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As an increasingly well-known derivative of coumarin, daphnetin (7,8-dithydroxycoumarin) has demonstrated various pharmacological activities, including anti-inflammation, anti-cancer, anti-autoimmune diseases, antibacterial, organ protection, and neuroprotection properties. Various studies have been conducted to explore the action mechanisms and synthetic methods of daphnetin, given its therapeutic potential in clinical. Despite these initial insights, the precise mechanisms underlying the pharmacological activities of daphnetin remain largely unknown. In order to address this knowledge gap, we explore the molecular effects from the perspectives of signaling pathways, NOD-like receptor protein 3 (NLRP3) inflammasome and inflammatory factors; and try to find out how these mechanisms can be utilized to inform new combined therapeutic strategies.

To investigate the correlation between cytokines at different time points after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the onset, severity, and therapeutic efficacy of acute graft-versus-host disease (aGVHD). We performed a retrospective analysis of patients who underwent allo-HSCT from January 2019 to December 2021. Patients were divided into a training (first two years) and validation cohort (third year). Serum cytokines levels (TNF-α, IL-2, IL-4, IL-6, IL-10) on days +7, +14, +21, and +28 were measured and compared between patients developed aGVHD and those did not. Clinical characteristics were analyzed. Training cohort results were verified in the validation cohort to identify potential predictive markers for aGVHD. The training cohort included 89 patients who underwent allo-HSCT, in which 29 patients developed aGVHD. Forty patients were enrolled in the validation cohort and 17 patients suffered aGVHD. Significant differences were observed in the doses of infused CD34 and mononuclear cells between the two cohorts, whereas other baseline clinical characteristics were comparable. In the training set, the ratio of IL-2/IL-4 ≥1.103 on day +7 associated with an 8.87-fold increased risk of aGVHD. After excluding sepsis and engraftment syndrome cases, the IL-2/IL-4 ratio on day +7 remained associated with aGVHD. Under these conditions, IL-2/IL-4 ≥0.989 on day +7 suggested a 5.875-fold increased aGVHD risk. The validation set confirmed IL-2/IL-4 as an early and reliable aGVHD indicator. Among the 29 patients with aGVHD in the training set, 17 had grade I and 12 had grade II-IV aGVHD. TNF-α (day +7) and IL-2 (day +28) significantly increased in grade I aGVHD. After excluding sepsis and ES cases, 19 had aGVHD (12 grade I and 7 grade II-IV aGVHD). No cytokine was significantly associated with aGVHD severity. Twenty-two of 29 patients received corticosteroids as first-line treatment; the complete remission (CR) rate was 68.2% (15/22). Subgroup analysis revealed cytokines were comparable between patients achieved CR and those did not. A higher IL-2/IL-4 ratio on day +7 may be an early predictive biomarker of aGVHD onset. Nevertheless, whether these five cytokines could predict aGVHD severity or therapeutic efficacy remain unclear.

Chronic myeloid leukemia (CML) is a malignant clonal disease involving hematopoietic stem cells that is characterized by myeloid cell proliferation in bone marrow and peripheral blood, and the presence of the Philadelphia (Ph) chromosome with BCR-ABL fusion gene. Treatment of CML has dramatically improved since the advent of tyrosine kinase inhibitors (TKI). However, there are a small subset of CML patients who develop resistance to TKI. Mutations in the ABL kinase domain (KD) are currently recognized as the leading cause of TKI resistance in CML. In this review, we discuss the concept of resistance and summarize recent advances exploring the mechanisms underlying CML resistance. Overcoming TKI resistance appears to be the most successful approach to reduce the burden of leukemia and enhance cures for CML. Advances in new strategies to combat drug resistance may rapidly change the management of TKI-resistant CML and expand the prospects for available therapies.

