HBV integrations reshaping genomic structures promote hepatocellular carcinoma.

OBJECTIVE: Hepatitis 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. DESIGN: Here, 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. RESULTS: These 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. CONCLUSION: HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.

Satellite Interference Source Direction of Arrival (DOA) Estimation Based on Frequency Domain Covariance Matrix Reconstruction.

Direction of arrival (DOA) estimation is an effective method for detecting various active interference signals during the satellite navigation process. It can be utilized for both interference detection and anti-interference applications. This paper proposes a DOA estimation algorithm for satellite interference sources based on frequency domain covariance matrix reconstruction (FDCMR) to address various types of active interference that may occur in the satellite navigation positioning process. This algorithm can estimate the DOA of coherent signals from multiple frequency points under low signal-to-noise ratio (SNR) conditions. The signals received from the array are transformed from the time domain to the frequency domain using a fast Fourier transform (FFT). The data corresponding to the frequency point of the target signal is extracted from the signal in the frequency domain. The frequency domain covariance matrix of the received array signals is reconstructed by utilizing its covariance matrix property. The spatial spectrum search method is used for the final DOA estimation. Simulation experiments have shown that the proposed algorithm performs well in the DOA estimation under low SNR conditions and also resolves coherency. Moreover, the algorithm's effectiveness is verified through comparison with three other algorithms. Finally, the algorithm's applicability is validated through simulations of various interference scenarios.

Electromagnetic Modulation Signal Classification Using Dual-Modal Feature Fusion CNN.

AMC (automatic modulation classification) plays a vital role in spectrum monitoring and electromagnetic abnormal signal detection. Up to now, few studies have focused on the complementarity between features of different modalities and the importance of the feature fusion mechanism in the AMC method. This paper proposes a dual-modal feature fusion convolutional neural network (DMFF-CNN) for AMC to use the complementarity between different modal features fully. DMFF-CNN uses the gram angular field (GAF) image coding and intelligence quotient (IQ) data combined with CNN. Firstly, the original signal is converted into images by GAF, and the GAF images are used as the input of ResNet50. Secondly, it is converted into IQ data and as the complex value network (CV-CNN) input to extract features. Furthermore, a dual-modal feature fusion mechanism (DMFF) is proposed to fuse the dual-modal features extracted by GAF-ResNet50 and CV-CNN. The fusion feature is used as the input of DMFF-CNN for model training to achieve AMC of multi-type signals. In the evaluation stage, the advantages of the DMFF mechanism proposed in this paper and the accuracy improvement compared with other feature fusion algorithms are discussed. The experiment shows that our method performs better than others, including some state-of-the-art methods, and has superior robustness at a low signal-to-noise ratio (SNR), and the average classification accuracy of the dataset signals reaches 92.1%. The DMFF-CNN proposed in this paper provides a new path for the AMC field.

Low-frequency ultrasound and nitrogen limitation induced enhancement in biomass production and lipid accumulation of Tetradesmus obliquus FACHB-12.

The two-stage cultivation strategy was optimized in this study to simultaneously promote the growth and lipid accumulation of Tetradesmus obliquus. Results showed that the optimal dual-stress conditions were nitrogen concentration at 25 mg N·L-1 and low-frequency ultrasound at 200 Watt, 1 min, and 8 h interval. The biomass and lipid content of Tetradesmus obliquus were increased by 32.1% and 44.5%, respectively, comparing to the control, and the lipid productivity reached 86.97 mg-1·L-1·d-1 at the end of the cultivation period. The protein and photosynthetic pigment contents of microalgae decreased by 22.4% and 14.0% under dual stress comparing to the control environment. In addition, dual stress cultivation of microalgae presented higher level of antioxidant capacity to balance to oxidation level in microalgal cells. This study provides a new insight for microalgae growth and lipid accumulation with dual stress stimulation.

RING finger 138 deregulation distorts NF-кB signaling and facilities colitis switch to aggressive malignancy.

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138-/- mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.

Feasibility and comparative analysis of cadmium biosorption by living scenedesmus obliquus FACHB-12 biofilms.

