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Introduction: Cancer treatment underwent significant changes in the last few years with the introduction of novel treatments targeting the immune system. Objectives: The objective of this review is to discuss novel anticancer drugs including kinase inhibitors, biologics and cellular therapy with CAR-T cells. Methods: Most recent research articles were extracted from PubMed using keywords such as "kinases inhibitors", "CAR-T cell therapy". Results and discussion: The number of kinase inhibitors is significantly increasing due to their demonstrated effectiveness in combination with biologics. CAR-T represented a major breakthrough in the field. Also, it focused on their mechanisms of action and the rational of their use either alone or in combination in relation to their modes of action. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest a potential link between interstitial lung diseases (ILD) and EGFR-TKI use, with proton pump inhibitors (PPIs) possibly affecting EGFR-TKI-associated ILD differently. Our objective is to use the US Food and Drug Administration Adverse Event Reporting System (FAERS) database to explore the potential link between ILD and the combination of PPIs and EGFR-TKI. Methods: A retrospective examination of adverse event reports in the FAERS database spanning from the initial quarter of 2016 and the fourth quarter of 2023 was conducted. Disproportionality analysis, generalized linear models, and adjusted multivariable logistic regression were employed to assess the occurrence of EGFR-TKI-associated ILD in non-small cell lung cancer (NSCLC) patients receiving PPIs compared to those not receiving PPIs. Results: The reporting odds ratio (ROR) for PPIs combined with EGFR-TKIs demonstrated statistical significance (ROR 1.84, 95% CI 1.54–2.19). Significant increases were noted in both additive and multiplicative models (p < 0.001), as well as in the adjusted odds ratios derived from multivariate analysis (1.77, 95% CI 1.42–2.19, p < 0.001). Stratified analysis reveals that the combination of lansoprazole or esomeprazole and EGFR-TKI was linked to an elevated risk of ILD, with a ROR of 2.37 (95% CI 1.84–3.04) and 2.90 (95% CI 2.11–3.98), respectively, surpassing the risk associated with either medication used independently. Similarly, the ROR for osimertinib or gefitinib combined with PPIs stands at 2.20 (95% CI 1.83–2.66) and 2.33 (1.35–4.02), respectively, exceeding the risk when either drug is used alone. Conclusions: Our study uncovered a heightened risk of ILD in NSCLC patients receiving certain EGFR-TKI in conjunction with specific PPIs, as opposed to EGFR-TKI monotherapy. Subsequent analysis indicates that different PPIs may elicit divergent effects on EGFR-TKI-associated ILD, with different EGFR-TKIs exhibiting distinct responses to combinations with different PPIs. Therefore, NSCLC patients undergoing such treatments should be meticulously monitored for ILD. [ABSTRACT FROM AUTHOR]

Background: Almonertinib is a third-generation EGFR-TKI, and studies on its resistance mechanisms are lacking. Cancer-associated fibroblasts (CAFs) can influence resistance to targeted therapeutics, but their role and mechanism of action in relation to almonertinib resistance are unclear. The study explored relationships among glycolysis, cancer-associated fibroblasts (CAFs), and almonertinib resistance. Methods: A dose-escalation method was used to develop the almonertinib-resistant cell line H1975AR. Hexokinase 2 (HK2) effects on almonertinib resistance were evaluated using Cell Counting Kit-8 assays, transcriptome sequencing, western blotting, real-time PCR, siRNA assays, glucose consumption, and lactate production assays. Differential gene expression analysis and siRNA assays in H1975 cells cultured with CAF-conditioned medium (H1975/CAF-CM) revealed S-phase kinase-associated protein 2 (SKP2) as a target driving the effects of HK2. The impact of almonertinib and HK2 inhibitors on H1975/CAF-CM cells was assessed using colony formation, wound healing, transwell, and flow cytometry apoptosis assays. Results: H1975AR cells displayed elevated glycolysis and HK2. Subsequently, we showed that knockdown reduced almonertinib resistance in cells. H1975/CAF-CM induced almonertinib resistance and upregulation of HK2, which was reversed by knockdown of SKP2. CAFs regulate HK2-mediated glycolysis through SKP2, promoting almonertinib resistance in NSCLC. Conclusions: CAFs regulate HK2-mediated glycolysis through SKP2, which promotes almonertinib resistance in NSCLC. [ABSTRACT FROM AUTHOR]

Kinases are attractive drug targets, but the design of highly selective kinase inhibitors remains challenging. Selectivity may be evaluated against a panel of kinases, or – preferred – in a complex proteome. Probes that allow photoaffinity-labeling of their targets can facilitate this process. Here, we report photoaffinity probes based on the imidazopyrazine scaffold, which is found in several kinase inhibitors and drugs or drug candidates. By chemical proteomics experiments, we find a range of off-targets, which vary between the different probes. In silico analysis suggests that differences between probes may be related to the size, spatial arrangement and rigidity of the imidazopyrazine and its substituent at the 1-position. Kinases are attractive drug targets, but the design of highly selective kinase inhibitors remains challenging. Here, the authors report photoaffinity probes based on the imidazopyrazine scaffold, which is found in several kinase inhibitors and drugs or drug candidates, and use proteome selectivity profiling to show the varying off-target profiles of different probes. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts the cognitive function and memory of a person. Despite the significant research efforts, the ability to completely prevent or effectively treat AD and its related dementias remains limited. Protein kinases are integral to AD pathology and represent promising targets for therapeutic intervention. Methods: A series of pyrimidine-based compounds 4-(4-(arylsulfonyl)piperazin-1-yl)-6-(thiophen-3-yl)pyrimidine derivatives (8 - 14) were synthesized and characterised. ATPase inhibition was carried out against the MARK4 enzyme. Molecular docking and molecular dynamics (MD) simulation at 500 ns was carried out against MARK4 (PDB: 5ES1). The drug-likeness feature and toxicity of the molecules were evaluated using QikProp and other tools. Results: Compounds were synthesized following a multi-step approach and characterized using multi-nuclear magnetic resonance (1H/13C-NMR) and mass spectrometry. ATPase inhibition assay of the compounds against MARK4 showed an IC50 value in the micromolar (μM) range. The results of the docking studies were consistent with the in-vitro experiments and identified (9) and (14) as the candidates with the highest affinity towards MARK4. MD simulation further supported these results, showing that the binding of ligands stabilises the target protein. Conclusion: Using experimental and theoretical approaches, we demonstrated that the reported class of pyrimidine derivatives are an excellent starting point for developing the next-generation anti-AD drugs. [ABSTRACT FROM AUTHOR]

