Subtype selectivity is critical in drug development, since off-target effects can restrict clinical application. Kv7.2 is a key target for treating neuronal hyperexcitability disorders. Nonselective activation of Kv7 channels can cause multisystem effects and increase therapeutic risk. Through a detailed analysis of Kv7 subtypes, we identified Kv7.2-specific residues to design a selective binding pocket. E0714 was then developed based on this pocket by virtual screening and compound modification. Electrophysiology assays demonstrated that E0714 potently activates Kv7.2 without significantly affecting Kv7.1, Kv7.3, Kv7.4, or Kv7.5. E0714 exhibited an excellent antiepileptic effect in classical epilepsy models without causing motor coordination problems. Mechanistic studies revealed that E0714 targets the Kv7.2-specific residues F112, Y118, and N289, which are responsible for the compound's subtype-selective activation. These findings clarify the mechanism of action of E0714 and provide a framework for designing highly selective drugs against other Kv7 subtypes.

BackgroundPapillary thyroid carcinoma (PTC) predominantly affects women, particularly during the reproductive years, suggesting that reproductive factors may influence not only tumor occurrence but also metastatic behavior. However, evidence regarding the association between reproductive history and lymph node metastasis (LNM) in women with established PTC remains limited.MethodsWe conducted a retrospective cohort study of 1,828 women with pathologically confirmed PTC who underwent initial surgery. The primary outcome was any cervical lymph node metastasis (LNM). Secondary outcomes included isolated central lymph node metastasis (CLNM) and combined central and lateral lymph node metastasis (CLNM+LLNM). Multivariable logistic regression models were used to evaluate the associations between reproductive history, gravidity, parity, and abortion history and nodal outcomes. Reproductive variables were analyzed in separate models to reduce collinearity. Sensitivity and subgroup analyses were performed to examine the stability of the observed associations.ResultsCervical LNM was identified in 903 patients (49.4%). In the primary adjusted model, ever pregnancy was associated with lower odds of any LNM (adjusted OR 0.420, 95% CI 0.276-0.640; P<0.001). Compared with nulligravid women, the adjusted ORs for any LNM were 0.404 (95% CI 0.260-0.628), 0.480 (95% CI 0.306-0.751), and 0.356 (95% CI 0.224-0.567) for women with 1, 2, and ≥3 pregnancies, respectively (P for trend <0.001). Similar inverse associations were observed for isolated CLNM and CLNM+LLNM. However, the category-specific estimates were not strictly monotonic, suggesting a threshold-like rather than a linear dose-response pattern. Similar inverse associations were observed for isolated CLNM and CLNM+LLNM in the primary models. In sensitivity analyses, the associations generally remained directionally inverse but were attenuated in some analyses, including models using flexible adjustment for continuous age. Analyses involving lateral disease were interpreted cautiously because lateral neck dissection was not performed uniformly across the cohort.ConclusionsIn women with PTC, ever pregnancy was associated with lower odds of cervical LNM, particularly for central compartment disease. This association appeared to be more closely related to ever having been pregnant than to a linear increase in gravidity or parity. Reproductive history may provide supplementary context for nodal risk assessment, but it should not replace established clinicopathological factors or independently alter surgical decision-making.

