Search

Background: The advent of biologics and janus kinase inhibitors has revolutionized treatment of atopic dermatitis (AD). Objective: To investigate preferences of patients with AD for attributes of currently approved systemic treatments and assess influencing factors. Methods: An online discrete choice experiment was conducted in patients with AD throughout Germany to analyze preferences for outcome (probability of (almost) clear skin at week 16, probability of significant itch improvement, time to onset of itch relief and type of side effects) and process attributes (application method and frequency of laboratory tests). Results: Participants (n=182, 75.3% female) considered side effects (Relative Importance Score (RIS): 31.2), (almost) clear skin (RIS: 24.2) and probability of itch improvement (RIS: 16.0) most important. Application method (RIS: 14.4), time to onset of itch relief (RIS: 7.4) and frequency of laboratory tests (RIS: 6.8) were less relevant. Preferences were significantly influenced by sex, age, psychiatric comorbidity, current therapy and health-related quality of life according to multivariate regression analysis. Conclusions: Participants attached great importance to safety and symptom control. However, preferences were also dependent on individual characteristics, underscoring the importance of personal counseling. Conjoined with medical considerations, patients’ preferences have fundamental impact on shared decisions for treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Janus kinase 1 inhibitor upadacitinib is therapeutically effective for atopic dermatitis (AD). However, predictive factors for high responders to upadacitinib have not been established in real-world clinical practice. Objectives: To identify predictive factors for responders to upadacitinib 15mg or 30mg, defined as achievers of investigator’s global assessment (IGA) 0/1 with ≥ 2-point improvement from basal IGA. Methods: A retrospective study was conducted from August 2021 to July 2023 on 159 AD patients treated with upadacitinib 15mg and 52 patients with 30mg. Patients in each group were categorized into responders (achievers of IGA 0/1 at week 12) and non-responders (non-achievers). We compared baseline values of clinical and laboratory parameters between responders and non-responders. Logistic regression analysis was used to detect variables predicting responders. Receiver-operating characteristic curves were used for evaluating prediction capabilities of the variables. Results: In logistic regression analysis, responders to 15mg upadacitinib were associated with lower total EASI and higher age whereas responders to 30mg were associated with lower LDH and lower IgE. Conclusions: Lower total EASI and higher age may predict responders to upadacitinib 15mg while lower IgE and lower LDH may predict responders to 30mg. [ABSTRACT FROM AUTHOR]

Background: Previous clinical trials presented efficacy and safety of Janus kinase 1 inhibitor upadacitinib through 52weeks for moderate-to-severe atopic dermatitis (AD). Objectives: To assess the effectiveness and safety of upadacitinib through 48weeks in real-world clinical practice for Japanese AD patients (aged ≥12years). Methods: This retrospective study included 287 patients with moderate-to severe AD treated with 15mg (n=216) or 30mg (n=71) of upadacitinib daily. Effectiveness was assessed using eczema area severity index (EASI) scores, atopic dermatitis control tool (ADCT), peak pruritus-numerical rating scale (PP-NRS), and investigator’s global assessment (IGA). Safety was evaluated through the incidence of treatment-emergent adverse events. Results: From baseline, EASI, ADCT, PP-NRS, and IGA rapidly reduced at week 4, and the reduction was maintained until week 48 of treatment with upadacitinib at both doses. Achievement rates of EASI 75, EASI 90, and EASI 100 at week 48 were 63.5, 30.2, and 7.9 in 15mg group, and 77.4, 54.8, and 3.2% in 30mg group, respectively. Acne and herpes zoster were frequent, but no serious adverse events occurred. Conclusions: Upadacitinib was therapeutically effective and tolerable for moderate-to-severe AD through 48weeks in real-world clinical practice. [ABSTRACT FROM AUTHOR]

Background: Though Janus kinase inhibitors such as upadacitinib rapidly relieve itch in atopic dermatitis (AD) patients, how early itch relief impacts later skin clearance is not examined. Objectives: This study aims to determine if early itch relief by upadacitinib could predict complete skin clearance in later phases. Methods: This retrospective study involved 105 patients with moderate-to-severe AD treated with upadacitinib 15mg/day. Eczema area and severity index (EASI), atopic dermatitis control tool, and achievement rate of EASI 100 were evaluated at weeks 4, 12, and 24. The threshold of early peak pruritus-numerical rating scale (PP-NRS) predicting later skin clearance was assessed by area under the receiver-operating characteristic curve, and predictors for EASI 100 achievement were determined by logistic regression analysis. Results: The rate of achieving EASI 100 at week 24 was extremely higher in patients who achieved week 2 PP-NRS ≤ 1 (42.9%) than in non-achievers (1.4%). The logistic regression analysis showed that the achievement of week 2 PP-NRS ≤ 1 and low body mass index were associated with achievement of EASI 100 at weeks 12 and 24. Conclusions: The achievement of week 2 PP-NRS ≤ 1 may predict later skin clearance in upadacitinib treatment. [ABSTRACT FROM AUTHOR]

AURKA is a threonine or serine kinase that needs to be activated by TPX2, Bora and other factors. AURKA is located on chromosome 20 and is amplified or overexpressed in many human cancers, such as breast cancer. AURKA regulates some basic cellular processes, and this regulation is realized via the phosphorylation of downstream substrates. AURKA can function in either the cytoplasm or the nucleus. It can promote the transcription and expression of oncogenes together with other transcription factors in the nucleus, including FoxM1, C-Myc, and NF-κB. In addition, it also sustains carcinogenic signaling, such as N-Myc and Wnt signaling. This article will focus on the role of AURKA in the nucleus and its carcinogenic characteristics that are independent of its kinase activity to provide a theoretical explanation for mechanisms of resistance to kinase inhibitors and a reference for future research on targeted inhibitors. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Aim Materials/Methods Results Conclusion Alopecia areata is a common autoimmune disease which results in reversible hair loss. Janus kinase inhibitors are prescribed for severe alopecia areata with encouraging results. There are no studies comparing the efficacy and safety of Janus kinase inhibitors to traditional treatment options, such as topical immunomodulators and traditional immunosuppressants.To retrospectively compare the efficacy and safety of baricitinib, an approved Janus kinase inhibitor, to other treatments for severe AA during a 6‐month treatment period.We included patients with newly presenting, relapsing or treatment‐resistant alopecia areata with Severity of Alopecia Tool (SALT) score ≥ 50, for the period between July 2021 and July 2023. Medical histories were reviewed and possible side effects were recorded. Primary endpoints were SALT ≤ 20 and SALT ≤ 10 after 6 months of treatment.Seventy‐five patients (53 females) were divided into three groups: topical immunomodulators (51 patients); baricitinib (19 patients); and a group receiving pulsed intramuscular corticosteroids or traditional immunosuppressants (11 patients). Twenty‐one patients received more than one treatment options within 2 years. After 6 months, the baricitinib group showed superior efficacy with 32% and 26% of patients achieving SALT ≤ 20 and SALT ≤ 10, compared to 12% and 9% in both other groups. Baricitinib demonstrated better secondary outcomes (50% and 90% reduction from initial SALT scores). All treatments exhibited mild‐to‐moderate and expected side effects. Weight gain, which had not been reported in clinical trials for alopecia areata, was observed in three baricitinib‐treated patients.Baricitinib was superior to traditional treatments for severe alopecia areata after 6 months. Weight gain concerned 16% of patients receiving baricitinib. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the most applied targeted therapy for EGFR-mutant lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, osimertinib, is widely used throughout lung cancer treatment, with single or combination modes. One of the main barriers in osimertinib treatment is the acquired resistance and mechanisms are not fully understood. Gene expression other than genetic mutations might predict drug response and mediate resistance occurrence. We analyzed six datasets of osimertinib-resistant LUAD cells from the Gene Expression Omnibus (GEO) database and identified two hub genes, named MRAS and HEG1. We found that the expression mode of MRAS/HEG1 in LUAD was osimertinib-dependent and contributed to drug resistance. We also explored potential mechanisms of hub genes related osimertinib resistance and emphasized the M2 infiltration involved. Moreover, potential therapeutic agents conquering MRAS/HEG1-related resistance were also identified. In conclusion, MRAS and HEG1 might be responsible for osimertinib resistance and could be promising prognostic biomarkers for osimertinib response in LUAD, which might provide insights into therapeutic strategies. [ABSTRACT FROM AUTHOR]