Background and Objective: Janus kinase (Jak) inhibitors may have increased risk of thromboembolism compared to tumor necrosis factor (TNF) inhibitors. This study investigates the association between Jak inhibitor use and retinal vein occlusion. Patients and Methods: This retrospective, non-randomized cohort study used a federated health research network. Propensity-score matched risk ratios with 95% CI were calculated for central and branch retinal vein occlusion (CRVO, BRVO) in patients with immune-mediated inflammatory diseases (IMIDs) treated with Jak inhibitors versus TNF inhibitors. Results: Jak and TNF inhibitor cohorts each had 5,249 patients. Risk ratio for CRVO with Jak inhibitors (n = 11) versus TNF inhibitors (n = 18) was 0.61 [CI (0.29,1.29)]. Risk ratio for BRVO with Jak inhibitors (n = 17) compared to TNF inhibitors (n = 19) was 0.89 [CI (0.47,1.72)]. Conclusion: This study did not find evidence of increased risk of RVO with the use of Jak inhibitors compared to TNF inhibitors among patients with IMIDs, contributing to literature on Jak inhibitor safety. [Ophthalmic Surg Lasers Imaging Retina 2025;56:72–78.] [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis (PSO) and atopic dermatitis (AD) have traditionally been considered distinct diseases, respectively, mediated by T-helper 1 (Th1) and the T-helper 2 (Th2) immune pathway. In recent years, there has been a growing body of evidence highlighting an overlap between the two conditions, such as Asian AD, pediatric PSO, or "psoriasis dermatitis/PSOREMA". Moreover, psoriasis dermatitis can be induced by therapeutic interventions. For instance, anti-IL-4/IL-13 monoclonal antibodies, commonly used to treat AD, can induce psoriasiform reactions by inhibiting the Th2 pathway, thereby unmasking Th1/Th17-driven PSO. Conversely, anti-TNFα and anti-IL-17 therapies, effective for PSO, may induce eczematous reactions promoting a switch toward Th2-driven inflammation. Janus Kinase Inhibitors (JAK-i) and IL-23 antagonists may represent valid therapeutic options for managing psoriasis dermatitis. JAK-i exert broader immunomodulatory effects, inhibiting both Th1 and Th2 pathways; however, they require careful monitoring due to potential adverse events. In contrast, IL-23 antagonists specifically suppress the IL-23/IL-17 axis inhibiting the p19 subunit of IL-23 and could represent a safer option for patients with psoriasis dermatitis. Materials and Methods/Results: We present a series of five cases of psoriasis dermatitis, including both patients who had the condition from the onset and those who developed it during treatment, with tailored therapeutic strategies based on individual patient profiles, comorbidities, and the specific characteristics of their overlapping disease presentation. Conclusion: JAK-i and IL-23 antagonists are both valid therapeutic options for managing psoriasis dermatitis, but with different immunomodulatory effects and safety profiles. Future research should focus on a better understanding of the immune pathway and identifying specific biomarkers of psoriasis dermatitis, to optimize therapeutic strategies. [ABSTRACT FROM AUTHOR]

Dynamic control of signaling events requires swift regulation of receptors at an active state. By focusing on the Arabidopsis ERECTA (ER) receptor kinase, which perceives peptide ligands to control multiple developmental processes, we report a mechanism preventing inappropriate receptor activity. The ER C-terminal tail (ER_CT) functions as an autoinhibitory domain: Its removal confers higher kinase activity and hyperactivity during inflorescence and stomatal development. ER_CT is required for the binding of a receptor kinase inhibitor, BKI1, and two U-box E3 ligases, PUB30 and PUB31, that trigger activated ER to degradation through ubiquitination. We further identify ER_CT as a phosphodomain transphosphorylated by the coreceptor BAK1. The phosphorylation impacts the tail structure, likely releasing ER from autoinhibition. The phosphonull version enhances BKI1 association, whereas the phosphomimetic version promotes PUB30/31 association. Thus, ER_CT acts as an off-on-off toggle switch, facilitating the release of BKI1 inhibition, enabling signal activation, and swiftly turning over the receptors afterward. Our results elucidate a mechanism that fine-tunes receptor signaling via a phosphoswitch module, maintaining the receptor at a low basal state while ensuring robust yet transient activation upon ligand perception. [ABSTRACT FROM AUTHOR]

Reversible protein phosphorylation directs essential cellular processes including cell division, cell growth, cell death, inflammation, and differentiation. Because protein phosphorylation drives diverse diseases, kinases and phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most protein kinases are activated by phosphorylation of their activation loops, which shifts the conformational equilibrium of the kinase toward the active state. To turn off the kinase, protein phosphatases dephosphorylate these sites, but how the conformation of the dynamic activation loop contributes to dephosphorylation was not known. To answer this, we modulated the activation loop conformational equilibrium of human p38a MAP kinase with existing kinase inhibitors that bind and stabilize specific inactive activation loop conformations. From this, we identified three inhibitors that increase the rate of dephosphorylation of the activation loop phospho-threonine by the PPM serine/threonine phosphatase WIP1. Hence, these compounds are "dual-action" inhibitors that simultaneously block the active site and promote p38a dephosphorylation. Our X-ray crystal structures of phosphorylated p38a bound to the dual-action inhibitors reveal a shared flipped conformation of the activation loop with a fully accessible phospho-threonine. In contrast, our X-ray crystal structure of phosphorylated apo human p38a reveals a different activation loop conformation with an inaccessible phospho-threonine, thereby explaining the increased rate of dephosphorylation upon inhibitor binding. These findings reveal a conformational preference of phosphatases for their targets and suggest a unique approach to achieving improved potency and specificity for therapeutic kinase inhibitors. [ABSTRACT FROM AUTHOR]

Background: The study is to evaluate the efficacy and safety of combined anlotinib and EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) who had gradual, oligo, or potential progression after previous EGFR-TKIs treatment. Methods: We conducted an open-label, single-arm, multicenter, phase II trial in China. Eligible patients were 18–75 years old with histologically or cytologically confirmed NSCLC who were EGFR mutation positive and showed gradual, oligo, or potential progression after EGFR-TKIs. Anlotinib (12 mg/day) was administered orally for 2 weeks and then off 1 week in a 3-week cycle. EGFR-TKIs were continue used. The primary endpoint was progression-free survival (PFS). The secondary endpoints included 6- and 12-month PFS rate, objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From July 2019 to December 2022, 120 patients were enrolled. The median PFS (mPFS) was 9.1 months (95% CI 6.8–11.7). The PFS rates at 6 and 12 months was 68.5% and 38.8% respectively. For 86 patients with first-line 1st /2nd generation EGFR-TKIs, the mPFS was 9.2 months (95% CI 6.7–12.6). For 32 patients with first-line 3rd generation EGFR-TKIs, the mPFS was 10.3 months (95% CI 6.1–13.3). Overall ORR and DCR were 6.7% (95% CI 2.9–12.7) and 87.5% (95% CI 80.2–92.8), respectively. 52.5% of patients had grade 3 or higher treatment-emergent adverse events (TEAEs). Conclusion: Anlotinib in combination with continuation of EGFR-TKIs prolonged the clinical benefit of EGFR-TKIs, demonstrating favorable survival outcomes and manageable toxicity in NSCLC treated with EGFR-TKIs and had specific progression modes, such as gradual progression. Trial registration: NCT04007835. [ABSTRACT FROM AUTHOR]

Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2‐b]pyridine scaffold. The weak interaction of the thieno[3,2‐b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome‐wide selectivity, as illustrated by the isomers MU1464 and MU1668. Thus, this core structure provides a template of ATP‐competitive but not ATP‐mimetic inhibitors that are anchored at the kinase back pocket. Mapping the chemical space around the central thieno[3,2‐b]pyridine pharmacophore afforded highly selective inhibitors of the kinase Haspin, exemplified by the compound MU1920 that fulfils criteria for a quality chemical probe and is suitable for use in in vivo applications. However, despite the role of Haspin in mitosis, the inhibition of Haspin alone was not sufficient to elicit cytotoxic effect in cancer cells. The thieno[3,2‐b]pyridine scaffold can be used in a broader context, as a basis of inhibitors targeting other underexplored protein kinases, such as CDKLs. [ABSTRACT FROM AUTHOR]

Objective. Telecontrol approaches for rheumatoid arthritis (RA) management aim to enhance patient outcomes. This pilot study assessed whether the Rheumatoid Arthritis Impact of Disease (RAID) approach could be used during teleconsultations to monitor RA disease activity through a web-based platform called iARPlus (Innovative Approach in Rheumatology). Methods. Forty RA patients participated in two in-person visits (baseline and 12 months) and seven teleconsultations over 12 months, collected via the iARPlus portal and accessible through an internet browser. Disease activity, at baseline and follow-up, was measured using the Clinical Disease Activity Index (CDAI) and self-reported RAID scores throughout the study. The RAID approach, developed by the European Alliance of Associations for Rheumatology (EULAR), combines key patient-reported outcomes (PROs). Results. Nineteen patients (mean age: 49.3 years) were treated with Janus kinase inhibitors (JAKis), and 21 patients (mean age: 48.1 years) received adalimumab. All patients had active disease (mean CDAI 27.9 ± 4.8). Strong correlations were found between CDAI and RAID scores at baseline (ρ = 0.809, p < 0.0001) and at follow-up (ρ = 0.789, p < 0.0001). JAKi-treated patients showed greater reductions in RAID scores, pain relief, and higher rates of disease remission compared to adalimumab-treated patients. Conclusions. RAID scores were effective in teleconsultations for assessing RA disease activity. JAKi treatment resulted in better pain control and disease activity improvement compared to adalimumab. Further studies are needed to confirm the clinical and economic benefits of telecontrol for RA management. [ABSTRACT FROM AUTHOR]

Purpose: To report the long-term outcome of three refractory anterior scleritis cases successfully treated with tofacitinib, a Janus-associated kinase inhibitor. Methods: Three patients with systemic autoimmune disease-associated anterior scleritis (two with rheumatoid arthritis and one with systemic lupus erythematosus), resistant to conventional immunomodulatory therapy, were subsequently treated with tofacitinib (10 mg/day). Results: Tofacitinib resulted in complete resolution of scleritis in all patients. During the 39–78 months of follow-up, no recurrence of scleritis occurred, and no adverse effects associated with tofacitinib were noted. At the last follow-up, all patients were free of scleritis with two patients receiving tofacitinib monotherapy and one without. Conclusion: Tofacitinib can be a safe and effective treatment for noninfectious refractory scleritis, warranting further investigation in large clinical trials. [ABSTRACT FROM AUTHOR]

Background/Aim: The disruption of cell-cycle control can lead to an imbalance in cell proliferation, often accompanied by genomic instability, which in turn can facilitate carcinogenesis. This study aimed to examine the impact of CDKN1A rs1801270 and rs1059234 polymorphisms on the risk of childhood acute lymphocytic leukemia (ALL) in Taiwan. Materials and Methods: The genotypes of CDKN1A rs1801270 and rs1059234 in 266 childhood ALL cases and 266 controls were determined using PCR-RFLP techniques. Results: The genotypic and allelic frequencies for CDKN1A rs1801270 and rs1059234 did not significantly differ between childhood ALL cases and controls (all p>0.05). However, stratified analysis revealed that the CDKN1A rs1801270 AA variant was associated with a reduced risk of childhood ALL in males (OR=0.40, 95%CI=0.20-0.82, p=0.0178). Additionally, the AC and AA genotypes of rs1801270 were linked to a lower risk classification for childhood ALL and longer survival times (OR=0.57 and 0.31, 95%CI=0.33-0.97 and 0.18-0.56, p=0.0538 and 0.0001, respectively). No significant associations were found for rs1059234 in the stratified analyses (p>0.05 for all). Conclusion: Although CDKN rs1801270 and rs1059234 genotypes were not associated with an overall risk of childhood ALL, CDKN1A rs1801270 polymorphism may serve as a protective predictor in males and as a potential marker for better prognosis of childhood ALL. Validation in larger and more diverse populations is necessary to confirm the feasibility of this predictor. [ABSTRACT FROM AUTHOR]

Background: Cell cycle inhibition is an established therapeutic approach for some cancers. A multicenter, single‐arm, phase 2 trial (ClinicalTrials.gov identifier NCT00937937) of the cyclin‐dependent kinase inhibitor SCH 727965 (NSC 747135; dinaciclib) was conducted in patients with metastatic melanoma to determine its clinical activity. Methods: Patients with metastatic melanoma of cutaneous or mucosal origin were eligible if they had zero to one previous treatments, a Zubrod performance status of 0–1, and adequate organ function. SCH 727965 50 mg/m2 was given intravenously every 3 weeks until progression. Co‐primary end points were 1‐year overall survival (OS) and 6‐month progression‐free survival (PFS). Results: Seventy‐two patients were enrolled from July 1, 2009, to November 1, 2010, at 24 institutions. Sixty‐eight percent of patients had M1c disease, and 43% had elevated lactate dehydrogenase levels. Twenty‐eight patients (39%) experienced grade 4 adverse events, including 20 cases of neutropenia. Sixty‐seven patients were evaluable for response. There was a response in zero of 67 patients (95% confidence interval [CI], 0%–5%), and stable disease was observed in 21%. The estimated median PFS was 1.4 months (95% CI, 1.4–1.5 months), and the 6‐month PFS rate was 6% (2%–13%). The median OS was 8.2 months (95% CI, 5.5–10.5 months), and the 1‐year OS rate was 38% (95% CI, 26%–49%). Conclusions: This multicenter, US National Cancer Institute Cancer Therapy Evaluation Program‐sponsored trial of SCH 727965 was conducted at a time when the current generation of effective therapies for melanoma were not available. Although the null hypothesis of 1‐year OS was rejected, the minimal PFS impact and substantive toxicity indicated that this regimen lacks justification for further investigation as a single agent. A multicenter, US National Cancer Institute Cancer Therapy Evaluation Program‐sponsored, single‐arm, phase 2 trial (ClinicalTrials.gov identifier NCT00937937) of the cyclin‐dependent kinase inhibitor SCH 727965 (NSC 747135, dinaciclib) was conducted in patients with metastatic melanoma to determine its clinical activity. Dinaciclib failed to demonstrate sufficient clinical activity to justify its further investigation as a single agent. [ABSTRACT FROM AUTHOR]

