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ObjectiveHepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further.DesignHere, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice.ResultsThese HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials.ConclusionHBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient’s life.

Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival ( P  = 0.025) and overall survival ( P  = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3 - FGFR1 . Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies.

The Li + -transport mechanisms in both solid polymer electrolytes (SPEs) and liquid electrolytes (LEs) are fundamentally governed by solvation dynamics, requiring an optimal balance between continuous coordination and moderate binding strength. Poly(ethylene oxide) (PEO) is a classic SPE matrix that leverages its –CH 2 –CH 2 –O– (EO) segments to provide continuous oxygen coordination for Li + transport via amorphous regions. While continuous EO segments facilitate the intra-chain Li + -transport, their strong multidentate solvation of Li + through a chelate effect – each Li + chelates with 4–6 ethylene oxide (EO) units – significantly hinders the inter-chain Li + mobility. This effect creates rigid solvation cages that both immobilize Li + and resist modification by alternative moieties (e.g. carbonate or nitrile groups), resulting in poor room-temperature ionic conductivity ( σ ) and low Li + transference number ( t Li+ ). To address these challenges, we developed a series of precise Li + -transport models (LTMs) through click chemistry, strategically combining acrylate-PEG and acrylonitrile to engineer balanced interactions between multidentate (EO) and monodentate (C = O, C ≡ N) coordination sites. This design achieved synergistic enhancement of both inter- and intra-chain transport pathways, demonstrated by significantly improved performance with σ  = 6.40 × 10 − 5 S/cm and t Li+ = 0.44 at 25 °C. This approach permits tailored control of dynamic solvation structures, offering new opportunities to enhance Li + transport in PEO-based solid polymer electrolytes.

Background The prognostic values of preoperative aspartate aminotransferase (AST), monocyte-to-lymphocyte ratio (MLR), AST·MLR index (AMLRI) and operation injury condition in patients with colorectal cancer liver metastases (CRLM) remains unclear. This retrospective study assessed the relationship between these markers, progression-free survival (PFS), and overall survival (OS) in CRLM patients undergoing resection. Methods AMLRI was defined as AST × MLR. Operation injury condition was defined according to operation time and blood loss. Cox regression analyses were used to identify risk factors and to develop nomograms. C-indexes, time-dependent receiver operating characteristic (time-ROC) curves and calibration curves were used to assess the models. Results A total of 379 patients were enrolled. The optimal cut-off value of the AMLRI was 3.33. In the multivariable analysis, AMLRI > 3.33 (hazard ratio [HR] = 2.162, p  = 0.002) and serious operation injury condition (HR = 1.539, p  = 0.012) were predictive for unfavourable OS, and AMLRI > 3.33 (HR = 1.462, p  = 0.021) was predictive for unfavourable PFS. The nomograms were superior to Fong’s Clinical Risk Score (CRS) according to the C-indexes (PFS: 0.682 vs. 0.600; OS: 0.730 vs. 0.586) and time-ROCs. Conclusions Preoperative AMLRI and operation injury condition are easily accessible predictors for prognosis. The nomograms performed better than CRS for the prediction of recurrence and survival.

Construction land development intensity is a spatial mapping of modern urbanization level, which integrally reflects urban development strategy, land use efficiency, and population carrying intensity. This article analyzed the spatial and temporal evolution of construction land development intensity using panel data of 31 provincial administrative divisions in China from 2002 to 2020, with the application of the Theil index and spatial autocorrelation. To further investigate the relationship between human activities and land development, the article used geographic detectors to analyze the influencing mechanisms. The results showed that: (1) The average intensity of construction land development of Chinese provinces from 2002 to 2020 showed a trend of \"steady increase, a short decline, and then a steady increase,\" and there were significant differences in the characteristics of construction land development intensity changes in different regions. (2) The regional differences in construction land development intensity between provinces showed a decreasing trend. There were uneven differences among regions, with more minor regional differences in Central, South, and North China but more significant differences in Northwest, East, Southwest, and Northeast China. (3) The spatial agglomeration of construction land development intensity in the region increased initially and then decreased during the study period. The overall pattern was \"small agglomeration and large dispersion.\" (4) Economic development factors such as GDP per land, industrial structure, and fixed asset investment completion significantly affect land development intensity. The interaction between the factors was apparent, and the effect of “1 + 1 > 2” was produced. Based on the study's results, it is suggested that scientific regional development planning, guiding inter-provincial factor flow, and rational control of land development efforts are the key to promoting sustainable regional development.

