Hierarchical Low-Temperature n-Type Bi2Te3 with High Thermoelectric Performances.

The high performance of a multistage thermoelectric cooler (multi-TEC) used in a wide low-temperature range depends on the optimized thermoelectric (TE) performance of materials during the corresponding working temperature range for each stage. Despite decades of research on the commercial TE materials of Bi2Te3, the main research is still focused on temperatures above 300 K, lacking suitable hierarchical low-temperature n-Bi2Te3 for multistage TEC. In this work, we systematically investigated the influence of doping concentration and matrix material compositions on the TE performance of n-Bi2Te3 below room temperature by the high-energy ball milling and hot deformation. Consequently, two hierarchical n-Bi2Te3 materials with excellent mechanical properties working below 248 and around 298 K, respectively, have been screened out. The Bi2Te2.7Se0.3 + 0.03 wt % TeI4 can be adopted in a low-temperature range that exhibits the high average figure of merit (zTave) of 0.61 within 173-248 K. Meanwhile, the Bi2Te2.7Se0.3 + 0.05 wt % TeI4 sample displays a competitive zTave of 0.85 within 248-298 K, which can be applied above 248 K. The research of hierarchical TE materials provides valuable insights into the high-performance design of multistage TE cooling devices.

Field-Scale Testing of a High-Efficiency Membrane Reactor (MR)-Adsorptive Reactor (AR) Process for H2 Generation and Pre-Combustion CO2 Capture.

The study objective was to field-validate the technical feasibility of a membrane- and adsorption-enhanced water gas shift reaction process employing a carbon molecular sieve membrane (CMSM)-based membrane reactor (MR) followed by an adsorptive reactor (AR) for pre-combustion CO2 capture. The project was carried out in two different phases. In Phase I, the field-scale experimental MR-AR system was designed and constructed, the membranes, and adsorbents were prepared, and the unit was tested with simulated syngas to validate functionality. In Phase II, the unit was installed at the test site, field-tested using real syngas, and a technoeconomic analysis (TEA) of the technology was completed. All project milestones were met. Specifically, (i) high-performance CMSMs were prepared meeting the target H2 permeance (>1 m3/(m2.hbar) and H2/CO selectivity of >80 at temperatures of up to 300 °C and pressures of up to 25 bar with a <10% performance decline over the testing period; (ii) pelletized adsorbents were prepared for use in relevant conditions (250 °C < T < 450 °C, pressures up to 25 bar) with a working capacity of >2.5 wt.% and an attrition rate of <0.2; (iii) TEA showed that the MR-AR technology met the CO2 capture goals of 95% CO2 purity at a cost of electricity (COE) 30% less than baseline approaches.

Extremely Low Contact Resistivity of Bi2Te3-Based Modules Enabled by NiP-Based Alloy Barrier.

Electrode diffusion barrier plays an important role in thermoelectric cooling devices. Compared with p-type Bi0.5Sb1.5Te3, the compatibility between commercial Ni barrier and n-type Bi2Te2.7Se0.3 is a key bottleneck to enhance the performance of Bi2Te3-based cooling devices. This paper proposed a NiP alloy barrier to improve the compatibility with n-type Bi2Te2.7Se0.3, and systemically investigated the contact and interfacial dynamics properties. Due to the low diffusion rate of NiP alloy, the initial interfacial contact resistivity of Bi2Te2.7Se0.3/NiP is as low as 0.90 µΩ cm2, and it further can be depressed below 1.98 µΩ cm2 even after aging at 423 K for 35 days, indicating the superior thermal stability of the NiP barrier layer compared to the commercial Ni barrier layer. Based on the NiP barrier, a 15-pair bismuth telluride device is prepared and a high cooling temperature difference of 71.5 K at a hot-side temperature of 304 K is achieved, which proves the practical applications potential of NiP barrier for Bi2Te3-based modules.

Enhanced Thermoelectric Properties of Nb-Doped Ti(FeCoNi)Sb Pseudo-Ternary Half-Heusler Alloys Prepared Using the Microwave Method.

