Bacterial microcompartments (BMCs) are proteinaceous organelles that spatially organize metabolic reactions in bacteria and represent an attractive scaffold for pathway engineering. Here, we present a proof-of-concept in vitro study demonstrating a simple, scalable, and modular BMC shell-based platform for enzyme encapsulation using the SpyCatcher-SpyTag (SC-ST) covalent conjugation system. To evaluate the generality of this approach, 16 dehydrogenases were selected, of which 13 were successfully expressed and purified as SC-tagged enzymes in E. coli by five research groups working in parallel. Twelve of these efficiently conjugated to ST-fused BMC-T1 proteins, and addition of urea-solubilized BMC-H triggered rapid self-assembly of HT1 shells, resulting in successful encapsulation of all conjugated enzymes. The only enzyme lacking detectable activity after encapsulation was also inactive in its free SC-fused form, indicating that encapsulation retained enzymatic activity for all tested enzymes. Encapsulation modulated enzymatic activity and kinetic parameters in an enzyme-dependent manner, likely arising from variations in catalytic mechanism, structural flexibility affected by immobilization, and sensitivity to the local microenvironment created by encapsulation. Functional characterization of a subset of encapsulated enzymes revealed enhanced thermal stability up to ∼50 °C and improved storage stability relative to free SC-fused enzymes. Enzyme-loaded shells could be lyophilized and reconstituted without loss of structural integrity or activity. Finally, we demonstrate co-encapsulation of two enzymes within a single shell and their cooperative function through cofactor recycling. Together, these results establish engineered BMCs as a versatile and modular platform for organizing multi-enzyme pathways, enabling rapid assembly, stabilization, and functional integration of enzymes for diverse metabolic engineering applications.
We study the prediction of T-cell response for specific given peptides, which could, among other applications, be a crucial step towards the development of personalized cancer vaccines. It is a challenging task due to limited, heterogeneous training data featuring a multi-domain structure; such data entail the danger of shortcut learning, where models learn general characteristics of peptide sources, such as the source organism, rather than specific peptide characteristics associated with T-cell response. Using a transformer model for T-cell response prediction, we show that the danger of inflated predictive performance is not merely theoretical but occurs in practice. Consequently, we propose a domain-aware evaluation scheme. We then study different transfer learning techniques to deal with the multi-domain structure and shortcut learning. We demonstrate a per-source fine tuning approach to be effective across a wide range of peptide sources and further show that our final model is competitive with existing state-of-the-art approaches for predicting T-cell responses for human peptides.
Based on multidimensional data analysis, potential biomarkers for ulcerative colitis were screened, and the effects of curcumin chitosan microspheres on the expression of key targets in ulcerative colitis and their role in alleviating inflammation were observed. Potential biomarkers related to UC progression were identified through differential expression analysis (using the limma package, with |log2FC| > 1 and corrected P < 0.05), weighted gene coexpression network analysis, and three machine learning algorithms (LASSO, random forest, SVM-RFE) on the basis of the datasets GSE107499 and GSE87473 in the GEO database. The core genes selected through this process were externally validated via the independent dataset GSE47908. A UC mouse model was constructed using 6-8-week-old C57BL/6 mice, and CCM was applied to the UC mice. Colonic tissues were collected for pathological examination and determination of inflammatory factor levels. Changes in the protein expression of the core genes were detected via immunohistochemistry. After rigorous screening and external validation, four core genes were finally identified: FCN3, FGR, HSD11B1 and PIM2. CCM treatment improved pathological damage and inflammatory factor levels in the colon tissue of UC mice, and the protein expression levels of FCN3, FGR, HSD11B1 and PIM2 in the colon tissue were inhibited. Four potential targets of UC, namely, FCN3, FGR, HSD11B1, and PIM2, were identified. CCM may improve the degree of the UC inflammatory response by downregulating the expression of key genes.