Phosphosignaling networks control cellular processes. We built kinase-mediated regulatory networks elicited by thrombin stimulation of brain endothelial cells using two computational strategies: Temporal Pathway Synthesizer (TPS), which uses phosphoproteomics data as input, and Temporally REsolved KInase Network Generation (TREKING), which uses kinase inhibitor screens. TPS and TREKING predicted overlapping barrier-regulatory kinases connected with unique network topology. Each strategy effectively describes regulatory signaling networks and is broadly applicable across biological systems. [ABSTRACT FROM AUTHOR]

Janus kinase inhibitors (JAKis) represent a fundamental therapeutic tool for the treatment of patients with immune-mediated inflammatory diseases. Although JAKis are often considered a homogeneous class of drugs whose members are thought to be largely interchangeable, there are significant differences in their efficacy and safety profiles. This narrative review analyzes the pharmacokinetic and pharmacodynamic differences among JAKIs, highlighting their clinical relevance based on the most recent available evidence. The article aims to provide rheumatologists, gastroenterologists and dermatologists with practical guidance for choosing the most appropriate JAKi for each patient, given the lack of evidence-based recommendations on this topic, to improve clinical outcomes. Due to its preferential action on JAK1, intestinal metabolization and proven absence of impact on male fertility, filgotinib may be characterized by an improved benefit/risk ratio compared with other less selective JAKis. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is highly enriched with tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). However, effective therapeutic agents targeting tumor-associated myeloid cells in HNSCC are currently lacking. Here, we employed a unique co-culture system to investigate how HNSCC cells affect tumor-associated myeloid cells. We found that the presence of cancer cells significantly enhances myeloid cell proliferation and promotes TAM differentiation. To identify potential therapeutic agents, we screened a custom library of 70 kinase inhibitors to assess their effects on distinct subsets of tumor-associated myeloid cells. We discovered specific inhibitors that differentially suppressed the populations of TAMs, monocytic MDSCs (M-MDSCs), or polymorphonuclear MDSCs (PMN-MDSCs), suggesting that inhibiting different targets could reduce distinct subsets of tumor-associated myeloid cells. Conversely, some inhibitors were found to increase the population of CD11b+Ly6G−Ly6C− myeloid cells. Among the promising inhibitors tested, vatalanib, a VEGF-R inhibitor, demonstrated significant in vivo efficacy at inhibiting tumor growth and reducing tumor-associated myeloid cells, thereby underscoring its potential as a therapeutic agent. Our findings highlight specific kinase inhibitors with differential modulatory effects on HNSCC-associated myeloid subsets and caution the application of some as anti-cancer drugs. This experimental system may provide a robust platform for identifying new agents targeting tumor-associated myeloid cells in HNSCC and beyond, and for elucidating mechanistic insights into tumor-myeloid cell interaction. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common form of primary bone cancer, which primarily afflicts children and adolescents. Chemotherapy, consisting of doxorubicin, cisplatin and methotrexate (MAP) increased the 5-year osteosarcoma survival rate from 20% to approximately 60% by the 1980s. However, osteosarcoma survival rates have remained stagnant for several decades. Patients whose disease fails to respond to MAP receive second-line treatments such as etoposide and, in more recent years, the kinase inhibitor regorafenib. BCL-2 and its close relatives enforce cellular survival and have been implicated in the development and progression of various cancer types. BH3-mimetics antagonize pro-survival members of the BCL-2 family to directly stimulate apoptosis. These drugs have been proven to be efficacious in other cancer types, but their use in osteosarcoma has been relatively unexplored to date. We investigated the potential efficacy of BH3-mimetics against osteosarcoma cells in vitro and examined their cooperation with regorafenib in vivo. We demonstrated that osteosarcoma cell lines could be killed through inhibition of MCL-1 combined with BCL-2 or BCL-xL antagonism. Inhibition of MCL-1 also sensitized osteosarcoma cells to killing by second-line osteosarcoma treatments, particularly regorafenib. Importantly, we found that inhibition of MCL-1 with the BH3-mimetic S63845 combined with regorafenib significantly prolonged the survival of mice bearing pulmonary osteosarcoma metastases. Together, our results highlight the importance of MCL-1 in osteosarcoma cell survival and present a potential therapeutic avenue that may improve metastatic osteosarcoma patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The serine/threonine kinase 17B (STK17B) is involved in setting the threshold for T cell activation and its absence sensitizes T cells to suboptimal stimuli. Consequently, STK17B represents an attractive potential target for cancer immunotherapy. Methods: To assess the potential of STK17B as an immuno-oncology target, we developed potent and selective tool compounds from starting points in Blueprint Medicines Corporation's proprietary kinase inhibitor library. To characterize these molecules, enzyme and cellular assays for STK17A and STK17B were established to drive chemistry optimization. Mass spectrometry-based phosphoproteomics profiling with tool inhibitors led to the identification of Ser19 on myosin light chain 2 as STK17B substrate, which is then developed into a flow cytometry-based pharmacodynamic readout of STK17B inhibition both in vitro and in vivo. Results: In a mouse T cell activation assay, STK17B inhibitors demonstrated the ability to enhance interleukin-2 (IL-2) production. Similarly, treatment with STK17B inhibitors resulted in stronger cytokine secretion in human T cells activated using a T cell bispecific antibody. Subsequent chemistry optimization led to the identification of a highly selective and orally bioavailable tool compound, BLU7482. In vivo , STK17B inhibition led to dose-dependent modulation of myosin light chain 2 phosphorylation and enhanced priming of naïve T cells, as determined by upregulation of CD69, IL-2 and interferon-γ secretion. In line with increased T cell activation, treatment with STK17B inhibitor enhanced antitumor activity of anti–PD-L1 antibody in the MCA205 model. Conclusions: In summary, we successfully identified and optimized STK17B kinase inhibitors which led to increased T cell responses in vitro and in vivo. This allowed us to evaluate the potential of STK17B inhibition as an approach for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review highlights the recent advances in the development and application of dual function kinase inhibitors that also bear fluorescent properties (fluorescent kinase inhibitors), thus can be used as theranostics in the field of cancer. This is a rapidly growing field with significant potential for cancer therapy and diagnosis. This work mainly focuses on the key design principles that guide the development of these multifunctional compounds, emphasizing the integration of essential components such as the kinase cytotoxic warhead, the fluorophore, the linkers, and additional modular elements to enhance the efficacy of the final assembled compound. We anticipate this review to propel the advancement of this field by improving the understanding of the design principles and ultimately leading to the development of more effective tools for the concurrent diagnosis and treatment of cancer. Kinase inhibitors are potent therapeutic agents in cancer treatment, but their effectiveness is frequently restricted by the inability to image the tumor microenvironment. To address this constraint, kinase inhibitor–fluorophore conjugates have emerged as promising theranostic agents, allowing for simultaneous cancer diagnosis and treatment. These conjugates are gaining attention for their ability to visualize malignant tissues and concurrently enhance therapeutic interventions. This review explores the design principles governing the development of multimodal inhibitors, highlighting their potential as platforms for kinase tracking and inhibition via bioimaging. The structural aspects of constructing such theranostic agents are critically analyzed. This work could shed light on this intriguing field and provide adequate impetus for developing novel theranostic compounds based on small molecule inhibitors and fluorophores. [ABSTRACT FROM AUTHOR]