Protein kinases are key regulators of numerous biological processes and aberrant kinase activity can cause various diseases, particularly cancer. Herein, we report the identification of new series of highly selective kinase inhibitors based on the thieno[3,2‐b]pyridine scaffold. The weak interaction of the thieno[3,2‐b]pyridine core with the kinase hinge region allows for profoundly different binding modes all of which maintain high kinome‐wide selectivity, as illustrated by the isomers MU1464 and MU1668. Thus, this core structure provides a template of ATP‐competitive but not ATP‐mimetic inhibitors that are anchored at the kinase back pocket. Mapping the chemical space around the central thieno[3,2‐b]pyridine pharmacophore afforded highly selective inhibitors of the kinase Haspin, exemplified by the compound MU1920 that fulfils criteria for a quality chemical probe and is suitable for use in in vivo applications. However, despite the role of Haspin in mitosis, the inhibition of Haspin alone was not sufficient to elicit cytotoxic effect in cancer cells. The thieno[3,2‐b]pyridine scaffold can be used in a broader context, as a basis of inhibitors targeting other underexplored protein kinases, such as CDKLs. [ABSTRACT FROM AUTHOR]

Background Janus kinase inhibitors (JAKi) have the potential to alter the landscape of atopic dermatitis (AD) management dramatically, owing to promising efficacy results from phase III trials and their rapid onset of action. However, JAKi are not without risk, and their use is not appropriate for all patients with AD, making this a medication class that dermatologists should understand and consider when treating patients with moderate-to-severe AD. Objectives To provide a consensus expert opinion statement from the International Eczema Council (IEC) that provides a pragmatic approach to prescribing JAKi, including choosing appropriate patients and dosing, clinical and laboratory monitoring and advice about long-term use. Methods An international cohort of authors from the IEC with expertise in JAKi selected topics of interest were placed into authorship groups covering 10 subsections. The groups performed topic-specific literature reviews, consulted up-to-date adverse event (AE) data, referred to product labels and provided analysis and expert opinion. The manuscript guidance and recommendations were reviewed by all authors, as well as the IEC Research Committee. Results We recommend that JAKi be considered for patients with moderate-to-severe AD seeking the benefits of a rapid reduction in disease burden and itch, oral administration and the potential for flexible dosing. Baseline risk factors should be assessed prior to prescribing JAKi, including increasing age, venous thromboembolisms, malignancy, cardiovascular health, kidney/liver function, pregnancy and lactation, and immunocompetence. Patients being considered for JAKi treatment should be current on vaccinations and we provide a generalized framework for laboratory monitoring, although clinicians should consult individual product labels for recommendations as there are variations among the different JAKi. Patients who achieve disease control should be maintained on the lowest possible dose, as many of the observed AEs occurred in a dose-dependent manner. Future studies are needed in patients with AD to assess the durability and safety of continuous long-term JAKi use, combination medication regimens and the effects of flexible, episodic treatment over time. Conclusions The decision to initiate JAKi treatment should be shared between the patient and provider, accounting for AD severity and personal risk–benefit assessment, including consideration of baseline health risk factors, monitoring requirements and treatment costs. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis is an infectious disease that has become endemic worldwide. The causative bacteria Mycobacterium tuberculosis (Mtb) is targeted via several exciting drug targets. One newly discovered target is the Fatty Acyl-CoA synthase, which plays a significant role in activating the long-chain fatty acids. Research design & methods: This study aims to generate novel compounds using Machine Learning (ML) algorithms to inhibit this synthase. Experimentally derived bioactive compounds were chosen from ChEMBL and used as inputs for effective molecule generation by Reinvent4. The library of new molecules generated was subjected to a two-tiered molecular docking protocol, and the results were further studied to obtain a binding free energy check. Results: The ML-based de novo drug design (DNDD) approach successfully generated a diverse library of novel molecules targeting Fatty Acyl-CoA synthase. After rigorous molecular docking and binding free energy analysis, four new compounds were identified as potential lead candidates with promising inhibitory effects on Mtb lipid metabolism. Conclusions: The study demonstrated the effectiveness of a machine-learning approach in generating novel drug candidates against Mtb. The identified hit compounds show potential as inhibitors of Fatty Acyl-CoA synthase, offering a new avenue for developing treatments for tuberculosis, particularly in combating drug-resistant strains. [ABSTRACT FROM AUTHOR]

Pterygium is an ocular disease in which the conjunctival tissue invades the cornea. When the pterygium tissue reaches the pupillary region, the visual function of the patient is affected. Currently, surgical removal is the only effective treatment. However, the recurrence rate of pterygium after surgery can be high. Pterygium is also a health disparity issue since it is more prevalent in the Hispanic and Latino American population. In this study, we determined if the Rho kinase inhibitor can be used to prevent pterygium recurrence since its anti-fibrosis effects have been reported in other cell and tissue types. We cultured primary pterygium cells from pterygium tissues from Hispanic and Latino American, African American, Caucasian, and Asian donors, and used those cells for viability assays, scratch assays, migration assays, and immunostaining of F-actin, fibronectin, collagen I and α smooth muscle actin. We found that the Rho kinase inhibitor Y27632 decreased cell viability, wound healing, cell migration, as well as the expression of extracellular matrix and myofibroblast markers in cultured pterygium cells. We believe that Rho kinase inhibitors are a potential post-surgical treatment to prevent pterygium recurrence. [ABSTRACT FROM AUTHOR]

Background: Aicardi-Goutières Syndrome is a monogenic type 1 interferonopathy with infantile onset, characterized by a variable degree of neurological damage. Approximately 7% of Aicardi-Goutières Syndrome cases are caused by pathogenic variants in the ADAR gene and are classified as Aicardi-Goutières Syndrome type 6. Here, we present a new homozygous pathogenic variant in the ADAR gene. Currently, Janus Kinase inhibitors have been proposed to treat selected interferonopathies such as Aicardi-Goutières Syndrome, although limited information is available on its use and results in the neonatal presentation of this disease. Case presentation: We present two siblings, a male neonate with congenital petechial rash, severe thrombopenia and generalized hypotonia and his deceased sister who had normal development until 5 months of age, when she suffered acute encephalopathy. We describe the clinical course, complementary examinations and follow-up with early treatment of the newborn with ruxolitinib. The homozygous variant c.2908G > A (p.Ala970Thr) in the ADAR gene was found in both siblings, parents were heterozygous carriers. Conclusions: The homozygous variant c.2908G > A (p.Ala970Thr) in the ADAR gene causes Aicardi-Goutières Syndrome type 6. Intrafamilial phenotypic spectrum of the disease varies among individuals with the same pathogenic variant. Early initiation of ruxolitinib improved systemic signs but did not prevent the progression of neurological disease. [ABSTRACT FROM AUTHOR]

