Aims:To explore the correlation between serum Methylglyoxal (MGO) and endothelial dysfunction in patients with type 2 diabetes mellitus, and to evaluate the clinical value of MGO in the development of diabetes mellitus and its complications. Methods:In this cross-sectional study, we enrolled 250 patients diagnosed with T2MD. Based on flow-mediated dilation (FMD) measurements, the patients were categorized into normal endothelial function group (FMD ≥6.4%, n = 61) and endothelial dysfunction group (FMD <6.4%, n = 189). Analysis of the relationship between MGO and FMD was conducted via Spearman's correlation, partial correlation, and multiple logistic regression. An ROC curve analysis was utilized to quantify the predictive performance of MGO for endothelial function. Results:Endothelial dysfunction was observed in 189 (76%) patients with type 2 diabetes. Patients with endothelial dysfunction had higher concentration of MGO in the serum (P < 0.001) than those without endothelial dysfunction. Spearman correlation analysis showed that there was a significantly negative correlation between FMD and MGO (R = -0.611, p < 0.001), and this negative correlation remained significant upon adjustment for age and sex. (R = -0.36, p < 0.001). Logistic regression analysis identified MGO as an independent risk factor for endothelial dysfunction (OR 1.099, (1.06-1.14), p < 0.001), and the odds of endothelial dysfunction increased 2.67-fold per standard deviation (SD) increment in MGO levels (OR: 2.67 (1.78-4.01), p < 0.001) (Model 1). After adjusting for gender, age, BMI, course of disease, hypertension, smoking and alcohol consumption (model 2) as well as HbA1c, HOMA-IR, C-reactive protein and TG (model 3), similar results were obtained. Restricted cubic spline (RCS) analysis revealed a significant non-linear does-response relationship between MGO levels and endothelial function (P overall<0.001, P non-linearing<0.001). Subgroup analyses demonstrated that the association between MGO levels and endothelial function remained consistent across various strata, including age, sex, and comoribidities (all P interaction>0.05). Receiver operating characteristic (ROC) curve: the area of under the ROC curve (AUC) for MGO was 0.785 (OR: 0.73-0.84, p < 0.001). Conclusion:MGO was significantly inversely associated with FMD and endothelial function in T2DM patients, and can be used as a biomarker to assess vascular endothelial health. Detection of serum MGO levels has clinical significance in the prevention of early diabetic vascular disease.

While formalin-fixed paraffin-embedded (FFPE) samples are invaluable for human non-Hodgkin B-cell lymphoma translational research, effective methods for spatial profiling of chromatin accessibility and histone modifications in these tissues remain limited. Here, we introduce epi-Patho-DBiT, a platform that combines reverse crosslinking of FFPE tissues with spatially resolved assays for transposase-accessible chromatin using sequencing (spatial-FFPE-ATAC) or cleavage under targets and tagmentation (spatial-FFPE-CUT&Tag). Using spatial-FFPE-ATAC, we map epigenetic landscapes in mucosa-associated lymphoid tissue and follicular lymphoma, identifying chromatin variants linked to B-cell malignancy and resolving tumor karyotypes. Mitotic age inference reveals spatial tumor dynamics and uncovers cholesterol-mediated cell proliferation. Furthermore, spatial-FFPE-CUT&Tag elucidates genomic alterations during transformation of follicular lymphoma into diffuse large B-cell lymphoma and identifies DIP2C with dysregulated H3K4me3 and H3K27me3 levels. Unexpectedly, we observe elevated H3K27me3 occupancy at a chromosome 2 locus containing tumor-promoting genes, attributed to copy number amplification and thereby upregulation in transformed diffuse large B-cell lymphoma.