Bloodstream infections (BSIs) are severe systemic disorders caused by pathogenic microorganisms, including bacteria and fungi, invading the bloodstream. Associated with high morbidity and mortality, BSIs represent one of the leading causes of death globally. There is an urgent demand for simple, rapid, and accurate laboratory biomarkers to facilitate the diagnosis and differential diagnosis of patients with suspected BSIs, thereby guiding timely and targeted antimicrobial therapy. To evaluate the value of serum procalcitonin (PCT), C-reactive protein (CRP), white blood cell count (WBC), and neutrophil percentage (NEUT%) for early and differential diagnosis of bacterial vs. fungal bloodstream infections (BSIs), a cross-sectional study was conducted. A total of 1649 patients with suspected BSI were included in this retrospective study. Of these, 1357 patients with positive blood cultures were classified as the BSI group (experimental group), and 292 patients with negative blood cultures were assigned to the non-BSI group (control group). Serum PCT, CRP, WBC/NEUT% were measured using a bioMerieux VIDAS 30 analyzer, SIEMENS ADVIA 2400 and by Sysmex XN-9000, respectively. Microbial identification was based on bioMerieux VITEK 2 systems. The diagnostic performance of these biomarkers in the discrimination in bacterial and fungal bloodstream infections were compared using receiver operating characteristic (ROC) curves. For BSI discrimination, a PCT level > 0.687 ng/mL could demonstrate the optimal performance (AUC = 0.788, sensitivity 61.7%, specificity 80.1%). The PCT level < 0.5 ng/mL for 3 consecutive days could effectively rule out BSI (sensitivity 98.1%, specificity 79.5%). Elevated PCT (> 1.78 ng/mL) and CRP (> 79.76 mg/L) levels were associated with bacterial BSIs (AUC = 0.686 for the combined markers). A PCT level > 1.98 ng/mL suggested Gram-negative BSI (sensitivity 68.4%). The positive diagnostic rates of the PCT + CRP+NEUT% combined test for G- bacterial and G+ bacterial BSIs reached 96.17% and 92.86% respectively, which significantly improved the diagnostic positive rate compared with single diagnosis. PCT could reliably excludes BSI (3-day < 0.5 ng/mL rule) and aids differentiation (bacterial/fungal: PCT + CRP; G-/G+: PCT+NEUT%). Multi-parameter approaches optimize diagnostic accuracy for timely intervention.
Serum CXCL10 is one of the chemokines that is strongly associated with systemic lupus erythematosus (SLE) and its related complications, particularly lupus nephritis (LN). Our study aimed to validate serum CXCL10 as a potential biomarker of LN and disease activity, and to assess its association with organ damage in Egyptian patients. A cross-sectional study was conducted among 100 SLE patients recruited from Ain Shams University Hospital, with 50 patients in group I (without LN) and 50 in group II (with LN). All patients underwent a medical history review, clinical examination, and assessment of disease activity using the SLE Disease Activity Index (SLEDAI-2K) and the Renal SLEDAI (R-SLEDAI). Damage scores were recorded for each patient. Laboratory investigations, such as serum CXCL10, complete blood count (CBC), blood urea nitrogen (BUN), serum creatinine, estimated glomerular filtration rate (eGFR), urine analysis, 24-h urinary protein excretion, antinuclear antibodies (ANA), anti-dsDNA antibodies, and serum complement (C3, C4). Serum CXCL10 levels were significantly elevated in patients with LN compared to those without (p < 0.001). Disease activity indices, renal function parameters, and damage scores were all increased in the LN group (p < 0.001). CXCL10 levels demonstrated strong positive correlations with 24-hour urinary protein, BUN, serum creatinine, disease activity and damage scores, and strong negative correlations with eGFR, C3, and C4 (all p < 0.001). Diagnostic accuracy analyses showed that serum CXCL10 predicted LN with 96% sensitivity and 94% specificity and was also predictive of renal and overall disease activity (sensitivity/specificity for R-SLEDAI: 100%/94.2%; for SLEDAI-2K: 81.97%/97.44%). Serum CXCL10 is a promising non-invasive biomarker for identifying LN and monitoring disease activity in SLE patients.