Obesity-induced cardiomyopathy involves cardiac hypertrophy, apoptosis, and fibrosis, contributing to cardiac dysfunction. Autophagy activation alleviates endoplasmic reticulum stress (ERS). Interleukin (IL)-38, an IL-1 family cytokine with anti-inflammatory and metabolic regulatory properties, protects against cardiovascular diseases. This study investigated whether IL-38 attenuates obesity-induced cardiomyopathy by activating the AMP-activated protein kinase (AMPK)/autophagy pathway to suppress ERS. Mice fed a high-fat diet (HFD) for 20 weeks received IL-38 for the final 8 weeks, with or without an autophagy inhibitor. Cardiac function, serum metabolic parameters, myocardial histology, cardiomyocyte hypertrophy, and apoptosis were assessed. Autophagy and ERS-related proteins and their upstream signaling were evaluated by Western blotting. Primary cardiomyocytes were used for in vitro validation. IL-38 treatment significantly ameliorated myocardial injury in HFD-fed mice and palmitate-treated cardiomyocytes. HFD-suppressed autophagy was restored by IL-38, while elevated ERS was markedly attenuated. The cardioprotection and ERS alleviation conferred by IL-38 were autophagy-dependent and mediated specifically through the AMPK/autophagy signaling pathway; inhibition of either autophagy or AMPK abolished these protective effects. These direct myocardial benefits were accompanied by improved systemic metabolic parameters and reduced cardiac inflammatory cytokines. In conclusion, IL-38 ameliorates obesity-induced cardiomyopathy primarily by activating AMPK/autophagy signaling to alleviate ERS, with concurrent metabolic and anti-inflammatory benefits, highlighting its potential as a therapeutic candidate.

ABSTRACT Given the limited evidence on prognostic factors specifically for older patients with extensive‐stage small cell lung cancer (ES‐SCLC), a population with distinct clinical characteristics, this study aimed to validate whether previously reported prognostic indicators retain their predictive value in this vulnerable group. A retrospective analysis was conducted on data from 270 older ES‐SCLC patients who received treatment at the Fourth Hospital of Hebei Medical University between December 2016 and June 2024. By the final follow‐up date of October 15, 2024, 212 deaths had been recorded. The median progression‐free survival (mPFS) was 6.7 months (95% confidence interval [CI] 6.0–7.4), and the median overall survival (mOS) was 13.1 months (95% CI 11.8–14.4). For PFS, univariate and multivariate Cox analyses identified first‐line chemotherapy (CT) and old‐old (≥ 75 years) as independent adverse prognostic factors. For OS, old‐old, a positive smoking history, bone metastasis, and high‐lactate dehydrogenase (> 250 U/L) were identified as significant adverse prognostic factors. Notably, high‐pro‐gastrin‐releasing peptide (ProGRP) (> 69.2 pg/mL) was significantly associated with an increased risk of death during the follow‐up period beyond 10 months (HR = 1.85, 95% CI 1.05–3.26, p = 0.032); conversely, no significant association was observed within the initial 10 months of follow‐up (HR = 0.84, 95% CI 0.44–1.60, p = 0.604). In conclusion, these findings not only corroborate the prognostic value of previously identified risk factors in older patients with ES‐SCLC but also demonstrate that the prognostic impact of ProGRP is distinctly time‐dependent.

Diabetic neuropathy affects approximately 50% of patients with diabetes, causing significant health issues and reducing quality of life. This review examined the associations between diabetic neuropathy and various laboratory parameters, including metabolic indicators, renal and hepatic function parameters, inflammatory biomarkers, thyroid hormones and vitamins. By summarizing the latest evidence on these easily accessible clinical parameters, the article aims to improve risk stratification, enable earlier diagnosis and develop personalized therapeutic strategies, emphasizing the potential of multi-parameter biomarker integration to optimize patient care.