The cell cycle is driven by cyclin‐dependent kinases (Cdks). The decision whether the cell cycle proceeds is made during G1 phase, when Cdk4/6 functions. Cyclin‐dependent kinase inhibitor 2 (Cdkn2) is a specific inhibitor of Cdk4/6, and their interaction depends on D84 in Cdkn2 and R24/31 in Cdk4/6. This knowledge is based mainly on studies in mammalian cells. Here, we comprehensively analyzed Cdk4/6 and Cdkn2 in invertebrates and found that Cdk4/6 was present in most of the investigated phyla, but the distribution of Cdkn2 was rather uneven among and within the phyla. The positive charge of R24/R31 in Cdk4/6 was conserved in all analyzed species in phyla with Cdkn2. The presence of Cdkn2 and the conservation of the positive charge were statistically correlated. We also found that Cdkn2 has been tightly linked to Fas associated factor 1 (Faf1) during evolution. We discuss potential interactions between Cdkn2 and Cdk4/6 in evolution and the possible cause of the strong conservation of the microsynteny. [ABSTRACT FROM AUTHOR]

The crystal structure of the intracellular domain of transforming growth factor β type I receptor (TβR1) in complex with the competitive inhibitor SB505124 is presented. The study provides insights into the structure and function of TβR1 in complex with SB505124, and as such offers molecular‐level understanding of the inhibition of this critical signalling pathway. The potential of SB505124 as an avenue for therapy in cancer treatment is discussed on basis of the results. [ABSTRACT FROM AUTHOR]

Summary: Background: Several new treatments including small molecules and biologics have been approved for the treatment of inflammatory bowel diseases in recent years. Clinicians and patients now have a wide variety of therapeutic options to choose from and these novel therapies provide several advantages including oral administration, lower immunogenicity, better selectivity and arguably better safety profiles. An increase in treatment options has increased the complexity of decision‐making. Both patients and clinicians have had to become rapidly familiar with efficacy of new medications balanced against a range of pre‐initiation requirements, dosing schedules and adverse event profiles. Aims: To provide a simple guide to practising clinicians on recently approved and emerging therapies and address key challenges around treatment strategies such as optimal sequencing and timing of treatment. Methods: We comprehensively searched the published literature and major conference abstracts to identify phase III placebo‐controlled and active comparator trials for Crohn's disease and ulcerative colitis. Results: Data for recently approved therapies including selective Janus kinase inhibitors, sphingosine‐1 receptor modulators and p19 interleukin (IL)‐23 inhibitors have demonstrated improved patient outcomes in both Crohn's disease and ulcerative colitis. Further comparative head‐to‐head studies have improved our understanding of when and how to optimally use newer therapies, specifically for IL‐23 inhibitors. Data for emerging treatment options and novel treatment strategies such as early effective treatment, combinations of treatments and implications for sequencing are continuing to transform IBD care continually. Conclusions: Recently approved novel therapies have expanded the range of medical options available to treat IBD. However, further data from long‐term extension studies, real‐world studies and head‐to‐head trials are warranted to better inform the long‐term safety and optimal sequencing of treatments for patients living with IBD. [ABSTRACT FROM AUTHOR]

This study evaluated the in vitro effectiveness of anti-cryptosporidial agents nitazoxanide, halofuginone, the pyrazolopyridine analog KDU731, and paromomycin (PMC) in combating the significant zoonotic pathogen Cryptosporidium parvum. The study utilized HCT-8 host cells to culture C. parvum and fluorescent microscopy/quantitative PCR (qPCR) for detecting parasitic growth. The efficacy of the compounds was assessed by calculating their inhibitory concentrations (IC) against the total growth of C. parvum at 48 h post-infection. The study further investigated the impact of these compounds on early parasitophorous vacuole (PV) formation, merozoite egress, host cell viability, and cell growth cycle. KDU731 displayed the most promising profile, with low nanomolar (102 nM ± 2.28) activity and negligible host cell toxicity. This study offers new insights into the relative efficacy and safety of various anti-cryptosporidial compounds, highlighting their stage-specific effects on C. parvum and the consequential impacts on host cells. Identifying safe and effective anti-cryptosporidial agents contributes significantly to the One Health approach, which emphasizes the importance of integrated strategies in controlling zoonotic diseases. [ABSTRACT FROM AUTHOR]

Structure-based virtual screening (SBVS) is a crucial computational approach in drug discovery, but its performance is sensitive to structural variations. Kinases, which are major drug targets, exemplify this challenge due to active site conformational changes caused by different inhibitor types. Most experimentally determined kinase structures have the DFGin state, potentially biasing SBVS towards type I inhibitors and limiting the discovery of diverse scaffolds. We introduce a multi-state modeling (MSM) protocol for AlphaFold2 (AF2) kinase structures using state-specific templates to address these challenges. Our comprehensive benchmarks evaluate predicted model qualities, binding pose prediction accuracy, and hit compound identification through ensemble SBVS. Results demonstrate that MSM models exhibit comparable or improved structural accuracy compared to standard AF2 models, enhancing pose prediction accuracy and effectively capturing kinase-ligand interactions. In virtual screening experiments, our MSM approach consistently outperforms standard AF2 and AF3 modeling, particularly in identifying diverse hit compounds. This study highlights the potential of MSM in broadening kinase inhibitor discovery by facilitating the identification of chemically diverse inhibitors, offering a promising solution to the structural bias problem in kinase-targeted drug discovery. [ABSTRACT FROM AUTHOR]

We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study, we synthesized and tested radically altered IMT isomers (IMTi's) that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization. [ABSTRACT FROM AUTHOR]

Pim-1 kinase, a serine/threonine kinase, is often overexpressed in various cancers, contributing to disease progression and poor prognosis. In this study, we explored the potential of flavonoids as inhibitors of Pim-1 kinase using a combination of molecular docking and steered molecular dynamics (SMD) simulations. Our docking studies revealed two main binding orientations for the flavonoid molecules. The SMD simulations showed that the binding mode with higher pulling forces was linked to stronger inhibitory activity, with a strong positive correlation (R2 = 0.92) between pulling forces and IC50 values. Quercetin stood out as the most potent inhibitor, showing a pulling force of about 820 pN and an IC_(5) 0 of less than 6 µM. Further dynamic simulations indicated that quercetin's hydroxyl groups at the C3, C-5 and C-7 positions formed stable hydrogen bonds with key residues GLU-121, Leu-44 and Val-126, respectively enhancing its binding stability and effectiveness. Our results emphasized the critical role of the hydroxyl group at the C-3 position, which plays a pivotal function in effectively anchoring these molecules in the active site of Pim-1 kinase. Principal component analysis (PCA) of Pim-1 kinase's conformational changes revealed that potent inhibitors like quercetin, galangin, and kaempferol significantly restricted the enzyme's flexibility, suggesting potential inhibitory effect. These findings provide insights into the structural interactions between flavonoids and Pim-1 kinase, offering a foundation for future experimental investigations. However, further studies, including in vitro and in vivo validation, are necessary to assess the pharmacological relevance and specificity of flavonoids in cancer therapy. [ABSTRACT FROM AUTHOR]