Infectious diseases and autoimmunity are leading causes of mortality worldwide. The lack of vaccines and resistance to current treatments by microbes highlight the importance of developing novel therapeutics. Similarly, treatments for autoimmune diseases are limited and require improved approaches. Identifying relevant proteins involved in host defense and tolerance to self-antigens is key to designing novel therapeutic strategies. Thrombospondin-1 (TSP-1) is a host glycoprotein involved in host defense and inflammation. Here, we analyze how TSP-1 interacts with different ligands involved in immunity. Then, we discuss the roles of TSP-1 in infection and autoimmunity to finally examine the therapeutic potential of TSP-1.
Female genital tuberculosis is an underdiagnosed cause of infertility and amenorrhea in tuberculosis-endemic regions. Hysteroscopy combined with histopathology can confirm the diagnosis even when molecular testing is negative. Clinicians should maintain a high index of suspicion and pursue multimodal diagnostic evaluation in women with unexplained infertility.
Patients with end-stage renal disease (ESRD) undergoing maintenance hemodialysis are at increased risk for persistent hepatitis B virus (HBV) infection. Host immunogenetic variations, particularly in cytokines regulating pro- and anti-inflammatory responses, may influence viral chronicity. This study evaluated the association of IL-6 - 174G/C and IL-10 - 1082G/A polymorphisms and their corresponding serum levels in Sudanese patients with overt HBV and ESRD-HBV. A case-control study was conducted among 68 HBV-infected individuals (31 ESRD-HBV and 37 overt HBV). Genotyping was performed using sequence-specific primer PCR (SSP-PCR), and serum cytokine concentrations were measured by ELISA. Statistical analyses were conducted using R software, applying non-parametric Wilcoxon rank-sum and Kruskal-Wallis tests. No significant differences were observed between groups in IL-6 serum levels (p = 0.29) or genotype frequencies (p = 0.738), nor in IL-10 genotype distribution (p = 0.194). In contrast, IL-10 serum levels were significantly higher in the ESRD-HBV group compared to the overt HBV group (p = 0.00024). A significant genotype-phenotype association for IL-10 was identified within the ESRD-HBV cohort (p = 0.018), where carriers of the GA genotype exhibited higher serum IL-10 levels compared to AA and GG genotypes. This association was not observed in the overt HBV group (p = 0.33). No significant variation in IL-6 or IL-10 genotype frequencies was detected between the groups. Nevertheless, the IL-10 (- 1082G/A) polymorphism was related to differences in serum IL-10 concentrations among patients with concurrent HBV infection and ESRD. However, given the limited sample size and absence of key clinical confounders, these findings should be interpreted as exploratory and require validation in larger, well-characterized cohorts.
Depression is a common comorbidity in autoimmune diseases (ADs), including inflammatory bowel disease (IBD), a well-characterized AD with prominent gut involvement and strong host-microbiome interactions. Yet, its underlying microbial associations remain insufficiently understood. This study aimed to explore the gut microbial composition and function in patients with ADs comorbid depression, including a subgroup with IBD comorbid depression, and to identify potential microbial and metabolic signatures associated with this comorbidity. We analyzed two curated cohorts from the American Gut Project: an AD cohort (n = 344; AD with depression: n = 115, AD without depression: n = 120, healthy controls: n = 109), and an IBD subgroup (n = 75; IBD with depression: n = 25, IBD without depression: n = 30, healthy controls: n = 20). Gut microbial profiles were evaluated using 16S rRNA gene sequencing (V4 region). Microbial diversity was assessed via α- and β-diversity indices. Differential abundance analysis was conducted using Linear Discriminative Analysis Effect Size (LEfSe) and Linear Discriminant Analysis (LDA) methods. Functional predictions were performed based on Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology inference. Microbial co-occurrence networks were also constructed to explore taxonomic interaction patterns. In the AD cohort, β-diversity was significantly reduced in patients with comorbid depression compared to those without, whereas α-diversity did not show statistically significant differences. A total of 40 microbial taxa were significantly different between patients with AD comorbid depression and AD without depression. In the IBD subgroup, 12 taxa were differentially abundant between patients with and without depression. Functional pathway predictions suggested disruptions in carbohydrate metabolism, energy metabolism, and glycan biosynthesis in patients with AD and comorbid depression compared to those without depression. Microbial network analysis revealed distinct co-occurrence structures in patients with comorbid depression. This exploratory study suggests that individuals with ADs or IBD and comorbid depression exhibit distinct gut microbiome compositions and functional potentials compared to non-depressed counterparts. These associations may offer insights into gut-brain interactions in autoimmunity and mental health. However, due to the cross-sectional design, mechanistic and clinical inferences remain speculative and require validation in future studies.