Diabetic cardiomyopathy (DCM) represents a distinctive myocardial disorder marked by detrimental structural remodeling, encompassing cardiac hypertrophy, myocardial fibrosis, compromised coronary microvascular perfusion, and myocardial dysfunction. Pyroptosis, a newly recognized form of programmed cell death, correlates with inflammatory responses. Chronic inflammation serves a pivotal function in DCM, with pyroptosis substantially contributing to myocardial inflammation in this pathological state. IL-38 demonstrates anti-inflammatory properties through the inhibition of inflammatory signaling pathways in target cells. This investigation sought to examine whether IL-38 could alleviate DM-induced myocardial injury through the modulation of pyroptosis. Following the induction of type 2 diabetes in mice, IL-38 treatment (with or without NLRP3 overexpression) was administered for an additional 8 weeks. Cardiac function, histological architecture, and cardiomyocyte apoptosis underwent assessment. Levels of pyroptosis-related proteins and associated signaling pathways regulating pyroptosis were evaluated. Additionally, the influence of IL-38 on pyroptosis was examined in cultured primary cardiomyocytes. IL-38 demonstrated protective effects against myocardial damage both in vivo and in vitro. The expression levels of pyroptosis-associated proteins increased in type 2 diabetic mice, while IL-38 administration suppressed the pyroptotic process. Additionally, IL-38 reduced pyroptosis via modulation of the STING/NLRP3 signaling cascade. Nevertheless, enhanced NLRP3 expression or STING pathway stimulation counteracted the beneficial outcomes of IL-38.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) has been increasing globally, and data indicate that ferroptosis participates in the pathogenesis of MAFLD. Angiopoietin-like protein 7 (ANGPTL7) is a novel secretory glycoprotein that participates in the pathogenesis of many metabolic diseases. However, the role of ANGPTL7 in MAFLD has been poorly investigated. A total of 194 participants were enrolled, including 104 participants with MAFLD (MAFLD) and 90 healthy controls (Cons). Baseline characteristics and serum biochemical parameters were collected. Serum levels of ANGPTL7, inflammatory factors, and ferroptosis-related proteins were measured by enzyme-linked immunosorbent assay (ELISA). Liver biopsy tissues were obtained from six participants with nonalcoholic steatohepatitis and the trimmed liver tissues from five healthy liver transplant donors; H&E, Masson, Perls Prussian blue, and immunohistochemical staining were performed. Compared with healthy Con, BMI, SBP, and DBP were significantly increased, and ALT, AST, TC, TG, LDL-C, GLU, HbA1c, INS, Hcy, and UA levels were all significantly increased, while HDL-C levels were decreased in MAFLD patients (MAFLD vs. Con, p < 0.05 or p < 0.001). Serum levels of ANGPTL7, TNF-α, IL-6, ACSL4, Keap-1, HO-1, and ferritin were significantly increased, while IL-10, GPX4, and Nrf2 levels were decreased in MAFLD patients when compared with the Con group (MAFLD vs. Con, all p < 0.001). Immunohistochemical staining showed that the expression of ANGPTL7, Keap-1, and HO-1 was significantly increased, while Nrf2 expression was significantly decreased in liver tissue from the MAFLD group (MAFLD vs. Con, all p < 0.05). ROC analysis showed that the optimal cut-off value of serum ANGPTL7 for MAFLD was 9.75 ng/mL, suggesting it could serve as a potential biomarker for the diagnosis of MAFLD. ANGPTL7 may participate in the pathogenesis of MAFLD, and serum ANGPTL7 has predictive value for the diagnosis of MAFLD.

Rationale:Wernicke encephalopathy (WE) results from thiamine deficiency and frequently affects nonalcoholic surgical patients with prolonged fasting and parenteral nutrition. Perioperative WE is often misdiagnosed due to nonspecific symptoms, and its intraoperative electroencephalographic and anesthetic features remain poorly understood.Patient concerns:A 68-year-old male underwent hepatic surgery for malignant obstructive jaundice. Postoperative biliary anastomotic leakage and aphagia led to long-term parenteral nutrition. The patient subsequently developed confusion, somnolence, nystagmus, visual loss, and peripapillary retinal hemorrhage. He also showed abnormal cerebral reactivity to anesthetics during secondary surgery.Diagnoses:Clinical diagnosis: nonalcoholic WE with thiamine-deficiency retinopathy. Infectious, septic encephalopathy and cerebral infarction were excluded.Interventions:Immediate high-dose intramuscular thiamine and magnesium supplementation were initiated. During secondary surgery, anesthesia was cautiously titrated with continuous electroencephalography and patient state index monitoring, with reduced anesthetic doses. Maintenance thiamine therapy was continued postoperatively.Outcomes:Neurological symptoms markedly improved within 3 days after thiamine treatment. Intraoperative electroencephalography revealed diffuse slowing and burst suppression under low anesthetic doses. The patient fully recovered without permanent neurological or ophthalmic sequelae and was discharged uneventfully.Lessons:Prolonged postoperative parenteral nutrition confers high WE risk in nonalcoholic surgical patients. Early empirical thiamine supplementation is essential. Thiamine deficiency increases neuronal sensitivity to anesthetics. Clinicians should enhance perioperative nutritional risk assessment and optimize anesthetic management to avoid severe cerebral complications.