Background Bruton tyrosine kinase (BTK) inhibitors have demonstrated a high degree of efficacy in the treatment of B cell malignancies characterized by constitutive B cell receptor activation, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Methods The efficacy and safety of zanubrutinib, an investigational highly selective BTK inhibitor, was evaluated in this single-arm, phase 2 study of Chinese patients with relapsed/refractory CLL/SLL. The primary endpoint was overall response rate as assessed by an independent review committee. Results Of the 91 evaluable patients, 77 (84.6%) achieved a response, with three (3.3%), 54 (59.3%), and 20 (22%) patients achieving a complete response, partial response, and partial response with lymphocytosis, respectively, after a median follow-up of 15.1 months. The estimated 12-month event-free rate for duration of response was 92.9%. The most commonly reported grade ≥ 3 adverse events (AEs) were neutropenia (44%), thrombocytopenia (15.4%), lung infection/pneumonia (13.2%), upper respiratory tract infection (9.9%), and anemia (8.8%). The 12-month overall survival rate was 96%. Eight (9.0%) patients discontinued zanubrutinib due to AEs, and seven (8.0%) patients required at least one dose reduction. Conclusion Treatment of patients with relapsed/refractory CLL/SLL with zanubrutinib was generally well tolerated and resulted in a high overall response rate, thereby conferring a favorable benefit-risk profile. Trial registration Prospectively registered in China public registry (CTR20160890) on December 7, 2016: http://www.chinadrugtrials.org.cn/ . Retrospectively registered in ClinicalTrials.gov ( NCT03206918 ) on July 2, 2017.

Luteolin, a natural flavonoid, exerts broad immunomodulatory effects across multiple immune cell populations, positioning it as a promising candidate for treating inflammatory diseases, infections, and cancer. This review synthesizes current evidence on luteolin’s effects on T cells, natural killer (NK) cells, dendritic cells (DCs), macrophages, neutrophils, eosinophils, and basophils. Luteolin promotes the differentiation of regulatory T cells (Tregs) and suppresses pro-inflammatory T helper 17 (Th17) and Th2 responses, thereby restoring immune balance in sepsis, allergies, and autoimmunity. In macrophages, it skews polarization toward the anti-inflammatory M2 phenotype via the signal transducer and activator of transcription 3 (STAT3)/STAT6 and peroxisome proliferator-activated receptor γ (PPARγ) pathways, while inhibiting nuclear factor-κB (NF-κB) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation. Neutrophil functions are dampened by reduced oxidative stress, adhesion molecule expression, and induction of apoptosis. Luteolin may enhance NK-cell cytotoxicity and DC-mediated antigen presentation while curbing eosinophil and basophil activation in allergic disorders. Despite preclinical successes, future research should prioritize mechanistic insights, structural optimization, and clinical translation to unlock luteolin’s full therapeutic potential.

The treatment of Crohn's disease (CD) has received widespread attention in clinical practice, but there is currently a lack of quantitative evaluation of the literature published in this field. This study aimed to describe the development trends and research hotspots of CD treatment through bibliometric analysis. Publications related to CD treatment published from 2004 to 2023 were searched in the WoSCC. Microsoft Office Excel 2021 was used for the analysis and visualization of the annual number of publications. CiteSpace was used to visualize the collaboration networks of authors, institutions, and countries, as well as to construct a reference timeline visualization map and identify keywords with the strongest citation bursts. The bibliometric analysis included 25,608 publications between 2004 and 2023. The most productive year was 2021. The United States of America (n = 7,891) and the University of California System (n = 939) are the country and institution with the most published papers, respectively. Among the 97,564 authors, Peyrin-Biroulet, Laurent (n = 424) published the most articles. The core journals were Inflammatory Bowel Diseases, Journal of Crohns and Colitis, Alimentary Pharmacology and Therapeutics, etc. The timeline view showed that \"#5 JAK Inhibitor\" was the most recent topic. The keywords that burst and persist from 2020 to 2023 include \"ustekinumab\" and \"vedolizumab\". An increasing number of researchers are dedicating their efforts to exploring the treatment of CD, with the United States making the largest contribution to this field. Currently, the research hotspots predominantly involve drug therapy including ustekinumab, vedolizumab, and JAK inhibitors. Our study provides valuable information for scholars studying CD treatment.

Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4 + T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming. Mechanistically, dectin-1 activates Syk, Raf1 and NF-κB signalling pathways, resulting in increased p50 and RelB nuclear translocation and TNFSF15 and OX40L expression. Furthermore, immunization of tumour-bearing mice with dectin-1-activated DCs induces potent antitumour response that depends on Th9 cells and IL-9 induced by dectin-1-activated DCs in vivo . Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications. Dendritic cells instruct different types of T cell responses depending on the types of microbial ligands sensed. Here the authors show that dendritic cells stimulated via Dectin-1 receptor upregulate TNFSF15 and OX40L and induce T helper 9 response and efficient antitumour immunity in mouse models.

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51–67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9–18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7–55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3–4 drug-related treatment-emergent adverse events. The most common grade 3–4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. In this phase 2 study, golidocitinib showed a favourable benefit–risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. Dizal Pharmaceutical.

Background Ustekinumab (UST), a monoclonal antibody that blocks the p40 subunit of both interleukin (IL)-12 and IL-23, is widely used in inflammatory bowel disease (IBD) treatment. As UST use continues to increase in real-world clinical practice, it is becoming increasingly imperative to establish a more comprehensive understanding of its safety profile. The aim was to assess the safety of UST treatment in patients with IBD. Methods Data on adverse events experienced by UST-treated patients with IBD were extracted from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) for the period of Q4 2009–Q4 2024. Disproportionality was assessed using four statistical measures, including the reporting odds ratio, proportional reporting ratio, multi‑item gamma‑Poisson shrinker method, and Bayesian confidence propagation neural network model. Furthermore, a Weibull distribution analysis was conducted to model the time‑to‑onset of adverse events. Results A total of 22687 reports identified UST as the primary suspect drug for IBD and covered 27 system organ classes (SOCs), with injury, poisoning and procedural complications ( n  = 13676), gastrointestinal disorders ( n  = 9563), and infections and infestations ( n  = 8035) being the three with the highest frequency. Positive signals led to the identification of potential adverse events that are not widely documented in the labeling, including urinary tract infections, seizures, hepatic enzyme upregulation, hepatic steatosis, cholelithiasis, cerebrovascular accidents, and transient ischemic attacks. Furthermore, UST‑related adverse events follow an early‑failure model, and their reports gradually decline as treatment duration lengthens. Conclusions This study provides comprehensive real-world insights into the safety of UST use in IBD treatment, corroborating known adverse reactions and identifying additional potential risks. Robust pharmacovigilance and long-term monitoring are essential to support personalized UST therapy and facilitate informed risk–benefit assessments.

Infection is the main cause of death for patients after allogeneic hematopoietic stem cell transplantation (HSCT). However, pathogen profiles still have not been reported in detail due to their heterogeneity caused by geographic region. To evaluate the performance of metagenomic next-generation sequencing (mNGS) and summarize regional pathogen profiles of infected patients after HSCT. From February 2021 to August 2022, 64 patients, admitted to the Department of Hematology of The First Hospital of Jilin University for HSCT and diagnosed as suspected infections, were retrospectively enrolled. A total of 38 patients were diagnosed as having infections, including bloodstream ( =17), pulmonary ( =16), central nervous system (CNS) ( =4), and chest ( =1) infections. Human betaherpesvirus 5 (CMV) was the most common pathogen in both bloodstream ( =10) and pulmonary ( =8) infections, while CNS ( =2) and chest ( =1) infections were mainly caused by Human gammaherpesvirus 4 (EBV). For bloodstream infection, complex ( =3), ( =1), and ( =1) were also diagnosed as causative pathogens. Furthermore, mNGS combined with conventional tests can identify more causative pathogens with high sensitivity of 82.9% (95% CI 70.4-95.3%), and the total coincidence rate can reach up to 76.7% (95% CI 64.1-89.4%). Our findings emphasized the importance of mNGS in diagnosing, managing, and ruling out infections, and an era of more rapid, independent, and impartial diagnosis of infections after HSCT can be expected.