The pathogenesis of autoimmune diseases remains poorly understood, largely because existing models fail to capture both the initial triggers and the full spectrum of systemic manifestations. Here, we identify the skin epithelium as an initiating site of autoimmune activation. Specifically, we found that PPARγ levels are broadly reduced in basal-layer keratinocytes from patients across the lupus disease spectrum. To investigate the functional impact of this epithelial defect, we employed keratinocyte-specific gene editing in mice. Localized editing induced cutaneous lupus-like inflammation, while more extensive epithelial perturbation triggered rapid systemic autoimmunity, characterized by multi-organ inflammation and autoantibody production. Moreover, ultraviolet exposure accelerated the progression from cutaneous to systemic disease, recapitulating the spectrum transition and clinical photosensitivity. Mechanistically, we found that proinflammatory keratinocytes promoted the emergence of migratory CCR7⁺ dendritic cells, which appeared to initiate and amplify immune activation beyond the epithelial niche. Our findings establish the skin epithelium as a critical initiator of autoimmunity and provide a tunable model that recapitulates key features of human lupus spectrum.

MOTIVATION:Despite significant advances in spatial transcriptomics, the analysis of formalin-fixed paraffin-embedded (FFPE) tissues, which constitute most clinically available samples, remains challenging. Additionally, capturing both coding and non-coding RNAs in a spatial context poses significant challenges. We recently introduced Patho-DBiT, a technology designed to address these unmet needs. However, the marked differences between Patho-DBiT and existing spatial transcriptomics protocols necessitate specialized computational tools for comprehensive whole-transcriptome analysis in FFPE samples. RESULTS:Here, we present ASTRO, an automated pipeline developed to process spatial transcriptomics data. In addition to supporting standard datasets, ASTRO is optimized for whole-transcriptome analyses of FFPE samples, enabling the detection of various RNA species, including non-coding RNAs such as miRNAs. To compensate for the reduced RNA quality in FFPE tissues, ASTRO incorporates a specialized filtering step and optimizes spatial barcode calling, increasing the mapping rate. These optimizations allow ASTRO to spatially quantify coding and non-coding RNA species in the entire transcriptome and achieve robust performance in FFPE samples. AVAILABILITY AND IMPLEMENTATION:Codes are available at GitHub (https://github.com/gersteinlab/ASTRO) and Zenodo (doi: 10.5281/zenodo.17913760).

Resistance to cisplatin-based chemotherapy remains a major barrier to effective systemic treatment of bladder cancer, underscoring the need for predictive biomarkers and therapeutic targets. Here, we identify YAP1-K90la as a functional post-translational modification that causally drives cisplatin resistance. Across multi-center clinical cohorts, elevated YAP1-K90la levels were associated with poor therapeutic outcomes and outperformed total YAP1 expression in predicting cisplatin responsiveness. Mechanistically, YAP1-K90la enhances YAP1 nuclear localization and transcriptional activity to induce a FOSL1-dependent program that suppresses ferroptosis and promotes cell survival under cisplatin stress. Notably, AARS1 and SIRT1 function as the "writer" and "eraser" of YAP1-K90la, respectively, with SMURF2-mediated ubiquitination of SIRT1 stabilizing YAP1-K90la and driving resistance. Targeting YAP1-K90la using a cell-penetrating peptide restored ferroptotic vulnerability and sensitized bladder cancer cells to cisplatin. Collectively, these findings reveal the YAP1-K90la/FOSL1 pathway that drives cisplatin resistance and position YAP1-K90la as a clinically actionable biomarker and therapeutic target in bladder cancer.

Computational prediction of miRNA binding sites on target mRNAs facilitates experimental investigation of miRNA functions. In this chapter, we describe STarMir and STarMirDB, two application modules of the Sfold RNA package. STarMir is a Web server for performing miRNA binding site predictions for mRNA and target sequences submitted by users. STarMirDB is a database of precomputed transcriptome-scale predictions. Both STarMir and STarMirDB provide comprehensive sequence, thermodynamic, and target structure features, a logistic probability as a measure of confidence for each predicted site, and a publication-quality diagram of the predicted miRNA-target hybrid. In addition, STarMir now offers a new quantitative score to address combined regulatory effects of multiple seed and seedless sites. This score provides a quantitative measure of the overall regulatory effects of both seed and seedless sites on the target. STarMir and STarMirDB are freely available to all through the Sfold Web application server at http://sfold.wadsworth.org .