Colorectal cancer (CRC) diagnosis is challenging due to generalized symptoms. Various biomarker models exist, but their clinical application is limited by low sensitivity and heterogeneous cutoff values. This study aimed to develop and validate a diagnostic model for CRC. Data from 489 patients—337 with CRC and 152 with benign disease—were included. Patients were randomly assigned to training (n = 342) and validation (n = 147) cohorts. Logistic regression identified age (OR 1.06), CA153 (OR 0.26), CEA (OR 4.49), CYFRA 21-1 (OR 5.88), ferritin (OR 0.15), and hs-CRP (OR 0.05) as independent risk factors. Sensitivity and specificity were 88.61% and 82.86% in the training cohort and 90.00% and 76.60% in the validation cohort. Cutoff values for the biomarkers were: CA199, 9.809 U/mL; CA125, 7.743 U/mL; CA153, 6.295 U/mL; CEA, 3.982 ng/mL; CYFRA 21-1, 1.769 ng/mL; ferritin, 163.361 mg/L; hs-CRP, 0.196 mg/L; and serum albumin, 55.966 g/L. The model showed higher sensitivity for early-stage CRC (95.45%, 95% CI 87.2–98.6%) than late-stage CRC (87.27%, 95% CI 76.4–93.5%; P  = 0.08). AUCs were 0.907 (training) and 0.872 (validation). The model demonstrated higher sensitivity for early-stage CRC (95.45%) than late-stage CRC (87.27%), underscoring its utility in early detection.

Purpose Previous randomized studies have shown a survival benefit of using regorafenib but a high rate of adverse events in unresectable colorectal cancer patients. To reduce these adverse events and improve the tolerability, we examined the appropriate dose of regorafenib based on body weight. Methods We used a nationwide claims database in Japan and examined the efficacy and safety of regorafenib for patients with metastatic colorectal cancer between groups divided by body weight (60 kg) and median average dose (120 mg) between 2013 and 2018. We also assessed overall survival (OS) and adverse events between these groups. Results We identified 2530 Japanese patients (heavy weight/high dose: 513, light weight/low dose: 921, heavy weight/low dose: 452, and light weight/high dose: 644). There was no significant difference in the adverse events and OS after inverse probability treatment weighting (IPTW) adjustment between heavy weight/high dose group and light weight/low dose group (hazard ratio, HR=0.97). Among the light-weight patients, higher average dose was associated with shorter OS (IPTW adjusted HR=1.21, 95% CI 1.05 – 1.39, Table 3 ) while among the heavy-weight patients, there was no significant difference in OS between high and low dose groups (IPTW adjusted HR=1.14, 95% CI 0.95 – 1.37). Conclusion The findings suggest that a low dose of regorafenib for light-weight patients may be as safe and effective as high doses for heavy-weight patients. Further studies should be conducted to identify an appropriate dose based on each patient's physique and condition.

Aims Selective lateral pelvic lymph node (LPN) dissection (LPND) following neoadjuvant chemoradiotherapy (nCRT) for rectal cancer is widely recognized. This study aimed to determine the effects of nCRT before LPND on local control and prognosis of rectal cancer patients. Materials and methods Data were retrieved from a prospective database for rectal cancer patients with clinical LPN metastasis receiving total mesorectal excision and LPND at three institutions between January 2012 and December 2019. Selection bias was minimized using propensity score matching (PSM) and short-term and clinical outcomes were compared. Results Patients ( n  = 213) were enrolled and grouped as either nCRT ( n  = 97) or non-nCRT ( n  = 116). PSM was used to identify 83 matched pairs. In the matched cohort, nCRT patients had a longer operation duration (310.6 vs. 265.0 min, P  = 0.001), lower pathological LPN metastasis rate (32.5% vs. 48.2%, P  = 0.040), and fewer harvested lymph nodes (22 vs. 25, P  = 0.018) compared to the non-nCRT group. However, after PSM, the two groups had similar estimated overall 3-year survival (79.5% vs. 80.7%, P  = 0.922), 3-year disease-free survival (66.1% vs. 65.5, P  = 0.820), and 3-year local recurrence-free survival (88.6% vs. 89.7%, P  = 0.927). Distant metastasis was the predominant recurrence pattern in the overall (45/58, 77.6%) and matched (33/44, 75.0%) cohorts. Conclusions LPND without nCRT is effective and sufficient in preventing local recurrence in patients with LPN metastases. Future prospective randomized controlled studies are warranted to confirm these findings. Since systemic metastasis is the predominant recurrence pattern in patients with LPN metastasis post-LPND, improved perioperative systemic chemotherapy is needed to prevent micrometastasis.