Stress promotes the progression from borderline hypertension to sustained hypertension, but the mechanism remains unclear. We investigated the role of corticotropin-releasing factor (CRF)-expressing neurons in the central nucleus of amygdala (CeA) on arterial blood pressure (ABP) and sympathetic activity of borderline hypertensive rats (BHRs) subjected to chronic unpredictable mild stress (CUMS). CUMS induced sustained hypertension, and led to increased delta-FosB expression as well as enhanced spontaneous and evoked firing of CeA CRF-expressing neurons in BHRs. Furthermore, optogenetic activation of CeA CRF-expressing neurons significantly increased the sympathetic outflow and ABP in BHRs. Impaired GABAergic inhibition, a depolarizing shift of GABA reversal potential ( E GABA ), disrupted chloride homeostasis and increased NKCC1 expression were observed in CeA CRF-expressing neurons in BHRs subjected to CUMS. NKCC1 inhibition with bumetanide restored GABAergic inhibition and chloride homeostasis, normalized neuronal excitability, leading to reduced sympathetic vasomotor tone in CUMS BHRs. These results indicate that NKCC1-mediated disruption of chloride homeostasis in CeA CRF-expressing neurons contributes to elevated sympathetic activity and hypertension under chronic stress. These findings enhance our understanding of the neuronal and molecular mechanisms underlying stress-induced hypertension and reveal potential targets for its prevention and treatment.

IntroductionThyroid hormones (TH) play important role in retinal development and maintaining retinal functional hemostasis. Resting metabolic rate (RMR) provides an estimate of the minimum amount of energy expenditure and has a bearing on insulin resistance. Systemic immune-inflammation index (SII) is a new inflammatory biomarker associated with diabetic complications. Inflammation and energy metabolism imbalance are closely related to the pathogenesis of diabetes retinopathy (DR). However, few studies have investigated the relationship between TH, RMR, SII and DR in type 2 diabetic patients (T2DM) with euthyroidism. This study aims to investigate the association of TH, RMR and SII with DR in Chinese T2DM patients with euthyroidism.MethodsThis cross-sectional study was performed in 819 T2DM patients with euthyroidism. Patients were divided into NDR group (n=609) and DR group (n=210). Baseline data and biochemical parameters of patients were collected. Spearman’s correlation analysis, receiver operating characteristic (ROC) curve analysis and logistic regression analysis were performed to examine the association between TH, RMR, SII and DR.ResultsCompared with NDR patients, the FT3 levels were significantly lower in DR patients, no differences were found in FT4 and TSH levels between the two groups. Furthermore, the SII levels were significantly higher while RMR were lower in DR patients. In multivariate analysis, FT3 and RMR were inversely while SII were positively correlated with the occurrence of DR in T2DM patients with euthyroidism. After adjusting for age and sex, fourth quartile of FT3 showed significantly decreased OR of 0.615 while SII showed increased OR of 1.660 for DR with respect to its first quartile value. In the fully adjusted models, fourth quartile of RMR showed significantly decreased OR of 0.291 for DR with respect to its first quartile value.ConclusionIn euthyroidism patients with T2DM, decreased FT3, RMR and increased SII were correlated with the presence of DR.