The MAP2K7 signaling pathway activates the c-Jun NH2-terminal protein kinase (JNK) in response to stress signals, such as inflammatory cytokines, osmotic stress, or genomic damage. While there has been interest in inhibiting JNK due to its involvement in inflammatory processes and cancer, there is increasing focus on developing MAP2K7 inhibitors to enhance specificity when MAP2K7 activation is associated with disease progression. Despite some progress, further research is needed to fully comprehend the role of MAP2K7 in cancer and assess the potential use of kinase inhibitors in cancer therapy. This review examines the role of MAP2K7 in cancer and the development of small-molecule inhibitors. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown the impact of obesity on achieving low disease activity or remission in rheumatoid arthritis (RA) patients treated with tumor necrosis factor inhibitors. However, there is limited research on the effects of obesity on clinical responses to non-TNF-targeted treatments. Objectives: This study investigated the influence of body mass index (BMI) on clinical response to non-TNF-targeted treatments in RA patients. Design: We used data from the KOrean nationwide BIOlogics & targeted therapy (KOBIO) registry, a multicenter, prospective, observational cohort that included RA patients in South Korea. Methods: Patients who received at least one prescription for non-TNF-targeted treatments, including abatacept, tocilizumab, and Janus kinase inhibitors, were included. They were categorized into three BMI groups: under 25 kg/m2 (434 patients), between 25 and 30 kg/m2 (146 patients), and over 30 kg/m2 (22 patients). After 1 year of treatment, treatment continuation rates and clinical responses among these BMI groups were compared. Time on treatment for each category was analyzed using Kaplan–Meier curves and Cox regression, adjusting for confounders. Results: The 1-year continuation rate of the targeted treatment was significantly lower in the obese group (81.8%) compared to the normal BMI (93.8%) and overweight (89.0%) groups (p = 0.033). Disease Activity Score of 28 joints-erythrocyte sedimentation rate score improvement was less in the obese group (2.06 ± 2.14) than in the normal BMI group (2.76 ± 1.55) (p = 0.045). Multivariable Cox proportional hazard analysis showed a higher discontinuation rate in the obese group (hazard ratio: 3.407, 95% confidence interval: 1.157–10.211; p = 0.029). Conclusion: Higher BMI in RA patients was associated with poorer clinical response and higher discontinuation rates for non-TNF-targeted treatments. Plain language summary: How obesity affects treatment success in rheumatoid arthritis patients using non-TNF therapies This study looked at how body mass index (BMI) affects the success of certain rheumatoid arthritis (RA) treatments that don't target Tumor Necrosis Factor (TNF). It included patients taking abatacept, tocilizumab, and JAK kinase inhibitors. Patients were divided into three BMI groups: normal (under 25 kg/m²), overweight (25-30 kg/m²), and obese (over 30 kg/m²). We compared how well patients in these groups continued their treatment and responded clinically after one year. Our findings showed that obese patients were less likely to continue their treatment after one year (81.8%) compared to normal BMI (93.8%) and overweight (89.0%) patients. Additionally, obese patients had less improvement in their disease activity score (DAS28-ESR) compared to those with normal BMI. Further analysis indicated that obese patients were more likely to stop their treatment sooner, with a hazard ratio of 3.407, meaning they had over three times the risk of discontinuation compared to patients with normal BMI. In summary, RA patients with higher BMI had worse clinical responses and higher rates of stopping their non-TNF-targeted treatments. This suggests that obesity negatively impacts the effectiveness and continuation of these RA therapies. [ABSTRACT FROM AUTHOR]

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the latest and a vital treatment option for non-small cell lung cancer (NSCLC) patients. Although EGFR-sensitive mutations are an indication for third-generation EGFR-TKI therapy, 30% of NSCLC patients lack response and all patients inevitably progress. There is a lack of biomarkers to predict the efficacy of EGFR-TKI therapy. In this report, we performed comprehensive plasma metabolomic profiling on 186 baseline and 20 post-treatment samples, analyzing 1,019 metabolites using four ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) methods. The dataset contains detailed clinical and metabolic information for 186 patients. Rigorous quality control measures were implemented. No significant differences in body mass index and biochemical metabolic parameters were observed between responders and non-responders. The datasets were utilized to characterize the responsive metabolic traits of third-generation EGFR-TKI therapy. All datasets are available for download on the OMIX website. We anticipate that these datasets will serve as valuable resources for future studies investigating NSCLC metabolism and for the development of personalized therapeutic strategies. [ABSTRACT FROM AUTHOR]

In the era of targeted therapies, the clinical importance and utility of next-generation sequencing (NGS) has expanded significantly. Owing to the relative ease and financial feasibility of NGS, the use of personalized treatment strategies has the potential to revolutionize cancer care. In this case report, we explored the use of NGS in salivary gland carcinoma (SGC) and spindle cell neoplasm of the scalp. In our patient with SGC, NGS revealed a GPHN-ALK variant that allowed off-label treatment with alectinib, with a remarkable response in primary and metastatic foci. Similarly, the use of NGS in a cutaneous neoplasm in which no definitive diagnosis could be reached by pathology and which had progressed through standard of care treatment elucidated a PIK3CA mutation in which alpelisib was added and ultimately halted POD. Here, we discuss the use of NGS, future projections, and our recommendations. [ABSTRACT FROM AUTHOR]

Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-ΔNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-ΔNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS. [ABSTRACT FROM AUTHOR]

Introduction: Oncogenic-addicted non-small cell lung cancer (NSCLC) has emerged as the most prevalent form of lung cancer, presenting a dynamic landscape in treatment modalities. Among these, epidermal growth factor receptor (EGFR)-mutant NSCLC remains the predominant oncogenic mutation, particularly prevalent in regions such as Asia and Latin America. Case Presentation: This case study highlights the experience of a woman diagnosed with EGFR-sensitive (del exon 19) mutant NSCLC who demonstrated an extended duration of response to third-generation EGFR-tyrosine kinase inhibitor (TKI) therapy. Upon disease progression, detection of MET gene amplification prompted the addition of a selective MET inhibitor to the existing EGFR-TKI regimen, resulting in a complete response for the patient. Discussion: The molecular heterogeneity of this condition has significantly increased in complexity over recent years, marked by the identification of baseline co-alterations and development of a broad spectrum of resistance mechanisms post-EGFR-TKI therapy. This complexity poses a substantial challenge to clinicians. Despite the rapid advancement of targeted therapies and the implementation of treatment escalation through combination strategies, there remains an ongoing debate regarding which patients would benefit most from combination therapies, both in the initial treatment phase and in the setting of disease progression, particularly when off-target resistance mechanisms or co-alterations are identified. [ABSTRACT FROM AUTHOR]