Pseudo-ternary half-Heusler thermoelectric materials, which are formed by filling the B sites of traditional ternary half-Heusler thermoelectric materials of ABX with equal atomic proportions of various elements, have attracted more and more attention due to their lower intrinsic lattice thermal conductivity. High-purity and relatively dense Ti1-xNbx(FeCoNi)Sb (x = 0, 0.01, 0.03, 0.05, 0.07 and 0.1) alloys were prepared via microwave synthesis combined with rapid hot-pressing sintering, and their thermoelectric properties are investigated in this work. The Seebeck coefficient was markedly increased via Nb substitution at Ti sites, which resulted in the optimized power factor of 1.45 µWcm-1K-2 for n-type Ti0.93Nb0.07(FeCoNi)Sb at 750 K. In addition, the lattice thermal conductivity was largely decreased due to the increase in phonon scattering caused by point defects, mass fluctuation and strain fluctuation introduced by Nb-doping. At 750 K, the lattice thermal conductivity of Ti0.97Nb0.03(FeCoNi)Sb is 2.37 Wm-1K-1, which is 55% and 23% lower than that of TiCoSb and Ti(FeCoNi)Sb, respectively. Compared with TiCoSb, the ZT of the Ti1-xNbx(FeCoNi)Sb samples were significantly increased. The average ZT values of the Nb-doped pseudo-ternary half-Heusler samples were dozens of times that of the TiCoSb prepared using the same process.

Multiomics analyses reveal pathological mechanisms of HBV infection and integration in liver cancer.

Hepatitis B virus (HBV) infection and integration are important for hepatocellular carcinoma (HCC) initiation and progression, while disease mechanisms are still largely elusive. Here, we combined bulk and single-cell sequencing technologies to tackle the disease mechanisms of HBV-related HCC. We observed high HBV mutation rate and diversity only in tumors without HBV integration. We identified human somatic risk loci for HBV integration (VIMs). Transcription factors (TFs) enriched in VIMs were involved in DNA repair and androgen receptor (AR) signaling. Aberration of AR signaling was further observed by single-cell regulon analysis in HBV-infected hepatocytes, which showed remarkable interactions between AR and the complement system that, together with the X-linked ZXDB regulon that contains albumin (ALB), probably contribute to HCC male predominance. Complement system dysregulation caused by HBV infection was further confirmed by analyses of single-cell copy numbers and cell-cell communications. Finally, HBV infection-associated immune cells presented critical defects, including TXNIP in T cells, TYROBP in NK cells, and the X-linked TIMP1 in monocytes. We further experimentally validated our findings in multiple independent patient cohorts. Collectively, our work shed light on the pathogenesis of HBV-related HCC and other liver diseases that affect billions of people worldwide.

Simultaneous quantification of fatty acids in serum with dual derivatization by liquid chromatography-tandem mass spectrometry.

Fatty acids have multitudinous biological functions and play a crucial role in many biological processes, but due to poor ionization efficiency and lack of appropriate internal standards, the comprehensive quantification of fatty acids by liquid chromatography-tandem mass spectrometry is still challenging. In this study, a new, accurate, and reliable method for quantifying 30 fatty acids in serum using dual derivatization was proposed. Indole-3-acetic acid hydrazide derivants of fatty acids were used as the internal standard and indole-3-carboxylic acid hydrazide derivants of them were used to quantify. The derivatization conditions were systematically optimized and the method validation results showed good linearity with R2  > 0.9942, low detection limit (0.03-0.6 nM), precision (1.6%-9.8% for intra-day and 4.6%-14.1% for inter-day), recovery (88.2%-107.2% with relative standard deviation < 10.5%), matrix effect (88.3%-105.2% with the relative standard deviation < 9.9%) and stability (3.4%-13.8% for fatty acids derivants in 24 h at 4°C and 4.2%-13.8% for three freeze-thaw cycles). Finally, this method was successfully applied to quantify fatty acids in serum samples of Alzheimer's patients. In contrast to the healthy control group, nine fatty acids showed a significant increase in the Alzheimer's disease group.

Recent Advances in Nanoplatform Construction Strategy for Alleviating Tumor Hypoxia.