The protein kinases DYRK1A and DYRK1B are pivotal regulators of cell cycle progression by promoting cell cycle exit into quiescence. DYRK1B appears to play a more important role in cancer cell quiescence than DYRK1A, as evidenced by its overexpression or copy number variations in human tumour samples. Nonetheless, the stimuli driving DYRK1B upregulation and the potential divergence in expression patterns between DYRK1A and DYRK1B remain largely elusive. In the present study, we scrutinized the regulatory pathways modulating DYRK1B expression relative to DYRK1A in PANC-1 and A549 cancer cell lines across varying conditions. Serum deprivation, pharmacological mTOR inhibition and increased cell density resulted in the differential upregulation of DYRK1B compared to DYRK1A. We then aimed to assess the role of protein kinases MST1 and MST2, which are key transmitters of cell density dependent effects. Unexpectedly, exposure to the MST1/2 inhibitor XMU-MP-1 resulted in increased DYRK1B levels in A549 cells. Further investigation into the off-target effects of XMU-MP-1 unveiled the inhibition of Aurora kinases (AURKA and AURKB) as a potential causative factor. Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases. [ABSTRACT FROM AUTHOR]

Background: The treatment of head and neck tumors remains a challenge due to their reduced radiosensitivity. Small molecule kinase inhibitors (smKI) that inhibit the DNA damage response, may increase the radiosensitivity of tumor cells. However, little is known about how the immunophenotype of the tumor cells is modulated thereby. Therefore, we investigated whether the combination of ATM or ATR inhibitors with hypo-fractionated radiotherapy (RT) has a different impact on the expression of immune checkpoint markers (extrinsic), the release of cytokines or the transcriptome (intrinsic) of head and neck squamous cell carcinoma (HNSCC) cells. Methods: The toxic and immunogenic effects of the smKI AZD0156 (ATMi) and VE-822 (ATRi) in combination with a hypo-fractionated scheme of 2x5Gy RT on HPV-negative (HSC4, Cal-33) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC cell lines were analyzed as follows: cell death (necrosis, apoptosis; detected by AnxV/PI), expression of immunostimulatory (ICOS-L, OX40-L, TNFSFR9, CD70) and immunosuppressive (PD-L1, PD-L2, HVEM) checkpoint marker using flow cytometry; the release of cytokines using multiplex ELISA and the gene expression of Cal-33 on mRNA level 48 h post-RT. Results: Cell death was mainly induced by the combination of RT with both inhibitors, but stronger with ATRi. Further, the immune phenotype of cancer cells, not dying from combination therapy itself, is altered predominantly by RT+ATRi in an immune-stimulatory manner by the up-regulation of ICOS-L. However, the analysis of secreted cytokines after treatment of HNSCC cell lines revealed an ambivalent influence of both inhibitors, as we observed the intensified secretion of IL-6 and IL-8 after RT+ATRi. These findings were confirmed by RNAseq analysis and further the stronger immune-suppressive character of RT+ATMi was enlightened. We detected the down-regulation of a central protein of cytoplasmatic sensing pathways of nucleic acids, RIG-1, and found one immune-suppressive target, EDIL3, strongly up-regulated by RT+ATMi. Conclusion: Independent of a restrictive toxicity, the combination of RT + either ATMi or ATRi leads to comprehensive and immune-modulating alterations in HNSCC. This includes pro-inflammatory signaling induced by RT + ATRi but also anti-inflammatory signals. These findings were confirmed by RNAseq analysis, which further highlighted the immune-suppressive nature of RT + ATMi. [ABSTRACT FROM AUTHOR]

Background: Inorganic polyphosphate (polyP)-targeted polyphosphate kinase 1 (PPK1) has attracted much attention by virtue of its importance in bacterial pathogenicity and persistence, as well as its exclusive presence in microorganisms. However, only very few drugs have been found to be efficacious in inhibiting the Acinetobacter baumannii (A. baumannii) PPK1 protein. Results: In this study, we identified Scutellarein (Scu), a potent PPK1 inhibitor that could significantly influence PPK1-regulated motility, biofilm formation, and bacterial persistence, which was further validated by the results of transcriptome analysis. Mechanistic explorations revealed that Scu achieved its enzyme inhibitory activity predominantly through direct engagement with the active center of PPK1. Moreover, the survival rate of Galleria mellonella larvae was increased by about 35% with 20 mg/kg of Scu treatment. The remarkable therapeutic benefits of Scu were also observed in the mouse pneumonia model, shown mainly by reduced bacterial colonization, pathological lesions, and inflammatory factors. Conclusion: Our results revealed that Scu could attenuate the pathogenicity and persistence of A. baumannii by interfering with its important kinase PPK1. [ABSTRACT FROM AUTHOR]

Acute severe ulcerative colitis (ASUC) is a medical emergency that affects approximately 25% of patients with ulcerative colitis at some point in time in their lives. Outcomes of ASUC are highly variable. Approximately 30% of patients do not respond to corticosteroids and up to 50% of patients do not respond to rescue therapy (infliximab or cyclosporin) and require emergency colectomy. Data are emerging on infliximab dosing strategies, use of cyclosporin as a bridge to slower acting biologic agents and Janus kinase inhibition as primary and sequential therapy. In this review, we outline contemporary approaches to clinical management of ASUC in the setting of failure to respond to traditional rescue therapies. [ABSTRACT FROM AUTHOR]

Because host kinases are key regulators of multiple signaling pathways in response to viral infections, we previously screened a kinase inhibitor library using rhabdomyosarcoma cells and human intestinal organoids in parallel to identify potent inhibitors against EV-A71 infection. We found that Rho-associated coiled-coil-containing protein kinase (Rock) inhibitor efficiently suppressed the EV-A71 replication and further revealed Rock1 as a novel EV-A71 host factor. In this study, subsequent analysis found that a variety of vascular endothelial growth factor receptor (VEGFR) inhibitors also had potent antiviral effects. Among the hits, Pazopanib, with a selectivity index as high as 254, which was even higher than that of Pirodavir, a potent broad-spectrum picornavirus inhibitor targeting viral capsid protein VP1, was selected for further analysis. We demonstrated that Pazopanib not only efficiently suppressed the replication of EV-A71 in a dose-dependent manner, but also exhibited broad-spectrum anti-enterovirus activity. Mechanistically, Pazopanib probably induces alterations in host cells, thereby impeding viral genome replication and transcription. Notably, VEGFR2 knockdown and overexpression suppressed and facilitated EV-A71 replication, respectively, indicating that VEGFR2 is a novel host dependency factor for EV-A71 replication. Transcriptome analysis further proved that VEGFR2 potentially plays a crucial role in combating EV-A71 infection through the TSAd-Src-PI3K-Akt pathway. These findings expand the range of potential antiviral candidates of anti-enterovirus therapeutics and suggest that VEGFR2 may be a key host factor involved in EV-A71 replication, making it a potential target for the development of anti-enterovirus therapeutics. [ABSTRACT FROM AUTHOR]

Introduction: Rapid progress made in the management of atopic dermatitis (AD) in recent years and the differences in patient journey between Asian and non-Asian populations call for a review of current atopic dermatitis landscape in Asia. Methods: A roundtable meeting with nine regional dermatological experts was held in June 2023 to discuss the optimal management approaches for moderate-to-severe AD, focusing on the use of advanced therapies. Results: Disease burden on patients' quality of life, treatment adherence, and financial constraints were identified as major concerns when managing patients with moderate-to-severe AD in parts of Asia. It was agreed that the Hanifin and Rajka's criteria or the UK Working Party's Diagnostic Criteria for Atopic Dermatitis can be used to guide the clinical diagnosis of AD. Meanwhile, patient-reported outcome scales including the Dermatology Life Quality Index and Atopic Dermatitis Control Tool can be used alongside depression monitoring scales to monitor treatment outcomes in patients with AD, allowing a better understanding for individualized treatment. When managing moderate-to-severe AD, phototherapy should be attempted after failure with topical treatments, followed by conventional disease-modifying antirheumatic drugs and, subsequently, biologics or Janus kinase inhibitors. Systemic corticosteroids can be used as short-term therapy for acute flares. Although these advanced treatments are known to be effective, physicians have to take into consideration safety concerns and limitations when prescribing these treatments. Conclusions: Treatments in AD have evolved and its management varies country by country. Unique challenges across Asian countries necessitate a different management approach in Asian patients with AD. [ABSTRACT FROM AUTHOR]