Microalgal biofilm has been recognized as a cost-effective biorsorbent for heavy metal and a promising method for microalgae-water separation. In this study, living suspended Scenedesmus obliquus FACHB-12 (isolated from southern China) and its biofilm with different carriers were investigated to remove cadmium from aqueous solution. S. obliquus FACHB-12 biofilm with luffa sponge carrier showed highest cadmium removal efficiency at 92.7% compared to biofilm with K3 carrier (75.3%) and significantly higher than suspended S. obliquus FACHB-12 (61.8%) in 2 h experiment with initial Cd2+ concentration at 3.0 mg/L at pH = 6.0 with 0.8 g/L of biomass under room temperature. S. obliquus FACHB-12 biofilm with K3 and luffa sponge carrier also demonstrated higher tolerance towards increased Cd2+ concentration with highest biosorption efficiency at 85.1% and 90.35% respectively under 20 mg/L of Cd2+, while suspended S. obliquus FACHB-12 biosorption efficiency achieved 81.4% under 10 mg/L of Cd2+ and started to decline over increased cadmium concentration. The adsorption kinetics for all experimental groups followed the pseudo-second-order adsorption model, with biosorption equilibrium favored in Langmuir isotherm. The maximum biosorption capacity estimated by Langmuir isotherm reached 133.14 mg/g biomass in S. obliquus FACHB-12 biofilm with luffa sponge carrier, followed by 78.76 mg/g with K3 carrier, and 60.03 mg/g with suspended S. obliquus FACHB-12. Results suggest an efficient, inexpensive microalgal biofilm with biological carrier system could enhance high cadmium removal for advanced wastewater treatment and provide a cost-effective method for microalgae harvesting process.

Changes in serum lactate dehydrogenase levels as markers of pathological response and prognosis in colorectal liver metastases patients receiving neoadjuvant chemotherapy followed by resection.

BACKGROUND: This study sought to evaluate the effects of pre-neoadjuvant chemotherapy lactate dehydrogenase (pre-NAC LDH) levels, preoperative LDH levels, and changes in LDH levels on the pathological response and outcomes of colorectal liver metastases (CRLM) patients treated with liver resection after NAC. METHODS: This study included 152 colorectal CRLM patients, who underwent NAC followed by liver resection. Patients were excluded if they were diagnosed with other malignancies or lacked follow-up and clinical data. Demographic and clinicopathological data were collected from hospital records. Pathological response and postoperative complications were measured according to the tumor regression grade (TRG) and Clavien-Dindo classification system, respectively. The optimal cutoff values were determined by the receiver operating characteristic curve and the X-tile analysis. Changes in LDH levels were graded as 0, 1, and 2. A logistic regression analysis was conducted to identify the independent predictors of pathological response and postoperative major complications. Univariate and multivariate Cox regression analyses were used to identify the independent risk factors of progression-free survival (PFS) and overall survival (OS). RESULTS: The multivariate analysis indicated that a grade 2 LDH level change was a risk factor of an unfavorable histological response [odds ratio (OR) 0.249, 95% confidence interval (CI): 0.066-0.942; P=0.041] and major postoperative complications (OR 2.523, 95% CI: 1.179-10.530; P=0.024), which were independent of other clinical covariates. A pre-NAC LDH level ≥145 IU/L [hazards ratio (HR) 0.584, 95% CI: 0.359-0.950; P=0.030], a grade 1 LDH level change (HR 0.584, 95% CI: 0.359-0.950; P=0.030) and a grade 2 LDH level change (HR 0.447, 95% CI: 0.231-0.864; P=0.017) were independent prognostic predictors of PFS. A preoperative a LDH level ≥231 IU/L (HR 0.405, 95% CI: 0.192-0.852; P=0.017) and a grade 2 LDH level change (HR 0.362, 95% CI: 0.157-0.834; P=0.017) were independent prognostic factors of OS, which were independent of other clinical covariates. CONCLUSIONS: LDH levels and changes in LDH levels are potentially useful biomarkers for predicting the pathological response and prognosis of CRLM patients receiving NAC followed by liver resection.