Background:Heparin-binding growth and differentiation factors (GDFs) play roles in various cellular processes and are potential contributors to thyroid cancer. Although population-based studies have documented associations between heparin-binding GDFs and thyroid cancer, their causal relationships remain unclear. Methods:A two-sample Mendelian randomization (MR) analysis was conducted using published genome-wide association studies (GWASs) data. The primary method for estimating causal effects was the inverse-variance weighted (IVW) approach, supplemented by multiple sensitivity analyses including weighted median, MR-Egger, and MR-PRESSO. Heterogeneity and outlier effects were systematically evaluated. Additionally, key MR findings were validated at the transcriptomic level using differential expression analysis of data from the Cancer Genome Atlas (TCGA). Results:The IVW method revealed significant causal relationships between midkine levels (OR = 1.2099, 95% CI: 1.013-1.445, p = 0.0355) and IGF2 (OR = 0.7496, 95% CI: 0.6056-0.9279, p = 0.0081) with thyroid cancer and between heparin-binding EGF-like growth factor and malignant thyroid neoplasms (OR = 0.8821, 95% CI: 0.7873-0.9882, p = 0.0304). Heterogeneity was identified in the association between FGF1 and malignant thyroid neoplasms (Q = 20.725, p = 0.036). Neither MR-Egger analysis nor the MR-PRESSO global test found evidence of horizontal pleiotropy in the association between heparin-binding GDFs and thyroid cancer. The robustness of these findings was supported by sensitivity analyses, and transcriptomic analysis of TCGA data further revealed that midkine (MDK was significantly upregulated in thyroid tumor tissues. Conclusions:Genetically predicted midkine levels and IGF2 were associated with thyroid cancer, and heparin-binding EGF-like growth factor was associated with malignant thyroid neoplasms. Future studies are needed to validate these findings.

Tooth avulsion is the most serious dental trauma, mainly affecting anterior teeth in adolescents. Delayed tooth replantation is the most common situation in clinical, but root resorption is a common complication that can lead to tooth loss. As implant is not feasible in adolescents, strategies to mitigate root resorption remain a major challenge in dentistry. We aim to evaluate the therapeutic effect and potential target of periodontal ligament stem cell-conditioned medium (PDLSC-CM) to reduce root resorption in delayed replanted tooth. Clinical samples from delayed tooth replantation patients were analyzed by X-ray and histological staining. A rat model of delayed tooth replantation was established, with PDLSC-CM applied as the tooth preservative and irrigating solution. Root resorption was assessed by micro-CT and histopathology. Proteomic screening followed by Western blot and immunofluorescence was used to identify and validate key molecules. Macrophage polarization and osteoclastogenesis were examined in vitro using RAW264.7 and bone marrow-derived macrophages. Recombinant adeno-associated virus (rAAV) was used to validate the key protein molecules. Human avulsed tooth with delayed replantation shows obvious root resorption and high expressions of inflammatory cytokines and osteoclast-related factors in periapical tissue. PDLSC-CM reduces the root resorption and inhibits the expressions of inflammatory cytokines and osteoclast-related factors in root and periapical tissue of delayed replantation of avulsed tooth in rats. PDLSC-CM downregulates the expression of HAPLN1 mainly in macrophages, thereby inhibits inflammation and osteoclastogenesis of delayed replanted tooth root. Overexpression of HAPLN1 abolishes the protective effect of PDLSC-CM on delayed replanted tooth root. HAPLN1 reduction in macrophages plays a pivotal role in PDLSC-CM reducing root resorption. PDLSC-CM is a promising preservation medium for avulsed teeth with potential clinical applications, and the development of drug candidate targeting HAPLN1 has favorable clinical prospects.

>Dear Editor,Esophageal cancer is the seventh most common malignant tumor in China and has the third highest fatality rate worldwide(Siegel et al., 2022). The most common type in China is esophageal squamous cell carcinoma(ESCC), which has shown a promising response to immune checkpoint inhibitors(Doki et al., 2022; Sun et al., 2021). However, challenges remain in effectively using immunotherapy due to varying patient responses and difficulties in identifying suitable candidates.

The CRISPR (clustered regularly interspaced short palindromic repeats) system has emerged as a revolutionary gene-editing tool with immense potential in gene therapy, functional genomics, and beyond. However, achieving precise spatiotemporal control of gene editing in specific cells and tissues while effectively mitigating potential risks, such as off-target effects, remains a key challenge for its clinical translation. To overcome these limitations, researchers have developed innovative strategies based on chemical modifications of oligonucleotides to enhance the precision, efficiency, and controllability of CRISPR/Cas9-mediated gene editing. By introducing conditional responsive elements, such as photosensitive groups, small-molecule responsive units, and supramolecular structures, they have successfully achieved precise spatiotemporal and dose-dependent regulation of CRISPR/Cas9 function. This review provides a comprehensive overview of recent advancements in gRNA regulation strategies based on chemical modifications of oligonucleotides, discussing their applications in improving the efficiency, specificity, and controllability of CRISPR/Cas9 editing. We also highlight the challenges associated with the conditional control of gRNA and offer insights into future directions for the chemical regulation of gRNA to further advance CRISPR/Cas9 technology.