Canine malignant melanoma (CMM) is highly aggressive and mostly located in the oral cavity. CMM is the predominant type of canine oral malignancy and shows striking homologies with human mucosal melanoma. In comparative oncology, canine oral melanomas (COMs), as spontaneous tumor models, have the potential to acquire a unique value as a translational model of rare human melanoma subtypes. This review aims to provide a comprehensive summary of targeted therapies for canine malignant melanoma and to enrich the field of comparative oncology. Following the PRISMA guidelines, a comprehensive literature search was conducted across databases for studies from 1976 to April 2024. Studies were selected based on their relevance to targeted treatments. A total of 30 studies met the inclusion criteria. Based on the treatment approaches, the studies were further categorized into immunotherapies, small molecule signaling inhibitors, indirect kinase inhibitors, and other alternative strategies. Some treatments have been shown to result in stable disease or partial response, accounting for 29% (monoclonal antibody) and 76.5% (micro-RNA therapies) in clinical trials. Moreover, in vitro experiments of small molecule inhibitors, including cell signaling inhibitors and indirect kinase inhibitors, have shown the potential to be an effective treatment option for the development of therapeutic strategies in canine malignant melanoma. The observed response in in vitro experiments of CMM (particularly the oral and certain cutaneous subtypes) to drugs used in the treatment of human melanoma underlines the resemblance to human melanoma, therefore supporting the notion that CMM may be a valuable model for understanding rare human melanoma subtypes and exploring potential therapeutic avenues in preclinical trials. Finally, this literature review serves as a valuable resource for the development of therapeutic strategies for CMM and highlights the potential for translating these findings to human cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: Clinical remission is the main target in the management of patients with rheumatoid arthritis (RA). However, several authors found synovitis in patients with RA in clinical remission at ultrasonography (US). Upadacitinib is a selective Janus kinase 1 inhibitor that achieved significantly higher remission rates than adalimumab and abatacept in patients with RA. Here we present the 24-week data of the UPAdacitinib Rheumatoid Arthritis REmission UltraSonography (UPARAREMUS) study. Methods: This is a longitudinal multicenter observational study, enrolling bio-naïve and bio-inadequate responder patients affected by RA. The primary endpoint was the proportion of patients achieving both clinical and US remission at week 24. The proportion of patients achieving clinical remission with different composite indexes at week 12 and 24 was also evaluated. US of four target joints (wrists and second metacarpophalangeal bilaterally) was performed at baseline and weeks 12/24, and US remission was defined as the absence of power Doppler (PD) signal ≥ 2 in one target joint, or PD ≥ 1 in two target joints. Results: After 12 weeks and 24 weeks, 40% and 63.6% of patients achieved US plus clinical remission. The following parameters were associated with US plus clinical remission: being bio-naïve and having a shorter disease duration, although at multivariate analysis significant odds ratio (OR) was found only for being bio-naïve. Conclusions: UPARAREMUS is the first study evaluating the efficacy of upadacitinib in reaching both clinical and US remission in patients with RA. At 24 weeks, 63.6% of patients reached the primary endpoint, the only baseline associated parameter was being bio-naïve. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) is known for its oncogenic activities in diverse cancers, including non-small cell lung cancer (NSCLC). However, the prevalence of HER2 alterations in Malaysian NSCLC patients remains unreported. This study examined the prevalence and characteristics of HER2 mutations and amplification in a Malaysian cohort. Additionally, a systematic review was conducted to evaluate the global prevalence of HER2 alterations in NSCLC, as well as the efficacy of HER2-targeted therapies observed in clinical trials. NSCLC tumour samples received from October 2019 to December 2022 for next-generation sequencing diagnostics were included in the retrospective analysis. In this patient cohort, HER2 alteration was present in 5.8% of patients; 3.9% had HER2 mutations, 1.5% had HER2 amplifications and 0.4% were both HER2-mutated and amplified. HER2 exon 20 insertions were the most common HER2 variants, detected in 47/59 (79.7%) of HER2-mutated patients. Among cases with HER2 exon 20 insertions, the Y772_A775dup variant was found in 34 patient samples. HER2-mutated patients were significantly younger than non-HER2-mutants (61 versus 64 years old; p = 0.046) and were inclined to be female and never-smokers, albeit not statistically significant. Patients with HER2 amplification were more likely to have progressed post-tyrosine kinase inhibitor therapy (p = 0.015). The systematic review highlighted a global variation in the prevalence of HER2 alterations in NSCLC, ranging from 0.3% to 9.1% for mutations and 0.2% to 19% for amplification. Finally, phase II clinical trials involving HER2-altered NSCLC patients demonstrated promising treatment outcomes with trastuzumab deruxtecan, trastuzumab emtansine, pyrotinib, pyrotinib + apatinib and trastuzumab + pertuzumab + docetaxel. In conclusion, the prevalence of HER2 alteration among Malaysian NSCLC patients falls within the global range. A systematic review of clinical trials revealed promising treatment outcomes and Malaysian NSCLC patients with HER2 alterations are anticipated to similarly benefit from HER2-targeted therapies. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, with an unknown etiology and a multifactorial pathophysiology characterized by protein misfolding, neuroinflammation, and neuronal loss. There are three well-discussed main hypotheses for the pathophysiology of AD, which are related to i) the accumulation of amyloid β (Aβ) protein aggregates in the extracellular space, ii) deposition of hyperphosphorylated tau fragments as neurofibrillary tangles, and iii) dysregulation of hemostasis of some neurotransmitters involved in the disease, such as acetylcholine (ACh) and glutamate. The association of all these factors is responsible for installing oxidative stress and neuroinflammation, which contribute to progressive neuronal death in specific brain regions. More recently, other remarkable pathological characteristics have been described, involving changes in all levels of cellular components, especially in the action and function of protein kinases. These enzymes are crucial for cellular regulation since they play a pivotal role in the phosphorylation of protein substrates by transferring a phosphate group from the ATP molecule to threonine, serine, or tyrosine residues. In more recent studies, some kinases have been especially reported by their role in inflammatory and oxidative processes associated to AD, such as cAMP-dependent protein kinase A (PKA), cyclin-dependent protein kinase 5 (CDK5), glycogen synthase kinase 3β (GSK-3β), and the microtubule affinity regulatory kinases (MARKs). Under homeostatic conditions, protein kinases act as cellular signals, directing physiological responses, but in AD pathogenesis, these enzymes have an exacerbated activity in the brain, justifying the need for a better comprehension of their function and role, and how new kinase inhibitors could lead to innovative drugs. In this context, this brief review aimed to compile the literature data related to the most recent efforts and strategies in Medicinal Chemistry in the discovery of new kinase inhibitors, opening new ways to AD therapeutics.