Post tuberculosis lung disease (PTLD) is an increasingly recognized contributor of long-term morbidity among the estimated 155 million survivors of Mycobacterium tuberculosis disease. While a range of interventions may influence PTLD risk, the full spectrum has not been systematically reviewed. We conducted a scoping review following Joanna Briggs Institute methodology to identify interventions delivered during or after TB treatment with potential to affect PTLD outcomes. Embase was searched from inception to March 31, 2025, for seven intervention categories: host-directed therapy (HDT), therapeutic drug monitoring (TDM), inhaled pharmacotherapy, antimicrobials beyond TB treatment, treatment shortening, thoracic surgery, and microbiome-altering interventions. Outcomes were grouped into disability, lung function, radiology, biomarkers, and histopathology, and categorized as showing improvement, worsening, or no effect on PTLD. Of 7,965 records screened, 87 studies were included. Most were small, uncontrolled, and designed to assess microbiological cure rather than post-TB sequelae. Radiology and unstructured symptom reports were the most common outcomes, while validated disability tools and advanced lung function measures were rarely used. Corticosteroids and several HDTs showed signals of radiological or spirometric benefit, but the findings were inconsistent. Doxycycline and metformin improved cavity resolution in small trials. Inhaled bronchodilators demonstrated short-term spirometric gains in two studies and a survival benefit in one retrospective cohort. Antifungals for chronic pulmonary aspergillosis improved symptoms, radiology, and inflammatory biomarkers, whereas evidence for antibacterial or NTM-directed therapy was lacking. TDM was associated with faster culture conversion in some studies but was not linked to PTLD-specific outcomes. Microbiome studies consistently reported reduced diversity and altered composition during TB treatment, but no direct associations with PTLD. Evidence for interventions to prevent or mitigate PTLD remains sparse, heterogeneous, and largely incidental. High-quality studies using standardized, person-centered outcomes are urgently needed to guide care for TB survivors worldwide.
Oral HIV pre-exposure prophylaxis (PrEP) users are generally screened for sexually transmitted infections (STIs) every 3 months. The need for such frequent screening is debatable. We compared STI diagnoses and associated care between PrEP users who underwent 6-monthly versus 3-monthly PrEP monitoring. We conducted a secondary analysis of the EZI-PrEP study- a 2 × 2 factorial randomized controlled trial examining 6-monthly versus 3-monthly and online versus in-clinic PrEP monitoring among men who have sex with men (MSM) and transgender or gender-diverse persons in the Netherlands (2021-2024). Participants were followed for 24 months. Scheduled PrEP monitoring included bacterial STI screening (i.e., Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), syphilis). Unscheduled STI testing in-between monitoring visits was permitted. This secondary analysis compared several outcomes between the 6-monthly and 3-monthly monitoring groups, using Poisson regression: (i) visit rates as number of visits per person-year (PY), (ii) STI detection rates as number of STI diagnoses per 100PY (to assess STI detection and potential (over)treatment), and (iii) STI positivity as number of STI diagnoses per 100 visits (as proxy for diagnostic delay). We stratified outcomes by visit type (i.e., scheduled/unscheduled) and adjusted for sexual behavior. 