The skeletal muscle is highly susceptible to injury in daily life. Severe skeletal muscle injuries often result in incomplete regeneration, leading to functional impairment. In clinical practice, understanding the extent of skeletal muscle injury in limb trauma patients is crucial for selecting treatment modalities and assessing prognosis. Currently, there is a lack of specific indicators for evaluating the severity of mechanical skeletal muscle injury. Therefore, the aim of this study is to develop biomarkers for the early evaluation of different degrees of skeletal muscle injury. A rat model of skeletal muscle mechanical compression injury was established with varying degrees of injury severity, one control group, and two compression groups (Mild Injury and Severe Injury Group). LC-MS/MS-4D-DIA quantitative proteomics technology was used to detect the plasma proteome profile of rats in different injury groups at 3 hours post-injury, followed by bioinformatics analysis for data decoding. Rats in the mild and severe injury groups exhibited completely different degrees of injury and prognosis. The proteomic results of the plasma revealed that the relative quantification of 37 proteins increased along with the increase in injury, while 2 proteins decreased. These differentially expressed proteins (DEPs) included not only muscle-specific structural proteins but also metabolic-related proteins that might play crucial roles in tissue injury control, repair, and regeneration. Overall, the study has identified several potential protein biomarkers that can distinguish different degrees of skeletal muscle injury at an early stage. These protein biomarkers may be further developed to help clinicians identify patients with varying degrees of skeletal muscle injury, paving the way for personalized treatments.

BACKGROUND Colony-stimulating factor 3 (CSF3) and its receptor (CSF3R) are known to promote gastric cancer (GC) growth and metastasis. However, their effects on the immune microenvironment remain unclear. Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2 (LILRB2) in GC. We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands, angiopoietin-like protein 2 (ANGPTL2) and human leukocyte antigen-G (HLA-G), contributing to immunosuppression. AIM To investigate the relationship between CSF3/CSF3R and LILRB2, as well as its ligands ANGPTL2 and HLA-G, in GC. METHODS Transcriptome sequencing data from The Cancer Genome Atlas were analyzed, stratifying patients by CSF3R expression. Differentially expressed genes and immune checkpoints were evaluated. Immunohistochemistry (IHC) was performed on GC tissues. Correlation analyses of CSF3R, LILRB2, ANGPTL2, and HLA-G were conducted using The Cancer Genome Atlas data and IHC results. GC cells were treated with CSF3, and expression levels of LILRB2, ANGPTL2, and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting. RESULTS Among 122 upregulated genes in high CSF3R expression groups, LILRB2 showed the most significant increase. IHC results indicated high expression of LILRB2 (63.0%), ANGPTL2 (56.5%), and HLA-G (73.9%) in GC tissues. Strong positive correlations existed between CSF3R and LILRB2, ANGPTL2, and HLA-G mRNA levels (P < 0.001). IHC confirmed positive correlations between CSF3R and LILRB2 (P < 0.001), and HLA-G (P = 0.010), but not ANGPTL2 (P > 0.05). CSF3 increased LILRB2, ANGPTL2, and HLA-G expression in GC cells. Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression, impacting CSF3’s regulatory effects. CONCLUSION The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands, with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.