In 2022, the World Health Organization estimated that globally, ~2.5 billion adults were overweight, including 890 million individuals with obesity. Adipose tissue dysfunction in obese individuals is a key contributor to the pathogenesis of insulin resistance. Within the present study, the association between serum levels of C1q/TNF‑related protein 4 (CTRP4) and insulin resistance (IR) in overweight/obese patients was investigated and the effects and mechanisms of CTRP4 on IR in dexamethasone‑induced 3T3‑L1 adipocytes were evaluated. A total of 98 overweight/obese patients were enrolled in the present study. Serum CTRP4 concentration levels were measured with ELISA kits. Correlations between CTRP4 and the homeostatic model assessment of IR (HOMA‑IR) were evaluated using Spearman's correlation analysis. Recombinant CTRP4 protein was administered to fully differentiated 3T3‑L1 adipocytes to explore the impact of CTRP4 on lipid accumulation. In addition, the effects of CTRP4 on restoring impaired glucose uptake were examined through the glucose oxidase‑peroxidase method. Molecular marker expression levels in the insulin signaling pathway, in 3T3‑L1 adipocytes with IR induced by 1 µM dexamethasone, were also examined, through western blotting. The expression levels of CTRP4 exhibited a negative association with body mass index (r=‑0.35; P<0.001), HOMA‑IR (r=‑0.24; P=0.048), waist circumference (r=‑0.38; P<0.001) and abdomen circumference (r=‑0.39; P<0.001). Following treatment of cells with recombinant CTRP4, a significant reduction in lipid accumulation was observed in 3T3‑L1 adipocytes, alongside with an increase in the glucose uptake rate in dexamethasone‑induced 3T3‑L1 adipocytes (all, P<0.05). Furthermore, a marked elevation in the expression levels of insulin receptor substrate 1 (IRS‑1), PI3K and AKT phosphorylation and GLUT4 was observed in the IR model of 3T3‑L1 adipocytes. Serum CTRP4 concentration levels were negatively correlated with IR in overweight/obese patients. CTRP4 suppressed lipid accumulation and promoted glucose uptake through the IRS‑1/PI3K/AKT signaling pathway and caused increased GLUT4 expression in 3T3‑L1 adipocytes.8.

Vascular endothelium is integral to the regulation of vascular homeostasis and maintenance of normal arterial function in healthy individuals. Endothelial dysfunction is a significant contributor to the advancement of atherosclerosis, which can precipitate cardiovascular complications. A notable correlation exists between diabetes and endothelial dysfunction, wherein chronic hyperglycemia and acute fluctuations in glucose levels exacerbate oxidative stress. This results in diminished nitric oxide synthesis and heightened production of endothelin-1, ultimately leading to endothelial impairment. In clinical settings, it is imperative to implement appropriate therapeutic strategies aimed at enhancing endothelial function to prevent and manage diabetes-associated vascular complications. Various antidiabetic agents, including insulin, GLP-1 receptor agonists, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, thiazolidinediones (TZDs), and metformin, are effective in mitigating blood glucose variability and improving insulin sensitivity by lowering postprandial glucose levels. Additionally, traditional Chinese medicinal compounds, such as turmeric extract, resveratrol, matrine alkaloids, tanshinone, puerarin, tanshinol, paeonol, astragaloside, berberine, and quercetin, exhibit hypoglycemic properties and enhance vascular function through diverse mechanisms. Consequently, larger randomized controlled trials involving both pharmacological and herbal interventions are essential to elucidate their impact on endothelial dysfunction in patients with diabetes. This article aims to explore a comprehensive approach to the treatment of diabetic endothelial dysfunction based on an understanding of its pathophysiology.