451 participants (99% MSM) were followed for median 22.7 months (IQR 19.2-23.8). Compared to 3-monthly PrEP monitoring, 6-monthly monitoring led to 31% fewer visits in total (rate ratio = 0.69, 95%CI = 0.64-0.74), but 67% more unscheduled visits (rate ratio = 1.67, 95%CI = 1.42-1.98). The STI detection rate was 18% lower in the 6-monthly monitoring group (adjusted rate ratio = 0.82, 95%CI = 0.70-0.95). STI positivity at PrEP monitoring visits did not differ between monitoring groups (6-monthly: 23.8 STIs/100 visits; 3-monthly: 23.2 STIs/100 visits; adjusted positivity ratio = 1.09, 95%CI = 0.90-1.30). Reduced-frequency PrEP monitoring resulted in fewer total clinic visits, but more self-initiated STI testing. Furthermore, fewer STIs were diagnosed during follow-up, yet the number of STIs detected per scheduled monitoring visit was similar between groups. These findings suggest that less frequent PrEP monitoring could reduce the burden of PrEP care and the number of STIs that are detected and treated, without leading to a substantial rise in STIs. The trial has been registered with ClinicalTrials.gov, trial number NCT05093036 (https://clinicaltrials.gov/study/NCT05093036).
To estimate the yearly and 15-year cumulative incidence of scleritis requiring surgical repair in patients with a prior diagnosis of scleritis who received a subconjunctival or subTenon triamcinolone acetonide injection (STAI). A retrospective cohort study was conducted using the TriNetX US Collaborative Network. TriNetX is an electronic health records database with anonymized, deidentified encrypted data from 69 healthcare networks. Subjects with a history of scleritis were identified using ICD-10 (International Classification of Diseases, 10th Revision) code H15.0X and who subsequently underwent a STAI as identified using the CPT (current procedural terminology) code between January 1, 2009 to December 31, 2024. CPT codes were used to identify STAIs include subconjunctival injection (68200) or subTenon injection (67515) and injection of triamcinolone acetonide 10 mg (J3301). Please note that H15.0X codes specifying posterior scleritis were excluded from this cohort in an attempt to localize anterior scleritis. The time relation was set to ensure all patients in the cohort had an existing diagnosis of scleritis prior to any instance of STAI. The primary outcome measure was the annual and 15-year cumulative incidence of required surgical repair within 4 weeks, and 3, 6, 9, and 12 m after the STAI as best estimated by scleral graft reinforcement and repair of scleral staphyloma with graft, CPT 67255 or 66225. Final data collection ran on April 23, 2026. Possible confounding procedures such as cataracts were also excluded within the time period assessed in order to better localize the STAI for use in cases of scleritis. Out of 113,510,724 patients on the TriNetX database, 36,249 had a diagnosis of scleritis. Of those with a history of scleritis, 176 had a subconjunctival or subTenon triamcinolone injection (STAI). Of this cohort, 0 patients needed surgical interventions requiring a patch graft over the 15-year time period of the study giving an annual and cumulative incidence of 0 per 100,000 persons. The subjects were primarily female (112, 63.64%) with a mean age of 61 years (range 14-90, SD 16). Surgical intervention requiring a patch graft was not observed post-injection among patients with prior scleritis who received a STAI. Further studies with larger cohorts are necessary to accurately represent the risk profile of STAI in the greater population.
In this issue of Developmental Cell, Wang et al. establish a murine resectable pancreatic ductal adenocarcinoma (PDAC) model and identify circadian regulator Dec2 as a driver of dormant tumor cells to evade immune surveillance by suppressing antigen presentation. These findings highlight a temporal dimension of tumor immune evasion.