Hypoxia is a typical feature of most solid tumors and has important effects on tumor cells' proliferation, invasion, and metastasis. This is the key factor that leads to poor efficacy of different kinds of therapy including chemotherapy, radiotherapy, photodynamic therapy, etc. In recent years, the construction of hypoxia-relieving functional nanoplatforms through nanotechnology has become a new strategy to reverse the current situation of tumor microenvironment hypoxia and improve the effectiveness of tumor treatment. Here, the main strategies and recent progress in constructing nanoplatforms are focused on to directly carry oxygen, generate oxygen in situ, inhibit mitochondrial respiration, and enhance blood perfusion to alleviate tumor hypoxia. The advantages and disadvantages of these nanoplatforms are compared. Meanwhile, nanoplatforms based on organic and inorganic substances are also summarized and classified. Through the comprehensive overview, it is hoped that the summary of these nanoplatforms for alleviating hypoxia could provide new enlightenment and prospects for the construction of nanomaterials in this field.

Pan-cancer investigation of C-to-U editing reveals its important role in cancer development and new targets for cancer treatment.

RNA editing is prevalent in the transcriptome and is important for multiple cellular processes. C-to-U RNA editing sites (RES) are relatively rare and understudied in humans, compared to A-to-I editing. However, the functional impact of C-to-U editing in human cancers also remains elusive. Here, we conducted the first comprehensive survey of pan-cancer C-to-U RESs. Surprisingly, we found that the same subset of RESs were associated with multiple features, including patient survival, cancer stemness, tumor mutation burden (TMB), and tumor-infiltrated immune cell compositions (ICC), suggesting an RES-mediated close relationship between these features. For example, editing sites for GALM or IFI6 that led to higher expression were linked to lower survival and more cancer stemness. Also, TMB was found to be lower in prostate cancer cases with ICC-associated RESs in CAVIN1 or VWA8 or higher in prostate cancer cases with thymoma. With experimental support, we also found RESs in CST3, TPI1, or TNC that are linked to immune checkpoint blockade by anti-PD1. We also confirmed through experiments that two C-to-U RESs in CSNK2B or RPS14 had different effects on colon cancer cells. Patients with CSNK2B editing, which increased the expression of the oncogene CLDN18, had a lower response to drugs. On the other hand, drugs worked better on people who had RPS14 editing, which greatly increased ribosome production. In summary, our study demonstrated the important roles of C-to-U RESs across cancers and shed light on personalized cancer therapy.

Distribution characteristics of microplastics in storm-drain inlet sediments affected by the types of urban functional areas, economic and demographic conditions in southern Beijing.

A storm-drain inlet is an important link in the transport of microplastic pollutants in urban rainwater runoff. In three functional districts (agricultural, commercial, and residential) from Beijing South 2nd Ring Road to South 6th Ring Road, microplastics in storm-drain inlet sediments were analyzed for abundance and characteristics. The abundance of microplastics in the collected samples ranged from 1121 ± 247 items kg-1 to 7393 ± 491 items kg-1. Among the sample areas, the commercial area had the greatest abundance (11094 items kg-1), while the agricultural area had the lowest (833 items kg-1). The microplastics in the samples were mainly fragments, accounting for 50.4%. Microplastics of less than 1 mm accounted for 74.8%. The color of microplastics was diverse, with colored MPs accounting for 26% and transparent ones for 47.8%. Most of the polymers detected were PET, PS, and PP, which are the most commonly used polymers. Overall, the results provide baseline data on microplastic pollution and its associated risks, in addition to guidelines for controlling runoff pollution.

ACTB may serve as a predictive marker for the efficacy of lenvatinib in patients with HBV-related early-stage hepatocellular carcinoma following partial hepatectomy: a retrospective cohort study.

