Phocaeicola vulgatus alleviates diet-induced metabolic dysfunction-associated steatotic liver disease progression by downregulating histone acetylation level via 3-HPAA.

Diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited effective interventions available. A novel approach to address this issue is through gut microbiota-based therapy. In our study, we utilized multi-omics analysis to identify Phocaeicola vulgatus (P. vulgatus) as a potential probiotic for the treatment of MASLD. Our findings from murine models clearly illustrate that the supplementation of P. vulgatus mitigates the development of MASLD. This beneficial effect is partly attributed to the metabolite 3-Hydroxyphenylacetic acid (3-HPAA) produced by P. vulgatus, which reduces the acetylation levels of H3K27 and downregulates the transcription of Squalene Epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis that promotes lipid accumulation in liver cells. This study underscores the significant role of P. vulgatus in the development of MASLD and the critical importance of its metabolite 3-HPAA in regulating lipid homeostasis. These findings offer a promising avenue for early intervention therapy in the context of MASLD.

Small extrachromosomal circular DNA harboring targeted tumor suppressor gene mutations supports intratumor heterogeneity in mouse liver cancer induced by multiplexed CRISPR/Cas9.

BACKGROUND: Primary liver cancer has significant intratumor genetic heterogeneity (IGH), which drives cancer evolution and prevents effective cancer treatment. CRISPR/Cas9-induced mouse liver cancer models can be used to elucidate how IGH is developed. However, as CRISPR/Cas9 could induce chromothripsis and extrachromosomal DNA in cells in addition to targeted mutations, we wondered whether this effect contributes to the development of IGH in CRISPR/Cas9-induced mouse liver cancer. METHODS: CRISPR/Cas9-based targeted somatic multiplex-mutagenesis was used to target 34 tumor suppressor genes (TSGs) for induction of primary liver tumors in mice. Target site mutations in tumor cells were analyzed and compared between single-cell clones and their subclones, between different time points of cell proliferation, and between parental clones and single-cell clones derived from mouse subcutaneous allografts. Genomic instability and generation of extrachromosomal circular DNA (eccDNA) was explored as a potential mechanism underlying the oscillation of target site mutations in these liver tumor cells. RESULTS: After efficiently inducing autochthonous liver tumors in mice within 30-60 days, analyses of CRISPR/Cas9-induced tumors and single-cell clones derived from tumor nodules revealed multiplexed and heterogeneous mutations at target sites. Many target sites frequently displayed more than two types of allelic variations with varying frequencies in single-cell clones, indicating increased copy number of these target sites. The types and frequencies of targeted TSG mutations continued to change at some target sites between single-cell clones and their subclones. Even the proliferation of a subclone in cell culture and in mouse subcutaneous graft altered the types and frequencies of targeted TSG mutations in the absence of continuing CRISPR/Cas9 genome editing, indicating a new source outside primary chromosomes for the development of IGH in these liver tumors. Karyotyping of tumor cells revealed genomic instability in these cells manifested by high levels of micronuclei and chromosomal aberrations including chromosomal fragments and chromosomal breaks. Sequencing analysis further demonstrated the generation of eccDNA harboring targeted TSG mutations in these tumor cells. CONCLUSIONS: Small eccDNAs carrying TSG mutations may serve as an important source supporting intratumor heterogeneity and tumor evolution in mouse liver cancer induced by multiplexed CRISPR/Cas9.

Global development of artificial intelligence in cancer field: a bibliometric analysis range from 1983 to 2022.

Background: Artificial intelligence (AI) is widely applied in cancer field nowadays. The aim of this study is to explore the hotspots and trends of AI in cancer research. Methods: The retrieval term includes four topic words ("tumor," "cancer," "carcinoma," and "artificial intelligence"), which were searched in the database of Web of Science from January 1983 to December 2022. Then, we documented and processed all data, including the country, continent, Journal Impact Factor, and so on using the bibliometric software. Results: A total of 6,920 papers were collected and analyzed. We presented the annual publications and citations, most productive countries/regions, most influential scholars, the collaborations of journals and institutions, and research focus and hotspots in AI-based cancer research. Conclusion: This study systematically summarizes the current research overview of AI in cancer research so as to lay the foundation for future research.

Insight into the history and trends of surgical simulation training in education: a bibliometric analysis.