To prepare hydroxyapatite/chitosan (HA/CTS) nanocomposites at four weight ratios (85/15, 70/30, 50/50, 30/70) and two concentrations (3 and 5 wt.%), incorporate them into conventional glass ionomer cement (GIC), and evaluate their effect on compressive strength, shear bond strength to dentin, and antibacterial activity. HA/CTS nanocomposites were synthesized by co-precipitation and characterized by TEM and FTIR. Nine groups were prepared (n = 10): one unmodified control (Group I) and eight modified groups (Groups II-IX). Compressive strength was tested per ISO 9917-1:2007; shear bond strength to human dentin and antibacterial activity (agar diffusion against Streptococcus mutans, Staphylococcus aureus, and Escherichia coli) were also evaluated. One-way and two-way ANOVA with Tukey's HSD were applied (P ≤ 0.05). TEM confirmed nanoscale particles (7-50 nm) with dispersion improving at higher chitosan content. FTIR verified dual-phase incorporation and Ca2+-NH2 coordination bonding. Compressive strength (F(8,81) = 177.509; P < 0.0001) and shear bond strength (F(8,81) = 202.262; P < 0.0001) differed significantly among groups. A significant ratio × concentration interaction was confirmed for both properties (P < 0.0001). Only the 70/30 nanocomposite at 3 wt.% exceeded the control compressive strength (133.44 vs. 115.02 MPa; P < 0.05). All eight modified groups showed significantly higher shear bond strength than the control (6.04 MPa), with the 85/15 at 5 wt.% achieving the highest value (13.30 MPa). No inhibition zones were detected in any group. The 70/30 HA/CTS nanocomposite at 3 wt.% optimizes compressive strength, while the 85/15 at 5 wt.% optimizes dentin adhesion. Overall, the 70/30 HA/CTS nanocomposite at 3 wt.% demonstrated the most favorable balanced performance profile across both mechanical outcomes. The absence of detectable antibacterial activity under the present agar diffusion testing conditions may be related to chitosan immobilization within the nanocomposite matrix and the diffusion limitations of the assay method. Findings suggest the potential for application-specific optimization of HA/CTS-modified GIC under controlled in vitro conditions, pending further long-term and in vivo validation. HA/CTS nanocomposite modification enhanced the mechanical and adhesive performance of conventional GIC under the present experimental conditions. The observed improvement in compressive and shear bond strength across the modified formulations may support improved marginal integrity in esthetic GIC restorations. Two application-specific optimal formulations were identified based on the functional demands of the restoration site, with the 70/30 HA/CTS nanocomposite at 3 wt.% representing the most favorable overall formulation combining enhanced compressive strength with clinically acceptable dentin adhesion; however, further long-term and in vivo validation remains necessary before definitive clinical translation.
There is increasing evidence that gut microbiota is associated with cardiovascular health. In this exploratory study, the 16 S rRNA amplicon sequencing was employed to investigate the composition and differential abundances of bacterial gut microbiota of dogs at different stages of myxomatous mitral valve disease (MMVD): dogs with congestive heart failure (CHF, n = 38), dogs in the preclinical stage of the disease (non-CHF, n = 23) and healthy controls with no apparent heart disease (n = 17). Flow cytometry was performed to quantify T lymphocytes and their subtypes, as well as monocytes, natural killer (NK) cells and B lymphocytes. Concentrations of selected chemokines, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) were also measured. Correlation analysis was performed between immunological parameters and bacterial taxa of the gut microbiota. Alpha diversity did not differ significantly between the study groups; however, several differentially abundant taxa were identified. Escherichia/Shigella was overabundant in the CHF group and showed a positive correlation with activated T lymphocyte levels, whereas Megamonas was overabundant in the control group and was negatively correlated with monocytes and NT-proBNP levels. Lachnospiraceae was overabundant in the non-CHF group. These findings suggest that dogs with varying severity of heart disease differ in gut microbiota composition. The observed associations between microbiota profiles, immunological parameters and disease status indicate potential microbiome-immune interactions in disease progression.