Background: The lack of effective biomarkers for the treatment of postoperative recurrence in hepatocellular carcinoma (HCC) persists despite lenvatinib therapy. This study aims to identify beta-actin (ACTB) as a predictive biomarker for lenvatinib that can facilitate individualized treatment for HCC. Methods: This retrospective study included a subset of patients with HCC who underwent partial hepatectomy, with some receiving postoperative lenvatinib treatment and others not receiving lenvatinib treatment. A propensity score matching (PSM) analysis of patients who underwent treatment with or without lenvatinib following HCC partial hepatectomy was performed. Immunohistochemistry was employed to determine the levels of ACTB expression in HCC samples obtained from matched patients (n=225) enrolled in this study. The X-Tile was employed to determine the optimal cut-off point of ACTB levels for predicting time to recurrence (TTR). To assess the correlation between ACTB levels and lenvatinib efficacy, a subgroup analysis of TTR was conducted. A Cox regression model with an interaction term was utilized to assess the predictive significance of the model. Subsequently, a nomogram was developed and its discriminative ability and predictive accuracy were assessed using the concordance index (C-index) and calibration curve. For the investigation of the ACTB expression, HCC and para-tumoral normal tissues were employed. The patient-derived xenograft (PDX) model was utilized to validate the correlation between ACTB levels and lenvatinib responsiveness. Results: After PSM, a total of 76 patients who underwent postoperative lenvatinib treatment were included in the analysis, with a median TTR of 24.35 months. Early-stage HCC patients with lower levels of ACTB exhibited a more favorable response to lenvatinib therapy compared to those with higher levels. The reduced expression of ACTB was indicative of the benefits of lenvatinib, as opposed to higher levels {hazard ratio (HR) =0.243 [95% confidence interval (CI): 0.096-0.619], P<0.001, P value for interaction =0.014}. In approximately 81.8% of cases involving HCC patients, there was an observed increase in the expression of ACTB. Multivariate analysis of the lenvatinib cohort revealed Child-Pugh [HR =5.416 (95% CI: 1.390-21.104), P=0.015], Barcelona Clinic Liver Cancer (BCLC) stage [HR =2.508 (95% CI: 1.116-5.639), P=0.026], and ACTB [HR =5.879 (95% CI: 2.424-14.259), P<0.001] score as independent factors for TTR, and all were included in the nomogram. The survival probability based on the calibration curve showed that the prediction of the nomogram was in good agreement with the actual observation. The C-index of the nomogram for predicting survival was 0.76 (95% CI: 0.71-0.84). Moreover, the PDXs derived from tumors exhibiting low levels of ACTB expression demonstrated a heightened sensitivity to lenvatinib treatment. Conclusions: In patients with tumors treated with lenvatinib, low ACTB expression can predict a lower risk of recurrence. The validation of this potential biomarker in independent cohorts is necessary prior to its implementation for precision treatment stratification in patients undergoing partial hepatectomy for early-stage HCC.

One- versus two-stage partial hepatectomy for large resectable solitary hepatocellular carcinomas determined preoperatively to have a narrow resection margin: a propensity score matching analysis.

Background: For patients with a large but resectable solitary hepatocellular carcinoma (HCC) of >5 cm in diameter, it is often difficult to achieve a sufficient resection margin. There is still no study on whether a two-stage hepatectomy to increase a narrow resection margin would be beneficial. Methods: From August 2014 to February 2017, patients with a large but resectable solitary HCC of >5 cm and a preoperative estimated resection margin of <1.0 cm were retrospectively studied. They were divided into one- and two-stage resection groups. A retrospective analysis was performed, followed by propensity score matching (PSM) analysis. Disease recurrence, survival, intraoperative and postoperative data were compared. Results: Before PSM, the 1-, 2-, 3-and 4-year recurrence-free survival rates for the one- and two-stage groups were 44.3%, 31.7%, 24.3%, 19.2% versus 60.6%, 45.4%, 43.5%, 32.3%, respectively (P=0.007). The corresponding OS rates were 61.0%, 45.2%, 43.8%, 38.4% versus 69.6%, 62.5%, 60.7%, 57.3%, respectively (P=0.029). After PSM, the 1-, 2-, 3-and 4-year recurrence-free survival rates for the one- and two-stage groups were 44.0%, 31.5%, 27.3%, 21.0% versus 60.6%, 45.4%, 43.5%, 32.3%, respectively (P=0.013). The corresponding OS rates were 62.5%, 41.1%, 41.1%, 37.5% versus 69.6%, 62.5%, 60.7%, 57.3%, respectively (P=0.038). Differences in the resection margins between the one- and two-stage groups before [0.3 (0-0.5) versus 1.2 (0.8-2.2) cm] and after [0.2 (0-0.5) versus 1.2 (0.8-2.2) cm] PSM were also significant. Conclusions: Two-stage hepatectomy allowed a wider resection margin for patients with a resectable but solitary HCC of >5 cm, and resulted in significantly better long-term survival outcomes after partial hepatectomy.

Analysis of viral integration reveals new insights of oncogenic mechanism in HBV-infected intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.