A 69-year-old man with severe atopic dermatitis (AD) received a single 600 mg subcutaneous injection of dupilumab, which resulted in a psoriatic rash on day 10. He was then given 30 mg of oral upadacitinib daily, and after 10 weeks of treatment, both the AD and the psoriasis had significantly improved. However, at week 16, the patient had no bowel movement for a week, and paralytic ileus was suspected based on the patient's symptoms and laboratory findings. Without surgery or other treatment, one week after stopping upadacitinib, the patient resumed bowel movements and the ileus improved, suggesting a possible link between the drug and the ileus, which was considered to be possibly due to the off-target effect of Janus kinase inhibitor (JAKi). This case illustrates the complexity of the immunomodulatory effects of targeted therapies and the need for long-term observation of their mechanisms of action and side effects. [ABSTRACT FROM AUTHOR]

Objective: Eczema is the most burdensome skin condition worldwide and topical anti‐inflammatory treatments are commonly used to control symptoms. The relative effectiveness and safety of different topical anti‐inflammatory treatments is uncertain. Design: Network meta‐analysis performed within a Cochrane systematic review to compare and statistically rank efficacy and safety of topical anti‐inflammatory eczema treatments. Data Sources: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to June 2023. Eligibility Criteria for Selected Trials: Included trials were within‐participant or between‐participant randomised controlled trials. Participants had eczema that was not clinically infected and was not contact dermatitis, seborrheic eczema or hand eczema. Interventions were topical anti‐inflammatory treatments but not complementary treatments, antibiotics alone, wet wraps, phototherapy or systemic treatments. Comparators were no treatment/vehicle or another topical anti‐inflammatory. Results: We identified 291 trials (45,846 participants), mainly in high‐income countries. Most were industry‐funded with median 3 weeks treatment duration. Risk of bias assessed using the Cochrane Risk of Bias 2.0 tool was high in 89% of trials, mainly due to risk of selective reporting. Network meta‐analysis of binary outcomes ranked potent and/or very potent topical steroids, tacrolimus 0.1% and ruxolitinib 1.5% among the most effective treatments for improving patient‐reported symptoms (40 trials, all low confidence) and clinician‐reported signs (32 trials, all moderate confidence). For investigator global assessment, the Janus kinas inhibitors ruxolitinib 1.5%, delgocitinib 0.5% or 0.25%, very potent/potent topical steroids and tacrolimus 0.1% were ranked as most effective (140 trials, all moderate confidence). Continuous outcome data were mixed. Local application site reactions were most common with tacrolimus 0.1% (moderate confidence) and crisaborole 2% (high confidence) and least common with topical steroids (moderate confidence). Skin thinning was not increased with short‐term use of any topical steroid potency (low confidence) but skin thinning was reported in 6/2044 (0.3%) participants treated with longer‐term (6–60 months) topical steroids. Conclusion: Potent topical steroids, Janus kinase inhibitors and tacrolimus 0.1% were consistently ranked as among the most effective topical anti‐inflammatory treatments for eczema. [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]

Prostate, breast, and lung cancers are various human cancers that have been associated with SRC kinase mutations. Therefore, the development of potent and selective SRC kinase inhibitors is an exciting area of interest for researchers. In this study, we synthesized a series of 2-amino-4H-1-benzopyran-4-yl phosphonate derivatives through a one-pot reaction involving appropriately substituted salicylaldehydes, malononitrile, and diethyl phosphite, with meglumine as the catalyst. We conducted in vitro screening of these compounds for their anticancer activity against human prostate cancer (DU-145), breast cancer (MCF-7), and lung cancer (A549) cell lines using the MTT assay. Notably, compounds 4a, 4j, 4k, and 4l exhibited promising anticancer activity. Molecular docking studies of these compounds supported their potential as therapeutic agents for SRC kinase inhibition. Specifically, compounds 4a, 4b, 4c, 4d, and 4e demonstrated strong ΔG binding affinities ranging from −7.9 to −7.4 kcal/mol. These findings suggest that these molecules hold promise for cancer treatment. [ABSTRACT FROM AUTHOR]

MEN1703 is a first‐in‐class, oral, Type I dual PIM/FMS‐like tyrosine kinase 3 inhibitor (FLT3i) investigated in a Phase I/II DIAMOND‐01 trial in patients with acute myeloid leukaemia (AML). Gilteritinib is a highly potent and selective oral FLT3i approved for the treatment of relapsed/refractory AML with FLT3 mutations. Although gilteritinib showed strong single‐agent activity in FLT3‐mutated AML, the development of gilteritinib resistance limits response durability, indicating the importance of novel combination strategies to improve disease outcome. PIM kinases govern FLT3‐ITD signalling and increased PIM kinase expression is found in samples from AML patients relapsing on FLT3i. Here, we report that the simultaneous inhibition of PIM and FLT3, through the combination of MEN1703 and gilteritinib, can consistently improve the in vitro/in vivo antitumor activity over the single agents, demonstrating the benefit of this combination. Moreover, we demonstrate that resistance to gilteritinib can be circumvented by combining MEN1703 with gilteritinib. MEN1703 interferes with FLT3 upregulation, Mcl‐1 overexpression and PIM kinase signalling, which are all involved in FLT3i resistance. We also show that MEN1703 downregulates stromal cytokines that promote cytokine‐mediated resistance of AML blast cells to FLT3 inhibition. These results demonstrate the importance of the combination approach to overcome microenvironment‐mediated resistance to FLT3 inhibitors. [ABSTRACT FROM AUTHOR]

Osimertinib, a third-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI), has revolutionized one of the standard most efficient treatments for EGFR mutation-positive non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR–TKI, is currently one of most efficient treatments in clinical practice. However, it has a potentially fatal side effect: interstitial lung disease (ILD). When severe ILD occurs, a drug substitution is often required, and there is a rising concern about which drug to choose to inhibit the progression of NSCLC and avoid aggravating while alleviating ILD. Herein, we report an NSCLC case with osimertinib-induced ILD successfully rechallenged by almonertinib. In addition, we conducted a literature review on the clinical efficacy and adverse effects of almonertinib, hoping to provide insight into NSCLC treatment. [ABSTRACT FROM AUTHOR]

PURPOSE: MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. MDM2 amplification (MDM2amp) is mutually exclusive with TP53 mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations. However, the combination of MDM2 and RTK inhibitors in LUAD has not been studied. METHODS: We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD. RESULTS: In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone. CONCLUSION: These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach. [ABSTRACT FROM AUTHOR]