Abstract The protein kinases DYRK1A and DYRK1B are pivotal regulators of cell cycle progression by promoting cell cycle exit into quiescence. DYRK1B appears to play a more important role in cancer cell quiescence than DYRK1A, as evidenced by its overexpression or copy number variations in human tumour samples. Nonetheless, the stimuli driving DYRK1B upregulation and the potential divergence in expression patterns between DYRK1A and DYRK1B remain largely elusive. In the present study, we scrutinized the regulatory pathways modulating DYRK1B expression relative to DYRK1A in PANC-1 and A549 cancer cell lines across varying conditions. Serum deprivation, pharmacological mTOR inhibition and increased cell density resulted in the differential upregulation of DYRK1B compared to DYRK1A. We then aimed to assess the role of protein kinases MST1 and MST2, which are key transmitters of cell density dependent effects. Unexpectedly, exposure to the MST1/2 inhibitor XMU-MP-1 resulted in increased DYRK1B levels in A549 cells. Further investigation into the off-target effects of XMU-MP-1 unveiled the inhibition of Aurora kinases (AURKA and AURKB) as a potential causative factor. Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases.

There is an urgent need to fully understand the biology of third generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs), particularly osimertinib, and to develop mechanism‐driven strategies to manage their acquired resistance. Transient receptor potential melastatin‐2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR‐TKIs and acquired resistance to EGFR‐TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR‐TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy‐optimized TRPM2 inhibitors. [ABSTRACT FROM AUTHOR]

Background: Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. Methods: Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b+, CD68+, and CD11b+/CD68+ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. Results: Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1+/CD68+ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b+, CD68+, and CD11b+/CD68+ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1β, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. Conclusion: Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma. [ABSTRACT FROM AUTHOR]

Pulmonary mucoepidermoid carcinoma (PMEC) is a rare tumor with limited clinical data available due to its low incidence. So far, there are no universal treatment guidelines for this malignant tumor. We present here the case of a 59-year-old female never smoker who was initially referred to our hospital with cough and hemoptysis and was eventually diagnosed with PMEC. Based on further genetic testing, echinoderm microtubule-associated protein-like-4-anaplastic lymphoma kinase (EML4-ALK) fusion variants E20:A20 (V2) was found. The patient was treated with lorlatinib as the first-line treatment. This case is the first to describe the effectiveness of lorlatinib in treating an advanced high-grade PMEC with EML4-ALK fusion V2 mutation patient. [ABSTRACT FROM AUTHOR]

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis associated with substantial morbidity and mortality. The therapeutic landscape for MF has advanced with the development of Janus kinase inhibitors (JAKis) like ruxolitinib (RUX), fedratinib (FED), pacritinib (PAC), and momelotinib (MMB), aiming to alleviate symptoms and enhance patient comfort. Methods: A network meta-analysis was conducted to assess the efficacy and safety of eleven JAKi treatment regimens across nine randomized controlled trials (RCTs) with a total of 2340 participants. Outcomes were evaluated in terms of spleen volume reduction (SVR), total symptom score reduction (TSSR), hematological safety profiles, and overall survival (OS). Results: RUX and MMB were superior in achieving SVR and TSSR, with significant dose-response relationships observed. PAC and MMB were associated with a decreased risk of grade 3/4 anemia and thrombocytopenia compared to other JAKis. However, no substantial benefits in OS were observed with newer JAKis compared to RUX. The poorer OS outcomes with certain PAC dosages were likely influenced by baseline patient characteristics, particularly severe cytopenias. Conclusion: The introduction of JAKis significantly changed the treatment of MF. This meta-analysis reaffirms the core role of RUX and positions MMB as a potentially powerful alternative for treating symptoms and reducing spleen size. Meanwhile, MMB and PAC have a positive effect on anemia in MF while FED is more tolerable for patients with thrombocytopenia. However, it should be noted that these results are influenced by baseline patient characteristics, particularly cytopenias, which affects both management and overall survival. Therefore, there is an urgent need for personalized dosing strategies to optimize the balance between efficacy and safety, with careful consideration of patientspecific factors. [ABSTRACT FROM AUTHOR]

Advancements in human-engineered heart tissue have enhanced the understanding of cardiac cellular alteration. Nevertheless, a human model simulating pathological remodeling following myocardial infarction for therapeutic development remains essential. Here we develop an engineered model of myocardial repair that replicates the phased remodeling process, including hypoxic stress, fibrosis, and electrophysiological dysfunction. Transcriptomic analysis identifies nine critical signaling pathways related to cellular fate transitions, leading to the evaluation of seventeen modulators for their therapeutic potential in a mini-repair model. A scoring system quantitatively evaluates the restoration of abnormal electrophysiology, demonstrating that the phased combination of TGFβ inhibitor SB431542, Rho kinase inhibitor Y27632, and WNT activator CHIR99021 yields enhanced functional restoration compared to single factor treatments in both engineered and mouse myocardial infarction model. This engineered heart tissue repair model effectively captures the phased remodeling following myocardial infarction, providing a crucial platform for discovering therapeutic targets for ischemic heart disease. Engineered human models of hearts are needed to study pathology and repair. Here, the authors develop a model which replicates the phased remodelling process. The model is then used to study signalling pathway modulators for their therapeutic potential in a mini-repair model. [ABSTRACT FROM AUTHOR]

NXP900 is a selective and potent SRC family kinase (SFK) inhibitor, currently being dosed in a phase 1 clinical trial, that locks SRC in the “closed” conformation, thereby inhibiting both kinase-dependent catalytic activity and kinaseindependent functions. In contrast, several multi-targeted kinase inhibitors that inhibit SRC, including dasatinib and bosutinib, bind their target in the active “open” conformation, allowing SRC and other SFKs to act as a scaffold to promote tumorigenesis through non-catalytic functions. NXP900 exhibits a unique target selectivity profile with sub-nanomolar activity against SFK members over other kinases. This results in highly potent and specific SFK pathway inhibition. Here, we demonstrate that esophageal squamous cell carcinomas and head and neck squamous cell carcinomas are exquisitely sensitive to NXP900 treatment in cell culture and in vivo, and we identify a patient population that could benefit from treatment with NXP900. [ABSTRACT FROM AUTHOR]

Background and Objective: Adult-onset Still's disease (AOSD) is a recognized autoinflammatory disorder of unknown etiology. The standard initial management for AOSD includes conventional corticosteroids and disease-modifying antirheumatic drugs. In cases that are resistant to these treatments, additional therapeutic options such as immunosuppressants, biologics, and other alternative treatments may be considered. Yet, a significant proportion of patients remain unresponsive to these therapeutic interventions. Herein, a case is reported involving a patient with AOSD who had persistent pruritic lesions that did not respond to conventional therapy, but were alleviated with Janus kinase inhibitors (JAKi), namely baricitinib and upadacitinib. The objective is to expand the number of refractory AOSD cases treated with JAKi in clinical practice. Another aim is to offer potentially effective therapeutic options for AOSD patients who experience persistent pruritus. Methods: A case was reported involving AOSD characterized by persistent pruritic lesions that failed to respond to conventional treatment, but showed favorable outcomes with JAKi therapy. An analysis of the PubMed literature was performed to assess the medication's efficacy and explore possible mechanisms. Results: The present case study is one of the few documented instances exploring the use of JAKi for treating AOSD, aligning with previously published research. After initiating JAKi therapy, the patient exhibited significant improvement in symptoms, most notably a reduction in persistent pruritus. Additionally, there was a substantial decrease in the patient's glucocorticoid dosage. Aside from minor renal function anomalies, no adverse reactions were observed. Conclusions: The present case illustrates that JAKi can provide rapid and sustained clinical improvement in patients with AOSD, especially those who have not responded to conventional treatment, and they have the ability to alleviate persistent itching. Further investigation is needed to ascertain the precise mechanism. [ABSTRACT FROM AUTHOR]