BackgroundThe correlation between TREM-1 and vascular complications in patients with type 2 diabetes was a subject of debate. This study aimed to investigate the potential correlation between TREM-1 and flow-mediated dilatation (FMD) in patients with type 2 diabetes mellitus.MethodsIn this retrospective cohort research, 201 patients with type 2 patients diabetes were enrolled. The FMD Vascular Endothelial Cell Function Test Instrument was used to evaluate endothelial dysfunction. The serum levels of TREM-1 were measured using enzyme-linked immunosorbent assay. The Spearman correlation test was employed to determine the association between TREM-1 and FMD. Univariable logistic regression analysis was conducted to assess the relationship between TREM-1 and FMD. Additionally, receiver operating characteristic curve analysis was used to determine the TREM-1’s predictive value. The statistical significance was evaluated using a two-tailed P-value >0.05.ResultsThe study involved dichotomizing diabetic patients into low FMD (n = 138) and high FMD (n = 63) groups. The results showed that serum TREM-1 levels were significantly higher in the low FMD group than in the high FMD group (33.6 vs 58.0 pg/ml, P<0.001). A univariate logistic regression analysis revealed a statistically significant association between FMD and TREM-1 (P<0.05). The area under the curve for the receiver operating characteristic curve for model 1 (TREM-1) analysis was 0.66 (0.58-0.74) (P 0.001). Using the criteria of maximal Youden index, the threshold value for TREM-1 was found to be 38.16 ng/ml. This value showed a sensitivity of 75.4% and a specificity of 54% in predicting endothelial dysfunction in patients with type 2 diabetes mellitus.ConclusionSerum TREM-1 levels were associated with FMD, indicating that TREM-1 could be a valuable biomarker for assessing endothelial function in T2DM patients.

This review provides a comprehensive examination of the clinical pharmacological mechanisms and broad therapeutic applications of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual receptor agonists targeting both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. GLP-1RAs exert their effects by stimulating insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite through the activation of the GLP-1 receptor. These agents have demonstrated significant efficacy in the management of type 2 diabetes mellitus (T2DM) and obesity. Moreover, emerging evidence suggests that GLP-1RAs may confer cardiovascular protection, neuroprotective benefits, and positive effects on mental health. Dual GLP-1/GIP receptor agonists, such as tirzepatide, simultaneously activate both receptors, thereby potentiating glycemic control, promoting weight loss, and ameliorating metabolic dysfunction. This review also addresses recent advances in the development of other dual and triple receptor agonists. Distinct from prior reviews that predominantly focus on a single drug class or limited clinical indications, this article systematically contrasts the mechanistic pathways, therapeutic efficacy, and safety profiles of GLP-1RAs versus GLP-1/GIP dual receptor agonists. Notably, it integrates the most current evidence pertaining to novel domains, such as perioperative management, neuropsychiatric outcomes, and the innovation of multi-receptor agonists. This synthesis offers a timely and practical resource to inform clinical precision medicine and to guide future investigative efforts.

Nanoconfined selective ion transport shows promise for achieving biomimetic ion separation and iontronics information transmission. However, exploration of tunable nonlinearity of ion transport is formidable due to the challenge in fabrication of nanochannel devices of exquisite nanoconfined architectures. Here, we report a hierarchical metal-organic framework (MOF)-based nanofluidic device of multiscale heterogeneous channel junctions to achieve unprecedented triode-like nonlinear proton transport, in contrast with diode-like rectifying transport for metal ions. Through experiments and theoretical simulations, we unveil the underlying mechanism for this unique nonlinear proton transport property, i.e., the gating effect from the built-in electric potential across the MOF phase junctions enabled by voltage bias above a threshold. As a proof-of-concept application demonstration, the nanofluidic device exhibits an ionic memory property as a nanofluidic memristor. This finding of proton-specific nonlinear resistive switching and memristive phenomenon can inspire future studies into nanofluidic iontronics and mass transport by rational design of coupled nanometric and angstrom-sized confinement.