BACKGROUND: Integration of HBV DNA into the human genome could progressively contribute to hepatocarcinogenesis. Both intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC) are known to be associated with HBV infection. However, the integration of HBV and mechanism of HBV-induced carcinogenesis in ICC and CHC remains unclear. METHODS: 41 patients with ICC and 20 patients with CHC were recruited in the study. We conducted HIVID analysis on these 61 samples to identify HBV integration sites in both the tumor tissues and adjacent non-tumor liver tissues. To further explore the effect of HBV integration on gene alteration, we selected paired tumors and adjacent non-tumor liver tissues from 3 ICC and 4 CHC patients for RNA-seq and WGS. RESULTS: We detected 493 HBV integration sites in ICC patients, of which 417 were from tumor samples and 76 were from non-tumor samples. And 246 HBV integration sites were detected in CHC patients, of which 156 were located in the genome of tumor samples and 90 were in non-tumor samples. Recurrent HBV integration events were detected in ICC including TERT, ZMAT4, MET, ANKFN1, PLXNB2, and in CHC like TERT, ALKBH5. Together with our established data of HBV-infected hepatocellular carcinoma, we found that HBV preferentially integrates into the specific regions which may affect the gene expression and regulation in cells and involved in carcinogenesis. We further performed genomic and transcriptomic sequencing of three ICC and four CHC patients, and found that HBV fragments could integrate near some important oncogene like TERT, causing large-scale genome variations on nearby genomic sequences, and at the same time changing the expression level of the oncogenes. CONCLUSION: Comparative analysis demonstrates numerous newly discovered mutational events in ICC and CHC resulting from HBV insertions in the host genome. Our study provides an in-depth biological and clinical insights into HBV-induced ICC and CHC.

DNA hypermethylation modification promotes the development of hepatocellular carcinoma by depressing the tumor suppressor gene ZNF334.

DNA methylation plays a pivotal role in the development and progression of tumors. However, studies focused on the dynamic changes of DNA methylation in the development of hepatocellular carcinoma (HCC) are rare. To systematically illustrate the dynamic DNA methylation alternation from premalignant to early-stage liver cancer with the same genetic background, this study enrolled 5 HBV-related patients preceded with liver cirrhosis, pathologically identified as early-stage HCC with dysplastic nodules. Liver fibrosis tissues, dysplastic nodules and early HCC tissues from these patients were used to measure DNA methylation. Here, we report significant differences in the DNA methylation spectrum among the three types of tissues. In the early stage of HCC, DNA hypermethylation of tumor suppressor genes is predominant. Additionally, DNA hypermethylation in the early stage of HCC changes the binding ability of transcription factor TP53 to the promoter of tumor suppressor gene ZNF334, and inhibits the expression of ZNF334 at the transcription level. Furthermore, through a series of in vivo and in vitro experiments, we have clarified the exacerbation effect of tumor suppressor gene ZNF334 deletion in the occurrence of HCC. Combined with clinical data, we found that the overall survival and relapse-free survival of patients with high ZNF334 expression are significantly longer. Thus, we partly elucidated a sequential alternation of DNA methylation modification during the occurrence of HCC, and clarified the biological function and regulatory mechanism of the tumor suppressor gene ZNF334, which is regulated by related DNA methylation sites. Our study provides a new target and clinical evidence for the early diagnosis and sheds light on the precise treatment of liver cancer.

Association between serum iron status and primary liver cancer risk: a Mendelian randomization analysis.

BACKGROUND: Serum iron status has been reported as associated with primary liver cancer (PLC) risk. However, whether iron status plays a role in the development of PLC remains inconclusive. METHODS: Genetic summary statistics of the four biomarkers (serum iron, ferritin, transferrin saturation, and transferrin) of iron status and PLC were retrieved from two independent genome-wide association studies (GWAS) that had been performed in European populations. Two-sample univariate and multivariate Mendelian randomization (MR) analyses were conducted to determine the causal link between iron status and PLC risk. RESULTS: No significant horizontal pleiotropy was detected for the four biomarkers according to the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test. No evidence of between-single nucleotide polymorphism (SNP) heterogeneity and directional pleiotropy was detected by the Cochran's Q test and MR-Egger regression for serum iron, ferritin, and transferrin. For transferrin saturation, although no heterogeneity was detected, the directional pleiotropy was significant (P value for intercept of MR-Egger regression =0.033). Univariate MR estimates based on inverse variance weighting (IVW) method suggested that there was no causal link between serum iron [odds ratio (OR) =0.71, 95% confidence interval (CI): 0.45 to 1.11], ferritin (OR =0.56, 95% CI: 0.16 to 2.04), and transferrin (OR =0.91, 95% CI: 0.72 to 1.15) and PLC risk. We found a significant causal relationship between transferrin saturation and PLC risk (OR =0.45, 95% CI: 0.22 to 0.90), although this link was non-significant in multivariate MR analysis. CONCLUSIONS: There might be no causal relationship between iron status and PLC risk. However, data from larger sample size and people with different ethnic background were needed to further validate our findings.