Background and Objective: Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [14C]tinengotinib following a single oral dose in healthy subjects. Methods: Six healthy male subjects received a single oral dose of [14C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected. Phenotyping experiments were further conducted to confirm the enzymes involved in its metabolism. Results: Tinengotinib was rapidly absorbed in plasma with a time to peak drug concentration (Tmax) of 1.0–4.0 h post-dose and a long terminal half-life (t½) of 23.7 h. Blood-to-plasma radioactivity concentration ratios across timepoints ranged from 0.780 to 0.827, which indicated minimal association of radioactivity with blood cells. The mean cumulative excreted radioactivity was 99.57% of the dose, including 92.46% (68.65% as unchanged) in feces and 7.11% (0.28% as unchanged) in urine. In addition to unchanged tinengotinib, a total of 11 radioactive metabolites were identified in plasma, urine, and feces. The most abundant circulating radioactivity was the parent drug in plasma, which comprised 88.23% of the total radioactivity area under the concentration–time curve (AUC). Metabolite M410-3 was a major circulating metabolite, accounting for 5.38% of the parent drug exposure and 4.75% of the total drug-related exposure, respectively. All excreted metabolites accounted for less than 5.10% and 1.82% of the dose in feces and urine, respectively. In addition, no unique metabolites were observed in humans. Tinengotinib was metabolized mainly via CYP3A4. Conclusions: Overall, tinengotinib demonstrated a complete mass balance with limited renal excretion, no disproportionate blood metabolism, and slow elimination, primarily through the fecal route. The results of this study provide evidence to support the rational use of tinengotinib as a pharmacotherapeutic agent. Registration: ChinadrugTrials.org.cn identifier: CTR20212852. [ABSTRACT FROM AUTHOR]

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas characterised by high relapse rates and no curative treatments unless the allogeneic stem cell transplantation. The main complication in the management of this kind of malignancy is the variability that characterises the genetic and clinical features among the CTCL subtypes. JAK/STAT, MAPK/ERK, PI3K/Akt, and NF-kB are those signalling pathways that are found altered in CTCL and that are responsible for promoting both T-cell malignancy and the pro-tumorigenic microenvironment. Thus, targeting key players of these pathways can be an advantageous therapeutic option for CTCL. In this review, we aim to summarise the different approaches that precisely inhibit the kinases of each cited signalling. JAK inhibitors seem to be the most promising kinase inhibitors for CTCL. However, adverse events have been reported especially in patients with immunosuppression or an underlying autoimmune disease. More studies are needed, especially clinical trials, to investigate the benefits of these drugs for the treatment of cutaneous T-cell lymphomas. [ABSTRACT FROM AUTHOR]

Background: Building on our prior work that RNA alternative splicing modulates the druggability of kinase fusions, this study probes the clinical significance of sole reciprocal fusions. These rare genomic arrangements, despite lacking kinase domains at the DNA level, demonstrated potential RNA‐level druggability in sporadic cases from our prior research. Methods: Utilizing the large‐scale multicenter approach, we performed RNA sequencing and clinical follow‐up to evaluate a broad spectrum of kinase fusions, including ALK, ROS1, RET, BRAF, NTRK, MET, NRG1, and EGFR, in 1943 patients. Results: Our findings revealed 51 instances (2.57%) of sole reciprocal fusions, predominantly in lung (57%), colorectal (14%), and glioma (10%) cancers. Comparative analysis with an MSKCC cohort confirmed the prevalence in diverse cancer types and identified unique fusion partners and chromosomal locales. Cross‐validation through RNA‐NGS and FISH authenticated the existence of functional kinase domains in subsets including ALK, ROS1, RET, and BRAF, which correlated with positive clinical responses to targeted kinase inhibitors (KIs). Conversely, fusions involving EGFR, NRG1, and NTRK1/2/3 generated nonfunctional transcripts, suggesting the need for alternative therapeutic interventions. Conclusion: This inaugural multicenter study introduces a novel algorithm for detecting and treating sole reciprocal fusions in advanced cancers, expanding the patient population potentially amenable to KIs. [ABSTRACT FROM AUTHOR]

Atopic dermatitis often begins in infancy and follows a chronic course of exacerbations and remissions. The etiology is complex and involves numerous factors that contribute to skin barrier defect and inflammation. In the Middle East, the burden of atopic dermatitis is understudied. Epidemiological data specific to the Gulf region are scarce but reveal a prevalence of up to about 40% in the United Arab Emirates. Region-specific factors, such as the climate and the frequency of consanguineous marriages, may affect atopic dermatitis incidence, prevalence, and evolution over time. A panel of experts predominantly from the United Arab Emirates analyzed the evidence from published guidelines, and considered expert guidance and local treatment practices to develop clear recommendations for the management of atopic dermatitis in the United Arab Emirates. They encourage a systematic approach for the diagnosis and treatment, using disease severity scores and quality-of-life measurement tools. Treatment recommendations take into consideration both established therapies and the approved systemic biologics dupilumab and tralokinumab, and the Janus kinase inhibitors baricitinib, upadacitinib, and abrocitinib. [ABSTRACT FROM AUTHOR]

Background: Safety recommendations for Janus kinase inhibitors (JAKi) issued by the European Medical Agency (EMA) in 2023 could potentially influence treatment patterns for rheumatoid arthritis (RA) drugs, but little is known about the impact of these recommendations in routine clinical care. Methods: We retrospectively analyzed the German RHADAR rheumatology database for adult patients with RA and documentation of a new therapy with a JAKi, tumor necrosis factor inhibitor (TNFi), or interleukin-6 receptor inhibitor (IL-6Ri). Data were grouped into half-yearly intervals from quarter (Q)2/2020 to Q3/2023. The period from Q4/2022 to Q1/2023 immediately followed the initial EMA endorsement of Pharmacovigilance Risk Assessment Committee (PRAC) recommendations and Q2/2023-Q3/2023 immediately followed the direct healthcare provider communication (DHPC) containing the new safety JAKi recommendations. Results: Between April 1, 2020 and September 23, 2023, 3008 newly initiated therapies for TNFi (1499 [49.8%]), JAKi (1126 [37.4%]), and IL-6Ri (383 [12.7%]) were documented by the treating physicians. JAKi were increasingly used in the first two half-year periods (from 29.7% of these therapies in Q2/2020-Q3/2020 to 46.7% in Q2/2021-Q3/2021; odds ratio [OR] 2.08; p<0.001). The proportion of initiated JAKi therapies decreased significantly after the PRAC recommendations (32.9%; OR vs peak 0.56; p=0.001) and the DHPC letter (26.1%; OR vs peak 0.40; p<0.001). JAKi were more likely to be used as >3rd-line therapy in later time periods. Conclusions: This exploratory study suggests that EMA safety recommendations for JAKi influenced treatment patterns of RA patients who received JAKi in Germany. Additional studies will be needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Copyright of Ege Journal of Medicine is the property of Ege University, Faculty of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The development of acquired EGFR-TKI treatment resistance is still a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). This study aimed to investigate the role of HDAC1/FOXK1/miR-33a signaling in EGFR-TKI resistance. Methods: The expression levels of miR‐33a, HDAC1, and FOXK1 were examined using quantitative polymerase chain reaction (PCR) and bioinformatics analysis. Cell proliferation, migration, and apoptosis were explored by cell number assay, Transwell, and flow cytometry assays, respectively. After overexpression or knockdown of HDAC1, miR-33a expression in the cells, cell functions were tested. Immunoprecipitation and correlation analyses were used to evaluate the interaction between HDAC1 and FOXK1 protein. The tumor-suppressive role of miR-33a was investigated by animal experiments. Results: The suppression of miR-33a increased TKI resistance by affecting cell proliferation, migration, and apoptosis in gefitinib-resistant cells. HDAC1 is the key upstream molecule that inhibits miR-33 expression. HDAC1 upregulation increased gefitinib resistance by its binding to FOXK1 in cells to silence miR-33a expression. MiR-33a overexpression exerts tumor-suppressive effects by negatively regulating ABCB7 and p70S6K1 expression. Moreover, overexpression of miR-33a inhibited tumor growth in a xenograft nude mouse model. Conclusions: HDAC1/FOXK1 upregulation and miR-33a silencing are new mechanisms of EGFR-TKI resistance in NSCLC. [ABSTRACT FROM AUTHOR]

Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) are a class of oral targeted anticancer drugs that have been demonstrated to significantly inhibit tumor progression and improve clinical prognosis in patients diagnosed with EGFR-mutated tumors, particularly in those with non- small cell lung cancer. However, the sustained usage of EGFR-TKIs may cause potential cardiotoxicity, thus limiting their applicability. The primary objective of this review is to systematically analyze the evolving landscape of research pertaining to EGFR-TKI-induced cardiotoxicity and elucidate its underlying mechanisms, such as PI3K signaling pathway inhibition, ion channel blockade, oxidative stress, inflammatory responses, and apoptosis. Additionally, the review includes an exploration of risk assessment for cardiotoxicity induced by EGFR- TKIs, along with management and response strategies. Prospective research directions are outlined, emphasizing the need for more accurate predictors of cardiotoxicity and the development of innovative intervention strategies. In summation, this review consolidates recent research advances, illuminates the risks associated with EGFR-TKI-induced cardiac toxicity and presents crucial insights for refining clinical dosage protocols, optimizing patient management strategies, and unraveling the intricate mechanisms governing EGFR-TKI- induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to identify the safety and effectiveness of tofacitinib in patients with UC in routine clinical settings in Korea. Methods: This open-label, observational, prospective, post-marketing surveillance study was conducted at 22 hospitals in the Republic of Korea. Patients with moderate to severe active UC who received tofacitinib were included and followed up for up to 52 weeks. Tofacitinib was administered at a dosage of 10 mg twice daily for at least 8 weeks, followed by 5 or 10 mg twice daily at the investigator's discretion based on clinical evaluation according to the approved Korean label. Safety including adverse events (AEs) and effectiveness including clinical remission, clinical response, and endoscopic mucosal healing were evaluated. Safety analysis set was defined as all patients registered for this study who received at least one dose of tofacitinib according to the approved Korean label and followed up for safety data. Effectiveness analysis set included patients in the safety analysis set who were evaluated for overall effectiveness assessment and excluded patients who had received tofacitinib less than 8 weeks. Results: A total of 110 patients were enrolled, of whom 106 patients were included in the safety population. The median duration of treatment was 370 days and the treatment duration ranged from 16 to 684 days for the safety population. AEs occurred in 42 patients (39.6%). Serious AEs (SAEs) occurred in 7 patients (6.6%) and of them, there were 2 cases of serious infections. These serious infections were reported as Adverse Event of Special Interest (AESI) in this study and no other AESI were reported. There were no cases of death during the study period. Clinical remission rates were 40.0%, 46.7%, 57.6%, and 55.1% at 8, 16, 24, and 52 weeks, and clinical response rates were 77.8%, 87.9%, 56.6%, and 81.4% at each visit, respectively. Endoscopic mucosal healing rates were 58.7% at 16 weeks and 46.2% at 52 weeks. Conclusion: Tofacitinib was effective in Korean patients with moderate to severe active UC and the safety findings were consistent with the known safety profile of tofacitinib. Summary: This study confirmed the safety and effectiveness of tofacitinib in Korean patients with moderate to severe active UC in routine clinical settings. Trial registration: This study is registered in the ClinicalTrials.gov under the identifier NCT04071405, registered on 28 August 2019. [ABSTRACT FROM AUTHOR]

Vitiligo is a persistent autoimmune disease characterized by progressive depigmentation of the skin caused by the selective destruction of melanocytes. Although its etiopathogenesis remains unclear, multiple factors are involved in the development of this disease, from genetic and metabolic factors to cellular oxidative stress, melanocyte adhesion defects, and innate and adaptive immunity. This review presents a comprehensive summary of the existing knowledge on the role of different cellular mechanisms, including cytokines and chemokines interactions, in the pathogenesis of vitiligo. Although there is no definitive cure for vitiligo, notable progress has been made, and several treatments have shown favorable results. A thorough understanding of the basis of the disease uncovers promising drug targets for future research, providing clinical researchers with valuable insights for developing improved treatment options. [ABSTRACT FROM AUTHOR]

Background/Objectives: Janus kinase inhibitors (JAKis) belong to a new class of targeted oral drugs that have been added to the therapeutic arsenal for rheumatoid arthritis (RA). The aim of this study was to evaluate the efficacy and safety profiles of these four available molecules (tofacitinib, baricitinib, filgotinib, and upadacitinib) in real life. Methods: A retrospective, single-center observational study including all patients treated with JAKis for RA from 1 October 2017 to 1 December 2023. We assessed the maintenance rate at 24 months, which is an indirect reflection of the clinical and biological safety and efficacy profiles. Results: The 76 patients in our study were thus treated for the first time with anti-JAK, including 55 patients with baricitinib (BAR), 9 patients with tofacitinib (TOF), 4 patients with upadacitinib (UPA), and 8 patients with filgotinib (FIL). The majority of our patients had BAR introduced as the first intention. The therapeutic maintenance at 2 years for all our patients was 50%. The average maintenance duration was 8.6 months and was similar in all the groups. Of the 76 patients included in this study treated with Baricitinib (72.3%), 38 (50%) discontinued their treatment after two years of follow-up. Conclusions: Although this retrospective study is subject to various biases, it shows that the persistence rates of the four JAKi molecules in daily practice did not differ significantly, thus confirming the long-term efficacy of these drugs. [ABSTRACT FROM AUTHOR]

M64HCl, which has drug-like properties, is a water-soluble Focal Adhesion Kinase (FAK) activator that promotes murine mucosal healing after ischemic or NSAID-induced injury. Since M64HCl has a short plasma half-life in vivo (less than two hours), it has been administered as a continuous infusion with osmotic minipumps in previous animal studies. However, the effects of more transient exposure to M64HCl on monolayer wound closure remained unclear. Herein, we compared the effects of shorter M64HCl treatment in vitro to continuous treatment for 24 hours on monolayer wound closure. We then investigated how long FAK activation and downstream ERK1/2 activation persist after two hours of M64HCl treatment in Caco-2 cells. M64HCl concentrations immediately after washing measured by mass spectrometry confirmed that M64HCl had been completely removed from the medium while intracellular concentrations had been reduced by 95%. Three-hour and four-hour M64HCl (100 nM) treatment promoted epithelial sheet migration over 24 hours similar to continuous 24-hour exposure. 100nM M64HCl did not increase cell number. Exposing cells twice with 2-hr exposures of M64HCl during a 24-hour period had a similar effect. Both FAK inhibitor PF-573228 (10 μM) and ERK kinase (MEK) inhibitor PD98059 (20 μM) reduced basal wound closure in the absence of M64HCl, and each completely prevented any stimulation of wound closure by M64HCl. Rho kinase inhibitor Y-27632 (20 μM) stimulated Caco-2 monolayer wound closure but no further increase was seen with M64HCl in the presence of Y-27632. M64HCl (100 nM) treatment for 3 hours stimulated Rho kinase activity. M64HCl decreased F-actin in Caco-2 cells. Furthermore, a two-hour treatment with M64HCl (100 nM) stimulated sustained FAK activation and ERK1/2 activation for up to 16 and hours 24 hours, respectively. These results suggest that transient M64HCl treatment promotes prolonged intestinal epithelial monolayer wound closure by stimulating sustained activation of the FAK/ERK1/2 pathway. Such molecules may be useful to promote gastrointestinal mucosal repair even with a relatively short half-life. [ABSTRACT FROM AUTHOR]