Neutrophil granules are membrane-bound compartments crucial for host defense, mediating these leukocyte's potent antimicrobial, inflammatory, and cytotoxic responses. Mislocalization of granule proteins is a leading cause of hereditary immune disorders such as cyclic (CN) and severe congenital neutropenia (SCN). In contrast, excessive granule release contributes to inflammatory pathologies, including cytokine storms seen in severe infection. Despite their importance, the molecular mechanisms that underlie granule biogenesis remain poorly understood, limiting therapeutic progress. In this work, we identified a cohort of stage-specific regulators which mediate both functional and impaired granule biogenesis. Granule formation occurs sequentially during the differentiation of myeloblasts into mature segmented neutrophils, in a process called granulopoiesis. Previous work has established an intricate transcriptional program which induces granule protein expression at specific stages of differentiation, to allow for the formation of three different kinds of granule. The three granule subtypes—primary (azurophilic), secondary (specific), and tertiary (gelatinase)—are defined by their unique protein cargo and fusion machinery, yet all form via vesicle budding from the Golgi apparatus. Specifically, the endoplasmic reticulum synthesizes, folds, and quality checks proteins destined for granules before transporting them through the Golgi apparatus to the trans-Golgi Network (TGN), where they are sorted into the three different types of immature secretory granules. Previous work has suggested that the azurophilic granules further mature in conjunction with the endolysosomal system. However, the mechanism by which granule-destined proteins are separated from bulk TGN content and constitutively secreted proteins remain poorly understood. In spite of the physiological importance of neutrophil granules, there has yet to be a sorting receptor established for any granule protein within these cells. Our work shows that three granule-associated proteins: Serglycin (Srgn), Chromogranin A (ChgA), and Chromogranin B (ChgB), act as stage-specific regulators of granule biogenesis. Using ER-HoxB8 progenitor cells, we found that Srgn is enriched during the early stages of differentiation, colocalizing with azurophilic granule markers (MPO, ELANE) in the TGN and early endosomes. However, once matured into metamyelocytes the majority of Srgn is excluded from mature granules; relocated to a novel, non-endolysosomal membrane compartment. In contrast, ChgA and ChgB are expressed at later stages, selectively localizing with specific (lactoferrin-positive) and gelatinase (MMP9-positive) granules, respectively. In contrast to Srgn, ChgA and ChgB remain in their respective granules throughout neutrophil maturation. Given their granule-forming roles in endocrine cells, ChgA and ChgB likely drive subtype-specific cargo sorting and packaging in neutrophils. A breakdown of granulopoiesis is known to occur in promyelocytic leukemias, resulting in loss of the specific and gelatinase granules. We found that though specific granule cargo is expressed appropriately within these cells, the granule-associated proteins lose their stage specific expression and mislocalize. In these cells, ChgA is mistargeted to the azurophilic granules via an endolysosomal dependent mechanism. The specific granule proteins, instead, localize to the constitutively expressed pathway. These results indicate that mistargeting of granule proteins is driven by these granule-associated proteins, not simply timing. Notably, in Myelodysplastic Syndromes, neutrophils often present with abnormal granulation. In these cells, though capable of expressing granule proteins, we observe mislocalization of proteins from their stage-specific regulators. This may point to a common mechanism underlying failed granulopoiesis in these diseased states: the loss of granule-associated proteins. These findings establish a novel model for neutrophil granulopoiesis, identifying a new class of molecular actors which orchestrate this complex process. Further, we propose a stage-specific regulator dependent mechanism for the failed granulopoiesis, revealing potential targets for regulating these granule subtypes in disease.

Compared with acidic environments, promoting the water dissociation process is crucial for speeding up hydrogen evolution reaction (HER) kinetics in alkaline electrolyte. Although the construction of heterostructured electrocatalysts by hybridizing noble metals with metal (hydr)oxides has been reported as a feasible approach to achieve high performance, the high cost, complicated fabrication process, and unsatisfactory mass activity limit their large-scale applications. Herein, we report a single-phase HER electrocatalyst composed of single-atom ruthenium (Ru) incorporated into a cobalt oxide spine structure (denoted as Ru SA/Co3O4), which possesses exceptional HER performance in alkaline media via unusual atomic-scale Ru-Co pair sites. In particular, Ru SA/Co3O4 exhibits a very low overpotential of 44 mV at 10 mA cm-2 and an outstanding mass activity of 4700 mA mg-1 at 50 mV overpotential, superior to those of commercial Pt/C, Ru nanoparticles supported on Co3O4 (denoted as Ru NP/Co3O4) and other reported Ru-based electrocatalysts. With insights from theoretical calculations, the synergistic interactions between Ru and Co pair active sites in Ru SA/Co3O4 are revealed to catalyze diverse fundamental steps of the alkaline HER; i.e., the Ru sites can effectively accelerate water adsorption/dissociation and OH- desorption, whereas the Co sites are favorable for H* adsorption and H2 evolution.