Photoinduced Irreversible Intramolecular Proton Transfer of Arnebinones B, D, and E: The Case of Photoenolization at the p-Benzoquinone-CH2/CH-π System.

Arnebinones B, E, and D (1-3) have been found to be sensitive to light, generating complex and diverse proton transfer products when triggered by light. A unique two-step irreversible intramolecular proton transfer of 1 produced five scalemic mixtures, of which four possessed intriguing dual planar chirality. The unprecedented orientation epimerization equilibrium of the intra-annular double bond was first observed and researched in the homologous meroterpenoids by HPLC monitoring and DFT calculations. A "p-benzoquinone-CH2/CH-π" moiety in the structure was the common key feature for the occurrence of this type of photoenolization reaction. The product transformation processes and universality of this photoinduced irreversible proton transfer reaction were analyzed together with the cytotoxic activities of arnebinones B, D, and E, and their photoreaction products.

Inhibition of SIRT1 Limits Self-Renewal and Oncogenesis by Inducing Senescence of Liver Cancer Stem Cells.

PURPOSE: Cancer stem cells (CSCs) have been considered involving in tumorigenesis, local recurrence, and therapeutic drug resistance of hepatocellular carcinoma (HCC). To investigate novel and effective methods for targeting hepatic CSCs is crucial for a permanent cure of liver cancer. METHODS: The expression level of SIRT1 was detected in CSCs of HCC tissues and cancer cell lines. Expression of CSC markers, the self-renewal and tumorigenic ability of liver CSCs were analyzed with SIRT1 inhibition. Cellular senescence-related markers were used to detect CSCs senescence after inhibition of SIRT1. RESULTS: SIRT1 was highly expressed in CSCs of HCC cell lines and human HCC tissues. In vitro study revealed that decreasing of SIRT1 level significantly downregulated the stemness-associated genes of liver CSCs and reduced the CSC stemness properties. Also, downregulated SIRT1 suppressed liver CSCs proliferation by decreasing their self-renewal abilities. Furthermore, CSCs with decreased SIRT1 expression showed limited tumorigenicity and formed smaller HCC tumor in vivo. And SIRT1 decreased CSCs became more susceptible to chemotherapeutic drugs. Mechanistically, SIRT1 decreased CSCs became senescence through the activation of p53-p21 and p16 pathway. The data further indicated that the tumor formed from SIRT1-knockdown CSCs exhibited higher senescence-associated ß-galactosidase (SA-ß-Gal) activity but lower proliferative capacity. CONCLUSION: Taken together, these findings pointed that induction of senescence in liver CSCs is an effective tumor suppression method for HCC, and SIRT1 may be served as a promising target for HCC treatment.

Nomogram for prediction of fatal outcome in patients with severe COVID-19: a multicenter study.