Infantile bullous pemphigoid (BP) is a rare autoantibody‐mediated skin disorder. We report the effective treatment of a 6‐month‐old infant with BP using baricitinib, a Janus kinase (JAK) inhibitor, after failure with steroids and intravenous immunoglobulin. The patient achieved full remission and discontinued all medications without any relapses. To our knowledge, this is the first case of baricitinib used in an infant with BP. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. FGFR4 has been implicated in HCC progression, making it a promising therapeutic target. We introduce an approach for identifying novel FGFR4 inhibitors by sequentially adding fragments to a common warhead unit. This strategy resulted in the discovery of a potent inhibitor, 4c, with an IC50 of 33 nM and high selectivity among members of the FGFR family. Although further optimisation is required, our approach demonstrated the potential for discovering potent FGFR4 inhibitors for HCC treatment, and provides a useful method for obtaining hit compounds from small fragments. [ABSTRACT FROM AUTHOR]

New aromatic O-alkyl pyridine derivatives were designed and synthesised as Proviral Integration Moloney (PIM)-1 kinase inhibitors. 4c and 4f showed potent in vitro anticancer activity against NFS-60, HepG-2, PC-3, and Caco-2 cell lines and low toxicity against normal human lung fibroblast Wi-38 cell line. Moreover, 4c and 4f induced apoptosis in the four tested cancer cell lines with high percentage. In addition, 4c and 4f significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 4c and 4f showed potent PIM-1 kinase inhibitory activity with IC50 = 0.110, 0.095 µM, respectively. Kinetic studies indicated that 4c and 4f were both competitive and non-competitive inhibitors for PIM-1 kinase enzyme. In addition, in silico prediction of physiochemical properties, pharmacokinetic profile, ligand efficiency, ligand lipophilic efficiency, and induced fit docking studies were consistent with the biological and kinetic studies, and predicted that 4c and 4f could act as PIM-1 kinase competitive non-adenosine triphosphate (ATP) mimetics with drug like properties. [ABSTRACT FROM AUTHOR]

Doublecortin-like kinase 1 (DCLK) is a microtubule-associated serine/threonine kinase that is upregulated in a wide range of cancers and is believed to be related to tumour growth and development. Upregulated DCLK1 has been used to identify patients at high risk of cancer progression and tumours with chemotherapy-resistance. Moreover, DCLK1 has been identified as a cancer stem cell (CSC) biomarker in various cancers, which has received considerable attention recently. Herein, a series of DCLK1 inhibitors were prepared based on the previously reported XMD8-92 structure. Among all the synthesised compounds, D1, D2, D6, D7, D8, D12, D14, and D15 showed higher DCLK1 inhibitory activities (IC50 40–74 nM) than XMD8-92 (IC50 161 nM). Compounds D1 and D2 were selective DCLK1 inhibitors as they showed a rather weak inhibitory effect on LRRK2. The antiproliferative activities of these compounds were also preliminarily evaluated. The structure-activity relationship revealed by our compounds provides useful guidance for the further development of DCLK1 inhibitors. [ABSTRACT FROM AUTHOR]

Background: The current possible treatments of advanced medullary carcinoma (MTC) include different drugs belonging to the class of tyrosine kinase inhibitors (TKIs): vandetanib, cabozantinb, and selpercatinib. Although the effects of these TKIs have been well described in clinical trials, the real-practice evidence of the effectiveness and safety of these treatment is scant. This real-world case series aims to describe a niche of patients with advanced MTC treated with more than one TKI by focusing on treatment responses and any reported adverse events (AEs) and to provide additional insight on the individualized approach to the management of metastatic MTC. Methods: Five patients with a diagnosis of metastastic MTC, treated with at least two different molecules of TKIs, were retrospectively selected. Results: Three patients obtained a partial response (one with cabozantinb, one with selpercatinib, and one with vandetanib), and two patients obtained disease stability (both of them treated with all three TKIs, the first two lines discontinued for AEs). The AE profile agreed with the known clinical trials AEs except for non-neoplastic ascites related to selpercatinib and lung cavitations of non-neoplastic tissue related to cabozantinb. The latter was an AE never described so far in patients receiving TKIs. Conclusions: The best management of MTC relies on an individualized approach, keeping in mind and dealing with the potential toxicity in order to minimize the treatment withdrawal. [ABSTRACT FROM AUTHOR]

Axial spondyloarthritis (axSpA) is a chronic illness with limited treatment options. The role of Janus kinase (JAK) inhibition as a therapeutic option has increasingly become a focus of research in recent years as they have brought a new mode of action to the clinical armamentarium. This review assesses the efficacy and safety profile of these drugs in axSpA. The current phase 2 and 3 clinical trials data are summarized across tofacitinib, upadacitinib and filgotinib. Moreover, the safety profiles of these drugs, in the context of emerging safety signals such as during the ORAL surveillance study, are reviewed. In summary, JAK inhibitors offer a novel therapeutic target for axSpA and appear to address some of the unmet needs for patients who have either failed to respond to current treatment options or in whom they are contraindicated. There is a relative lack of evidence in non-radiographic axSpA and longer-term trials are needed to establish true efficacy and safety profile in radiographic axSpA. [ABSTRACT FROM AUTHOR]

Acute severe ulcerative colitis is a medical emergency requiring inpatient treatment with intravenous steroids. Approximately one-third of patients do not respond to steroids sufficiently and require medical rescue therapy. Infliximab and cyclosporine are equally effective rescue agents, though infliximab is often preferred by clinicians for ease of use and greater familiarity. The use of cyclosporine is becoming more frequent, however, in patients previously exposed to infliximab. Those patients not exhibiting an adequate response to rescue therapy require colectomy. There is increasing interest in modified medical treatment to rescue the need for surgery. Janus kinase inhibitors may provide benefits when used alongside steroids from admission or as a rescue agent, but further randomised trials are needed to clearly establish their role. Intensified dosing of infliximab when used as a rescue therapy has shown mixed results but seems sensible in patients with low albumin and high disease burden. In this review, we describe the current established treatment pathways and report newer developments and evolving concepts that may in the future improve the care of patients with acute severe ulcerative colitis. [ABSTRACT FROM AUTHOR]

Metastatic renal cell carcinoma (mRCC) carrying sarcomatoid features (sRCC) has aggressive biology and poor prognosis. First‐line immunotherapy (IO)‐based combinations have improved the outcome of clear cell RCC patients, including that of sRCC. Real‐world data confirming the adequate first‐line management of sRCC is largely lacking. We investigated the clinical features and the outcome of sRCC patients treated with IO‐based combinations within the ARON‐1 study population (NCT05287464). The primary objective was to define the incidence and baseline clinical characteristics of sRCC compared with non‐sRCC patients. The secondary objective was to describe the outcome of sRCC patients based on type of first‐line treatment (IO + IO vs. IO + tyrosin kinase inhibitor [TKI]). We identified 1362 mRCC patients with IMDC intermediate or poor risk, 226 sRCC and 1136 non‐sRCC. These two subgroups did not differ in terms of baseline characteristics. The median overall survival (OS) was 26.8 months (95%CI 21.6–44.2) in sRCC and 35.3 months (95%CI 30.2–40.4) in non‐sRCC patients (p =.013). The median progression‐free survival (PFS) was longer in non‐sRCC patients compared to sRCC (14.5 vs. 12.3 months, p =.064). In patients treated with first‐line IO + TKI the median OS was 34.4 months compared to 26.4 months of those who received IO + IO (p =.729). The median PFS was 12.4 months with IO + TKI and 12.3 months with IO + IO (p =.606). In conclusion, we confirm that sRCC are aggressive tumors with poor prognosis. IO‐based combinations improve survival outcomes of sRCC patients, regardless from the type of strategy (IO + IO versus IO + TKI) adopted. [ABSTRACT FROM AUTHOR]