Supplementary Figure S1-S10, supplementary table S1-S8, supplementary methods. Figure S1. The construction of sunitinib-resistant model and validation of sunitinib resistance. Figure S2. Screening and identification of lncRNA IGFL2-AS1 related to sunitinib resistance. Figure S3. IGFL2-AS1 promotes sunitinib resistance of RCC cells in vitro and in vivo. Figure S4. IGFL2-AS1 overexpression enhances autophagy in RCC cells by regulating alternative splicing of TP53INP2. Figure S5. IGFL2-AS1 functions by binding to hnRNPC protein. Figure S6. IGFL2-AS1 regulates alternative splicing of TP53INP2 through competitively binding to hnRNPC. Figure S7. hnRNPC mediates IGFL2-AS1 packaging into EVs and transmission of sunitinib resistance. Figure S8. m6A epigenetic modification is critical to IGFL2-AS1 interaction with hnRNPC. Figure S9. Characteristics of C-SLN nanoparticles and in vivo application of C-SLN/ASO-IGFL2-AS1 complexes. Figure S10. Extended applicability of IGFL2-AS1 to resistance of cabozantinib and axitinib. Supplementary Table S1. Correlations between IGFL2-AS1 tissue expressions and clinical characteristics of 72 ccRCC patients in the SYSU Cohort. Supplementary Table S2. Univariate and multivariate cox regression analysis of variables associated with PFS in the SYSU cohort. Supplementary Table S3. Correlations between IGFL2-AS1 expressions in serum-derived EVs and clinical characteristics of 60 ccRCC patients in the SYSU Cohort. Supplementary Table S4. Uivariate and multivariate cox regression analysis of variables associated with PFS in the SYSU cohort. Supplementary Table S5. Clinical characteristics of RCC patients in the PDX models. Supplementary Table S6. Targeting sequence of siRNA and ASO. Supplementary Table S7. Primers used in this study for qRT-PCR analysis. Supplementary Table S8. Primary antibodies applied in this study.

Motivation: Despite significant advances in spatial transcriptomics, the analysis of formalin-fixed paraffin-embedded (FFPE) tissues, which constitute most clinically available samples, remains challenging. Additionally, capturing both coding and noncoding RNAs in a spatial context poses significant challenges. We recently introduced Patho-DBiT, a technology designed to address these unmet needs. However, the marked differences between Patho-DBiT and existing spatial transcriptomics protocols necessitate specialized computational tools for comprehensive whole-transcriptome analysis in FFPE samples. Results: Here, we present ASTRO, an automated pipeline developed to process spatial transcriptomics data. In addition to supporting standard datasets, ASTRO is optimized for whole-transcriptome analyses of FFPE samples, enabling the detection of various RNA species, including non-coding RNAs such as miRNAs. To compensate for the reduced RNA quality in FFPE tissues, ASTRO incorporates a specialized filtering step and optimizes spatial barcode calling, increasing the mapping rate. These optimizations allow ASTRO to spatially quantify coding and non-coding RNA species in the entire transcriptome and achieve robust performance in FFPE samples. Availability: Codes are available at GitHub (https://github.com/gersteinlab/ASTRO). ### Competing Interest Statement The authors have declared no competing interest.

A new function of glycosylated RNAs has been discovered by Graziano et al.1 in which the glycosylation of RNA molecules shields acp³U RNA modification from triggering innate immune responses.