Background Colorectal neuroendocrine tumors with liver metastases (CRNELM) are associated with a poorer prognosis compared to their nonmetastatic counterparts. A comprehensive understanding of the tumor microenvironment (TME) heterogeneity between primary lesions (PL) and liver metastases (LM) could provide crucial insights for enhancing clinical management strategies for these patients. Methods We utilized single-cell RNA sequencing to analyze fresh tissue samples from CRNELM patients, aiming to elucidate the variations in TME between PL and LM. Complementary multidimensional validation was achieved through spatial transcriptomics, bulk RNA sequencing, and multiplex immunohistochemistry/immunofluorescence. Results Our single-cell RNA sequencing analysis revealed that LM harboured a higher proportion of CD8 + T cells, CD4 + T cells, NK cells, NKT cells, and B cells exhibiting a stress-like phenotype compared to PL. RGS5 + pericytes may play a role in the stress-like phenotype observed in immune cells within LM. MCs in PL (PL_MCs) and LM (LM_MCs) exhibit distinct activation of tumor-associated signaling pathways. Notably, COLEC11 + matrix cancer-associated fibroblasts (COLEC11_mCAFs) were found to be significantly associated with LM_MCs. Cell communication analysis unveiled potential targetable receptor-ligand interactions between COLEC11_mCAFs and LM_MCs. Multidimensional validation confirmed the prominence of the characteristic stress-like phenotypes, including HSPA6_CD8_Tstr, HSPA6_NK, and COLEC11_mCAFs in LM. Moreover, a higher abundance of COLEC11_mCAFs correlated with poorer survival rates in the neuroendocrine tumor patient cohort. Conclusion Overall, our study provides the first single-cell analysis of the cellular and molecular differences between PL and LM in CRNELM patients. We identified distinct cell subsets and receptor-ligand interactions that may drive TME discrepancies and support metastatic tumor growth. These insights highlight potential therapeutic targets and inform strategies for better managing CRNELM patients.

Dopamine (DA) is an important neurotransmitter in the hypothalamus and pituitary gland, which can produce a direct influence on mammals' emotions in midbrain. Additionally, the level of DA is highly related with some important neurologic diseases such as schizophrenia, Parkinson, and Huntington's diseases, etc. In light of the important roles that DA plays in the disease modulation, it is of considerable significance to develop a sensitive and reproducible approach for monitoring DA. The objective of this study was to develop an efficient approach to quantitatively monitor the level of DA using Ag nanoparticle (NP) dimers and enhanced Raman spectroscopy. Ag NP dimers were synthesized for the sensitive detection of DA via surface-enhanced Raman scattering (SERS). Citrate was used as both the capping agent of NPs and sensing agent to DA, which is self-assembled on the surface of Ag NP dimers by reacting with the surface carboxyl group to form a stable amide bond. To improve accuracy and precision, the multiplicative effects model for surface-enhanced Raman spectroscopy was utilized to analyze the SERS assays. A low limits of detection (LOD) of 20 pM and a wide linear response range from 30 pM to 300 nM were obtained for DA quantitative detection. The SERS enhancement factor was theoretically valued at approximately 10 by discrete dipole approximation. DA was self-assembled on the citrate capped surface of Ag NPs dimers through the amide bond. The adsorption energy was estimated to be 256 KJ/mol using the Langmuir isotherm model. The density functional theory was used to simulate the spectral characteristics of SERS during the adsorption of DA on the surface of the Ag dimers. Furthermore, to improve the accuracy and precision of quantitative analysis of SERS assays with a multiplicative effects model for surface-enhanced Raman spectroscopy. A LOD of 20 pM DA-level was obtained, and the linear response ranged from 30 pM to 300 nM for quantitative DA detection. The absolute relative percentage error was 4.22% between the real and predicted DA concentrations. This detection scheme is expected to have good applications in the prevention and diagnosis of certain diseases caused by disorders in the DA level.