GC metastasis [140]. Further, overexpression of miRNA-18a in GC which negatively regulates the expression of PIAS3, thereby resulting in increased STAT3 signaling [141]. A recent study demonstrated that the miRNA-340 affects GC cell proliferation, cell cycle blocking, and promoting apoptosis through SOCS3/JAK-STAT signaling pathway [142].
Related Knowledge Centers
- Interferon Gamma
- Interferon Type I
- Polymerase Chain Reaction
- Cytokine
- NON-Receptor Tyrosine Kinase
- Jak-Stat Signaling Pathway
- Janus Kinase 1
- Janus Kinase 2
- Janus Kinase 3
- Tyrosine Kinase 2