Chronic wounds, a major healthcare burden, are characterized by impaired fibroblast function and ECM remodeling. Thrombospondin-2 (TSP2), a matricellular glycoprotein, has been shown to negatively regulate wound healing. Here, we investigated the cellular and transcriptomic consequences of TSP2 deficiency in dermal fibroblasts, key cells in tissue repair and extracellular matrix (ECM) remodeling. Using bulk RNA sequencing of wild-type (WT) and TSP2 knockout (TSP2 KO) murine primary fibroblasts, we identified upregulation of pro-regenerative molecules and signaling pathways, specifically TGF-β3 and Wnt4/β-catenin, in the latter. To overcome the inherent variability of primary cells and establish a robust model, we generated a stable CRISPR/Cas9-engineered TSP2 knockout in NIH3T3 fibroblasts. This system confirmed that TSP2 depletion enhances fibroblast proliferation and migration, associated with increased activity of TGF-β3 and Wnt/β-catenin signaling pathways. These findings not only provide novel mechanistic insights into the role of TSP2 in regulating fibroblast function and ECM interactions during tissue repair, but also highlight TSP2 as a potential therapeutic target for promoting regeneration in healing-impaired or chronic wounds.

BACKGROUND:This study aimed to examine the association between branched-chain amino acids/branched-chain α-keto acids (BCAAs/BCKAs) and adipose tissue insulin resistance (Adipo-IR) in patients with type 2 diabetes mellitus (T2DM). METHODS:A total of 506 patients with T2DM were included in this cross-sectional study. Participants were categorized into two groups based on Adipo-IR levels (non-Adipo-IR: Adipo-IR<7.68; Adipo-IR: Adipo-IR ≥ 7.68). Serum BCAA/BCKA concentrations were measured using ELISA kits. Correlations between BCAAs/BCKAs and Adipo-IR or HOMA-IR were evaluated using Spearman correlation analysis. Binary logistic regression was used to examine the associations of BCKAs with both indices of insulin resistance. RESULTS:Median serum BCKA levels were significantly higher in the Adipo-IR group than in the non-Adipo-IR (128.27 vs. 121.16, p < 0.001), while there was no significant difference in median serum BCAA levels between the two groups (2.54 vs. 2.52, p = 0.714). BCKAs were positively correlated with both Adipo-IR and HOMA-IR (both p < 0.01), and the association with Adipo-IR was stronger. Binary logistic regression analysis revealed that BCKAs were associated with Adipo-IR regardless of adjustment for influencing factors, with increasing odds ratios across BCKAs quartiles (p for trend < 0.01). However, after adjusting for covariates, the association between BCKAs and HOMA-IR was no longer significant. CONCLUSIONS:Serum BCKA levels were elevated in T2DM patients with Adipo-IR and were more strongly correlated with Adipo-IR than HOMA-IR. BCKAs may serve as sensitive biomarkers for Adipo-IR. Consequently, we would promote their clinical usage in the early screening of individuals with obesity, insulin resistance and a high risk of T2DM.

Curative-intent hepatectomy in colorectal cancer liver metastasis (CRCLM) is guided by clinical criteria; however, molecular biomarkers may enhance prognostication. Homeobox (HOX) gene family is often dysregulated in cancer and may serve as a prognostic tool in metastatic colorectal cancer. Bulk RNA extraction was performed in frozen colorectal liver tumors (N = 39), and differentially expressed HOX genes using clinical risk scores were studied using supervised hierarchical clustering. In sum, 667 differentially expressed genes were found (p < 0.05), including multiple HOXA and HOXD family genes (p < 0.01; q<0.01). Three long non-coding RNA species (lncRNAs) were differentially expressed: HOTTIP, HOXA-AS5, and HOXD-AS2 (p < 0.01; q<0.01). HOXA13 and HOTTIP were more likely to be expressed in patients with metastatic recurrence (log-rank p = 0.004). A composite HOX score was found to be predictive of OS and RFS (log-rank p = 0.0269 and 0.0273, respectively). HOXA13, HOXD4, and HOXD8 were explored in five independent cohorts. HOX genes and their associated lncRNAs exhibit prognostic associations in patients with CRCLM and may act as biomarkers to refine clinical decision-making.