Microglia are the brain's resident immune cells, essential for homeostasis and implicated in common neurodegenerative diseases like Alzheimer's and Parkinson's disease (PD), where their early activation and sustained inflammatory mediator release contribute to neuronal loss. However, their role in rare disorders is unclear. β-propeller protein-associated neurodegeneration (BPAN), caused by WDR45 mutations, shares key features with PD, including iron accumulation and dopaminergic neuron loss, but the impact of microglia and mutant WDR45 in BPAN pathophysiology remains unexplored. To address this, we established the first induced pluripotent stem stell (iPSC)-derived microglia model from BPAN patients. Parallel targeted transcriptomic and secretomic profiling revealed a shift from a homeostatic microglial toward a stress-adapted and transcriptionally reprogrammed state characterized by selective remodeling of immune signaling pathways and dysregulation of autophagy and cellular stress responses. Complementary secretomic analysis identified reduced secretion of lysosomal enzymes alongside increased shedding of immune-associated surface proteins, indicating altered lysosomal trafficking and remodeling of microglial immune signaling. These findings identify a distinct microglial phenotype in BPAN and implicate microglial dysfunction as a potential contributor to disease mechanisms, highlighting new avenues for therapeutic strategies targeting neuroimmune pathways.
The favorable prognosis of pediatric AML1::ETO acute myeloid leukemia (AML) is well-established, yet the impact of co-occurring KIT mutations-particularly in exon 17-on clinical outcomes and chemosensitivity remains incompletely defined. We analyzed the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database comprising 957 pediatric AML patients to assess the clinical characteristics and prognosis of pediatric patients harboring AML1::ETO and KIT mutation using Kaplan-Meier survival analysis and Cox proportional hazards models. Subsequently, we performed experimental validation using bone marrow samples from 16 pediatric AML patients at Shenzhen Children's Hospital by high-throughput drug sensitivity (HDS) screening against therapeutic agents and whole transcriptome sequencing analysis of significant genes. Functional enrichment analysis of these differential expression genes was carried out by Gene Ontology. Analysis from the TARGET database revealed that while AML1::ETO AML generally carries a favorable prognosis, concomitant KIT exon 17 mutations significantly attenuate this survival advantage. Exploratory experimental validation in a limited cohort of AML1::ETO and KIT exon 17 mutation patients suggested a potential trend of broad drug resistance such as cytarabine and daunorubicin. Preliminary transcriptomic analysis identified upregulation of SOCS1, a negative regulator of the JAK-STAT pathway, as a potential feature of this resistant phenotype. Furthermore, elevated SOCS1 expression was associated with poor prognosis. We conclude that KIT mutations, especially exon 17, confer a high-risk phenotype in otherwise favorable pediatric AML1::ETO AML. Our exploratory data suggest this may be associated with a chemoresistant profile, potentially driven by SOCS1-associated JAK-STAT dysregulation. These findings highlight the necessity of refined risk stratification based on KIT exon profiling and support targeting the SOCS1/JAK-STAT axis to overcome therapy resistance.
This study aimed to assess serum fibroblast growth factor 21 (FGF-21) levels and explore their clinical significance in patients with rheumatoid arthritis (RA). A total of 187 patients with RA, who were treated at Xuzhou Central Hospital between January 2023 and December 2024, were enrolled in this study. Based on carotid intima-media thickness (cIMT) measurements, they were categorized into a plaque group (n = 118) and a plaque-free group (n = 69). Additionally, 139 healthy individuals undergoing routine physical examinations were recruited as healthy controls (HC). Clinical data were collected from all participants, including lipid profiles, HOMA-IR, ESR, CRP, RF, anti-CCP antibody levels, and serum FGF-21 concentrations. We analyzed the associations between serum FGF-21 levels and both disease activity and atherosclerotic status in RA patients. Statistical analyses, including the chi-square test, Student's t-test, Pearson correlation analysis, and logistic regression, were performed to evaluate these relationships. Serum levels of FGF-21 were significantly elevated in patients with RA compared with healthy controls (805.7 ± 188.68 vs. 203.8 ± 50.7 pg/mL, p < 0.001). Among RA patients, those with carotid plaques exhibited higher FGF-21 levels than those without plaques (840.7 ± 203.6 vs. 745.6 ± 142.2 pg/mL, p < 0.001). Correlation analyses revealed that serum FGF-21 levels were positively associated with LDL-C (r = 0.544), HOMA-IR (r = 0.625), anti-CCP antibodies (r = 0.617), rheumatoid factor (r = 0.366), DAS28 (r = 0.309), and cIMT (r = 0.604) (all p < 0.001). Conversely, FGF-21 levels were negatively correlated with the use of disease-modifying antirheumatic drugs (DMARDs) (r = - 0.569, p < 0.001) and flow-mediated dilation (FMD) (r = - 0.294, p < 0.001). Multivariate logistic regression analysis identified the serum FGF-21 level as an independent factor associated with increased cIMT (odds ratio [OR] = 1.003, 95% confidence interval [CI]: 1.001-1.006, p = 0.006). Our findings suggest a potential correlation between elevated FGF-21 levels and RA disease activity as well as certain metabolic parameters. Further replication studies are needed to clarify whether FGF-21 might serve as a research biomarker in the context of cardiovascular comorbidity in RA.