BACKGROUND: To develop an effective model of predicting fatal outcomes in the severe coronavirus disease 2019 (COVID-19) patients. METHODS: Between February 20, 2020 and April 4, 2020, consecutive confirmed 2541 COVID-19 patients from three designated hospitals were enrolled in this study. All patients received chest computed tomography (CT) and serological examinations at admission. Laboratory tests included routine blood tests, liver function, renal function, coagulation profile, C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and arterial blood gas. The SaO2 was measured using pulse oxygen saturation in room air at resting status. Independent high-risk factors associated with death were analyzed using Cox proportional hazard model. A prognostic nomogram was constructed to predict the survival of severe COVID-19 patients. RESULTS: There were 124 severe patients in the training cohort, and there were 71 and 76 severe patients in the two independent validation cohorts, respectively. Multivariate Cox analysis indicated that age ≥ 70 years (HR = 1.184, 95% CI 1.061-1.321), panting (breathing rate ≥ 30/min) (HR = 3.300, 95% CI 2.509-6.286), lymphocyte count < 1.0 × 109/L (HR = 2.283, 95% CI 1.779-3.267), and interleukin-6 (IL-6) >  10 pg/ml (HR = 3.029, 95% CI 1.567-7.116) were independent high-risk factors associated with fatal outcome. We developed the nomogram for identifying survival of severe COVID-19 patients in the training cohort (AUC = 0.900, 95% CI 0.841-0.960, sensitivity 95.5%, specificity 77.5%); in validation cohort 1 (AUC = 0.811, 95% CI 0.763-0.961, sensitivity 77.3%, specificity 73.5%); in validation cohort 2 (AUC = 0.862, 95% CI 0.698-0.924, sensitivity 92.9%, specificity 64.5%). The calibration curve for probability of death indicated a good consistence between prediction by the nomogram and the actual observation. The prognosis of severe COVID-19 patients with high levels of IL-6 receiving tocilizumab were better than that of those patients without tocilizumab both in the training and validation cohorts, but without difference (P = 0.105 for training cohort, P = 0.133 for validation cohort 1, and P = 0.210 for validation cohort 2). CONCLUSIONS: This nomogram could help clinicians to identify severe patients who have high risk of death, and to develop more appropriate treatment strategies to reduce the mortality of severe patients. Tocilizumab may improve the prognosis of severe COVID-19 patients with high levels of IL-6.

HIVID2: an accurate tool to detect virus integrations in the host genome.

MOTIVATION: Virus integration in the host genome is frequently reported to be closely associated with many human diseases, and the detection of virus integration is a critically challenging task. However, most existing tools show limited specificity and sensitivity. Therefore, the objective of this study is to develop a method for accurate detection of virus integration into host genomes. RESULTS: Herein, we report a novel method termed HIVID2 that is a significant upgrade of HIVID. HIVID2 performs a paired-end combination (PE-combination) for potentially integrated reads. The resulting sequences are then remapped onto the reference genomes, and both split and discordant chimeric reads are used to identify accurate integration breakpoints with high confidence. HIVID2 represents a great improvement in specificity and sensitivity, and predicts breakpoints closer to the real integrations, compared with existing methods. The advantage of our method was demonstrated using both simulated and real datasets. HIVID2 uncovered novel integration breakpoints in well-known cervical cancer-related genes, including FHIT and LRP1B, which was verified using protein expression data. In addition, HIVID2 allows the user to decide whether to automatically perform advanced analysis using the identified virus integrations. By analyzing the simulated data and real data tests, we demonstrated that HIVID2 is not only more accurate than HIVID but also better than other existing programs with respect to both sensitivity and specificity. We believe that HIVID2 will help in enhancing future research associated with virus integration. AVAILABILITYAND IMPLEMENTATION: HIVID2 can be accessed at https://github.com/zengxi-hada/HIVID2/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Senescence suppressed proliferation of host hepatocytes is precondition for liver repopulation.

In the fumarylacetoacetate hydrolase deficient (Fah-/-) mouse, massive liver repopulation can be easily obtained after transplanted hepatocytes. Understanding the mechanisms of complete liver repopulation in Fah-/- mice will be useful for future clinical application. Here, we found that the endogenous hepatocytes in liver of Fah-/- mice undertook senescence during the time of tyrosinemia symptoms. Increase of senescent hepatocytes in Fah-/- mice provided proliferative advantage to the transplanted hepatocytes. Importantly, senescent hepatocytes upregulated the expression of extracellular matrix enzyme, contributing to degradation of extracellular matrix components and weakness of cell adhesion and connection. The liver exhibiting a loose architecture provided the space for the engraftment and expansion of transplanted hepatocytes. These findings underscore the underlying mechanisms of completed liver repopulation in Fah-/- mice. Senescence followed by loose hepatic parenchyma is a preconditioning for liver repopulation, which would be a promising strategy to achieve therapeutic liver repopulation in clinical settings.

A novel HBx genotype serves as a preoperative predictor and fails to activate the JAK1/STATs pathway in hepatocellular carcinoma.

BACKGROUND & AIMS: Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact. METHODS: We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism. RESULTS: In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway. CONCLUSION: Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC. LAY SUMMARY: We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.