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Background: Capivasertib, a first-in-class AKT inhibitor, was recently approved as a second-line treatment for advanced breast cancer. However, capivasertib is expensive, raising questions over its economic value. This study provides the first evidence on the cost effectiveness of adding capivasertib to endocrine therapy (fulvestrant) for patients with PIK3CA/AKT1/PTEN-altered, hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer. Methods: A Markov model was built to compare the costs and effectiveness of three treatment strategies. The first strategy involved adding capivasertib to fulvestrant for all patients, while the second strategy involved adding it for only postmenopausal women. The third strategy involved treatment with fulvestrant alone. Analyses were conducted from a US payer perspective over a lifetime horizon. Costs were measured in 2023 US dollars, and effectiveness was measured in life years (LYs) and quality adjusted life years (QALYs), discounted at 3% per year. One-way sensitivity analyses, probabilistic sensitivity analyses, and scenario analyses were conducted to assess the robustness of results. Results: The addition of capivasertib to fulvestrant for all patients was associated with $410,765 higher costs and 1.46 additional quality adjusted life years (QALYs) compared with fulvestrant alone, resulting in an incremental cost effectiveness ratio of $280,854/QALY. The strategy of adding capivasertib for only patients who are postmenopausal was extended dominated, i.e., yielded fewer QALYs at a higher cost per QALY than if capivasertib was added for all patients. These results were found to be robust in sensitivity and scenario analyses. Conclusions: At its current price, our analysis suggests that the addition of capivasertib to fulvestrant as a second line treatment is not cost effective versus fulvestrant alone at a willingness-to-pay threshold of $100,000/QALY. The price of capivasertib will need to be reduced by nearly 70% (to $7000 per cycle) for it to become cost effective. [ABSTRACT FROM AUTHOR]

Lichen amyloidosis (LA) is a predominant type of primary cutaneous amyloidosis that is characterized by persistent and intense skin itching. Although multiple therapeutics strategies are available for its treatment, there is no standard treatment so far. Abrocitinib, an oral small-molecule Janus kinase 1 inhibitor, has been authorized for the treatment of severe atopic dermatitis (AD) and can also provide rapid relief from pruritus. Here, we discuss the case of a 32-year-old man who was diagnosed with LA with severe AD based on the presence of multiple, discrete, and hyperpigmented papules and pruritic, erythematous macules with lichenification of the limbs, trunk, and buttocks. Given the inefficacy of conventional therapy, abrocitinib treatment was recommended in this patient. After 1 month of treatment, the patient's Eczema Area And Severity Index score decreased significantly from 48 to 15 points, accompanied by a notable reduction in pruritus symptoms. Furthermore, significant improvements were observed in the thickness and pigmentation of the hyperkeratotic papules. Thus, abrocitinib exhibited excellent effectiveness and safety in the treatment of severe AD with LA and warrants further investigation for its potential therapeutic benefits. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the therapeutic efficacy and safety of Traditional medicine preparations (TMPs) given in combination with vascular endothelial growth factor receptor (VEGFR)-associated multi-targeted tyrosine kinase inhibitors (TKIs) for the treatment of middle to advanced-stage primary liver cancer (PLC). Methods: This systematic literature survey employed 10 electronic databases and 2 clinical trial registration platforms to identify relevant studies on the use of TMPs + VEGFR-TKIs to treat patients with middle-advanced PLC. Furthermore, a meta-analysis was performed following the PRISMA guidelines using the risk ratio (RR) at 95% confidence intervals (CI) or standardized mean difference as effect measures. Results: A total of 26 studies comprising 1678 middle-advanced PLC patients were selected. The meta-analysis revealed that compared with VEGFR-TKI mono-treatment, the co-therapy of TMPs + VEGFR-TKIs considerably enhanced the objective response rate (RR = 1.49, 95% CI: 1.31–1.69), disease control rate (RR = 1.23, 95% CI: 1.16–1.30), and one-year overall survival (RR = 1.49, 95% CI: 1.28–1.74). Furthermore, the co-therapy was associated with reduced incidences of liver dysfunction (RR = 0.64, 95% CI: 0.45–0.91), proteinuria (RR = 0.43, 95% CI: 0.24–0.75), hypertension (RR = 0.66, 95% CI: 0.53–0.83), hand-foot skin reactions (RR = 0.63, 95% CI: 0.49–0.80), myelosuppression (RR = 0.63, 95% CI: 0.46–0.87), and gastrointestinal reactions (RR = 0.64, 95% CI: 0.45–0.92). Moreover, the co-therapy indicated no increase in the incidences of rash and fatigue. Conclusion: This systematic analysis revealed that co-therapy with TMPs + VEGFR-TKIs has a higher effectiveness and safety profile for treating middle-advanced PLC patients. However, further validation using randomized control trials is required. PROSPERO registration no: CRD42022350634. [ABSTRACT FROM AUTHOR]

Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegic homolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non--small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer. Using DNA-encoded chemistry technology, we screened 3.94 billion unique compounds from our diverse DNA-encoded chemical libraries (DECLs) against the kinase domain of ALK2. Off-DNA synthesis of DECL hits and biochemical validation revealed nanomolar potent ALK2 inhibitors. Further structure--activity relationship studies yielded center for drug discovery (CDD)-2789, a potent [NanoBRET (NB) cell IC50: 0.54 μM] and metabolically stable analog with good pharmacological profile. Crystal structures of ALK2 bound with CDD-2281, CDD-2282, or CDD-2789 show that these inhibitors bind the active site through Van der Waals interactions and solvent-mediated hydrogen bonds. CDD-2789 exhibits high selectivity toward ALK2/ALK1 in KINOMEscan analysis and NB K192 assay. In cell-based studies, ALK2 inhibitors effectively attenuated activin A and BMP-induced Phosphorylated SMAD1/5 activation in fibroblasts from individuals with FOP in a dose-dependent manner. Thus, CDD-2789 is a valuable tool compound for further investigation of the biological functions of ALK2 and ALK1 and the therapeutic potential of specific inhibition of ALK2. [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]

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]

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]

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]