Nomograms predicting primary lymph node metastases and prognosis for synchronous colorectal liver metastasis with simultaneous resection of colorectal cancer and liver metastases.

BACKGROUND: It is necessary to identify valuable predictors of primary lymph node metastasis and prognosis for patients with synchronous colorectal cancer liver metastases (CRLM) with simultaneous resection of colorectal cancer (CRC) and liver metastases. This study constructed nomograms especially incorporating preoperative testing markers to predict primary lymph node metastases and prognosis in CRLM patients. METHODS: By the highest Youden index (sensitivity + 1-specificity), the optimal cut-off values of testing markers for postoperative major complications and lymph node metastasis were identified. Multivariate regression analysis was used to reveal independent predictors for primary lymph node metastasis, postoperative major complications and progression-free survival (PFS). Nomograms based on independent predictors were constructed, and the discrimination and calibration were evaluated. RESULTS: A nomogram predicting primary lymph node metastasis was based on four risky independent predictors: American Society of Anesthesiologists (ASA) score 3-4, preoperative albumin (ALB) <41.15 g/L, poor differentiation and multiple liver metastases. The performance of the model was acceptable in predicting lymph node metastasis, with an area under the receiver operating characteristic curve (AUROC) of 0.655 (95% CI: 0.591-0.739). Calibration curves and the Hosmer-Lemeshow test revealed desirable model calibration (chi-square: 13.26, P=0.815). In the multivariate analysis, preoperative lactate dehydrogenase (LDH) ≥202.5 U/L [odds ratio (OR) =2.084, 95% confidence interval (CI): 1.039-4.181, P=0.039] and operation time ≥350.5 min (OR =2.848, 95% CI: 1.418-5.723, P=0.003) were independently associated with the presence of postoperative major complications. A nomogram predicting PFS was constructed based on poor differentiation, positive lymph node metastasis, bilobar liver distribution and R0 resection with good discrimination (C-index: 0.656±0.021) and calibration. CONCLUSIONS: This study established predictive nomograms specifically incorporating preoperative ALB and LDH levels for the prediction of primary lymph node metastasis and prognosis in synchronous CRLM patients with simultaneous resection, which have favourable discrimination and calibration to make individualized predictions.

PDCD6 cooperates with C-Raf to facilitate colorectal cancer progression via Raf/MEK/ERK activation.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies, and it's expected that the CRC burden will substantially increase in the next two decades. New biomarkers for targeted treatment and associated molecular mechanism of tumorigenesis remain to be explored. In this study, we investigated whether PDCD6 plays an oncogenic role in colorectal cancer and its underlying mechanism. METHODS: Programmed cell death protein 6 (PDCD6) expression in CRC samples were analyzed by immunohistochemistry and immunofluorescence. The prognosis between PDCD6 and clinical features were analyzed. The roles of PDCD6 in cellular proliferation and tumor growth were measured by using CCK8, colony formation, and tumor xenograft in nude mice. RNA-sequence (RNA-seq), Mass Spectrum (MS), Co-Immunoprecipitation (Co-IP) and Western blot were utilized to investigate the mechanism of tumor progression. Immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) were performed to determine the correlation of PDCD6 and MAPK pathway. RESULTS: Higher expression levels of PDCD6 in tumor tissues were associated with a poorer prognosis in patients with CRC. Furthermore, PDCD6 increased cell proliferation in vitro and tumor growth in vivo. Mechanistically, RNA-seq showed that PDCD6 could affect the activation of the MAPK signaling pathway. PDCD6 interacted with c-Raf, resulting in the activation of downstream c-Raf/MEK/ERK pathway and the upregulation of core cell proliferation genes such as MYC and JUN. CONCLUSIONS: These findings reveal the oncogenic effect of PDCD6 in CRC by activating c-Raf/MEK/ERK pathway and indicate that PDCD6 might be a potential prognostic indicator and therapeutic target for patients with colorectal cancer.