Tertiary lymphoid structures (TLSs) have emerged as critical prognostic and immunotherapeutic indicators in cancer, with their clinical significance modulated by spatial distribution patterns and density. Here, we performed integrated single-cell and spatial transcriptomic profiling of 30 gastric cancer (GC) specimens stratified by TLS spatial localization patterns. Comparative analysis shows pronounced enrichment of CXCL13+ T lymphocytes (TLCs), CXCR5+ germinal center B lymphocytes (gc_B cells), LAMP3+CD80+ activated dendritic cells (DCs), and SELP+ACKR1+ high endothelial venule (HEV) cells within intratumoral-TLS (iTLS) rich tumors compared to peritumoral-TLS (pTLS) and desert-TLS (dTLS) tumor subtypes. Multimodal cell-cell interaction analysis and functional experiments demonstrate that HEV expressed VCAM1 and ICAM1 recruits and activates CXCL13+ TLC through the CXCL13-ACKR1 pathway, which promotes TLS formation via CXCL13-CXCR5-dependent crosstalk with B lymphocytes. We further develop a single-cell/spatial TLS signature that captures the cellular ecosystem of iTLS-containing tumor, demonstrating predictive value for immunotherapy outcomes in GC patients.

Colorectal cancer (CRC) presents a complex tumor microenvironment influenced by genetic and microbial factors. Microbial DNA from the gut and tumor microenvironment can translocate into the bloodstream, forming a circulating microbiome associated with prognosis and clinicopathological features. This study investigates the peripheral venous blood microbiome in CRC patients using 2bRAD-M sequencing and evaluates its clinical significance. Peripheral venous blood samples from 29 CRC patients (19 males, 10 females; mean age 57 years) and 10 healthy controls were analyzed to assess microbial diversity. Additionally, 20 tumor tissue samples from CRC patients were examined via RT-qPCR to validate blood-tumor microbial correlations. Statistical analyses evaluated associations between microbial abundance and clinical features, including metastasis and PD-L1 Combined Positive Score (CPS). Comparative analyses between CRC patients and healthy controls were performed to identify disease-specific microbial signatures. A total of 270 microbial species were identified, with dominant phyla including Actinomycetota, Bacillota, Bacteroidota, and Pseudomonadota. Bosea lupini was significantly associated with metastasis stage (p = 0.034), while Mycobacterium tuberculosis (p = 0.022), Porphyromonas pasteri (p = 0.017), and Bosea lupini (p = 0.045) correlated with CPS. Microbes such as Bosea lupini, Ralstonia mannitolilytica, and Porphyromonas pasteri suggested potential tumor-derived translocation into the bloodstream. This study identifies a distinct peripheral venous blood microbiome in CRC patients, highlighting specific microbes associated with clinicopathological features and disease progression. These findings suggest the potential of blood microbiomes as noninvasive biomarkers for CRC prognosis and therapeutic targets, warranting further investigation in larger cohorts.

In recent years, aurora kinase C (AURKC) has emerged as a potential therapeutic target for cancer, having been found to induce proliferation in a variety of cancers. However, at present, its precise mechanism remains unclear. In this study, the specific role of AURKC in renal clear cell carcinoma and its mechanism was investigated. The protein expression levels of AURKC were evaluated in clear cell carcinoma and adjacent normal tissues, followed by prognostic analysis. Subsequently, cell models with knocked-down and overexpressed AURKC were constructed for in vitro cell experiments, and tumor-bearing mouse models were constructed to confirm the specific role of AURKC in vivo. AURKC was found to be highly expressed in ccRCC, which was associated with poor prognosis. In the in vitro experiments, the expression levels of CyclinD1 and proliferating cell nuclear antigen (PCNA) proteins were downregulated after AURKC knockdown, and the cell proliferation ability was found to decrease significantly. After AURKC overexpression, the levels of ERp57 protein expression increased significantly, also significantly enhancing the cell proliferation ability. In addition, AURKC was found to interact with ERp57 and exhibited a colocalization relationship. In the in vivo experiments, AURKC downregulation significantly inhibited the expression of ERp57 protein and blocked the growth of tumor tissue in tumor-bearing mice. These results suggest that the abnormal expression of AURKC in ccRCC enhances the expression of ERp57 protein, thereby promoting the proliferation of clear cell renal cell carcinoma. Thus, AURKC shows potential as a target for the treatment of ccRCC.