T cell immunoglobulin and mucin-domain containing protein 3 (TIM-3) is an immune checkpoint that plays a crucial role in immune exhaustion. High expression of TIM-3 has been implicated in exerting immunosuppression across a variety of malignant tumors. Elucidating the expression profile of TIM-3 and its prognostic impact may hold great significance for the therapeutic management of intrahepatic cholangiocarcinoma (ICC). We analyzed 117 ICC patients using immunohistochemical staining for TIM-3 and other immune checkpoints to examined their expression and immune cell infiltration in ICC tissue samples. Furthermore, the correlation of checkpoint expression with clinical characteristics and prognosis were analyzed. High expression of TIM-3 in tumor cells was observed in 61 patients (52.1%) and was significantly correlated with poorer tumor differentiation (P = 0.019). Survival analysis showed that high TIM-3 expression in tumor cells was a prognostic factor for disease-free survival (DFS) and overall survival (OS) in univariate analysis, and an independent risk predictor for DFS in multivariate analysis (P = 0.048, HR = 1.589, 95%CI = 1.004-2.515). Furthermore, TIM-3 expression in ICC tissues was significantly correlated with CD4⁺ and CD8⁺ tumor-infiltrating lymphocytes (both P < 0.005). Patients with high TIM-3 expression in tumor cells had shorter DFS and OS, which could serve as a valuable biomarker for predicting the inflammatory status and prognosis of ICC. Targeting TIM-3 may represent a promising therapeutic strategy for ICC.
Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and progressive airflow limitation. Emerging evidence highlights the gut-lung axis as a potential therapeutic target, with probiotics proposed to modulate Th17-related inflammatory pathways. In this randomized, double-blind, placebo-controlled trial, 50 patients with mild-to-moderate COPD were enrolled; 44 completed the 8-week intervention (23 probiotics, 21 placebo). Participants received either a multistrain probiotic formulation or placebo. Outcomes included spirometry, COPD Assessment Test (CAT), modified Medical Research Council (mMRC) dyspnea scale, and serum IL-6, IL-17, and TGF-β levels. Probiotic supplementation significantly improved FEV1 and FVC within the intervention group, although between-group spirometric differences were not significant. IL-6 levels declined significantly following probiotic therapy, with a significantly greater reduction compared to placebo, whereas IL-17 and TGF-β remained unchanged. CAT scores improved significantly in the probiotic group, exceeding the minimal clinically important difference and demonstrating a significant between-group effect. No significant change was observed in mMRC scores. Eight weeks of probiotic supplementation was associated with reduced systemic IL-6 levels and clinically meaningful improvement in patient-reported outcomes in mild-to-moderate COPD. These findings support a potential adjunctive role for probiotics and warrant larger mechanistic trials. Registered on 26 December 2024 in the Iranian Registry of Clinical Trials (IRCT), registration number IRCT20241211064025N1.