BACKGROUND: Surgical simulation training enables surgeons to acquire clinical experience or skills from the operating room to the simulation environment. Historically, it has changed with advances in science and technology. Moreover, no previous study has analyzed this field from the bibliometric analysis dimension. The study aimed to review changes in surgical simulation training worldwide using bibliometric software. MATERIALS AND METHODS: Two searches were performed on the core collection database, Web of Science, regarding data from 1991 to the end of 2020 using three topic words (surgery, training, and simulation). From 1 January 2000, to 15 May 2022, the keyword 'robotic' was added for the hotspot exploration. The data were chiefly analyzed by publication date, country, author(s), and keywords using bibliometric software. RESULTS: A total of 5285 articles were initially analyzed, from which it was clear that laparoscopic skill, three-dimensional printing, and virtual reality were the main focuses during those study periods. Subsequently, 348 publications on robotic surgery training were identified. CONCLUSION: This study systematically summarizes the current status in the field of surgical simulation training and provides insights into the research focuses and future hotspot in a global context.

A Machine-Learning-Based Bibliometric Analysis of Cell Membrane-Coated Nanoparticles in Biomedical Applications over the Past Eleven Years.

Cell membrane encapsulation is a growing concept in nanomedicine, for it achieves the purpose of camouflage nanoparticles, realizing the convenience for drug delivery, bio-imaging, and detoxification. Cell membranes are constructed by bilayer lipid phospholipid layers, which have unique properties in cellular uptake mechanism, targeting ability, immunomodulation, and regeneration. Current medical applications of cell membranes include cancers, inflammations, regenerations, and so on. In this article, a general bibliometric overview is conducted of cell membrane-coated nanoparticles covering 11 years of evolution in order to provide researchers in the field with a comprehensive view of the relevant achievements and trends. The authors analyze the data from Web of Science Core Collection database, and extract the annual publications and citations, most productive countries/regions, most influential scholars, the collaborations of journals and institutions. The authors also divided cell membranes into several subgroups to further understand the application of different cell membranes in medical scenarios. This study summarizes the current research overview in cell membrane-coated nanoparticles and intuitively provides a direction for future research.

Identification and development of a novel risk model based on cuproptosis-associated RNA methylation regulators for predicting prognosis and characterizing immune status in hepatocellular carcinoma.

BACKGROUND: Cuproptosis, a novel cell death caused by excess copper, is quite obscure in hepatocellular carcinoma (HCC) and needs more investigation. METHODS: RNA-seq and clinical data of HCC patients TCGA database were analyzed to establish a predictive model through LASSO Cox regression analysis. External dataset ICGC was used for the verification. GSEA and CIBERSORT were applied to investigate the molecular mechanisms and immune microenvironment of HCC. Cuproptosis induced by elesclomol was confirmed via various in vitro experiments. The expression of prognostic genes was verified in HCC tissues using qRT-PCR analysis. RESULTS: Initially, 18 cuproptosis-associated RNA methylation regulators (CARMRs) were selected for prognostic analysis. A nine-gene signature was created by applying the LASSO Cox regression method. Survival and ROC assays were carried out to validate the model using TCGA and ICGC database. Moreover, there exhibited obvious differences in drug sensitivity in terms of common drugs. A higher tumor mutation burden was shown in the high-risk group. Additionally, significant discrepancies were found between the two groups in metabolic pathways and RNA processing via GSEA analysis. Meanwhile, CIBERSORT analysis indicated different infiltrating levels of various immune cells between the two groups. Elesclomol treatment caused a unique form of programmed cell death accompanied by loss of lipoylated mitochondrial proteins and Fe-S cluster protein. The results of qRT-PCR indicated that most prognostic genes were differentially expressed in the HCC tissues. CONCLUSION: Overall, our predictive signature displayed potential value in the prediction of overall survival of HCC patients and might provide valuable clues for personalized therapies.

Usefulness of the estimation of physiologic ability and surgical stress (E-PASS) system for prediction of complication and prognosis in hepatocellular carcinoma patients after hepatectomy.

Background: Estimation of physiologic ability and surgical stress (E-PASS) system was verified in predicting postoperative complications or mortality in many surgical operations. This research aimed to investigate whether the E-PASS system could predict postoperative complications and was related with long-term prognosis in primary hepatocellular carcinoma (HCC) patients. Methods: A total of 236 HCC patients who underwent liver resection were collected in this study. We performed univariate analyses to determine the potential risk factors for complications after hepatectomy. The potential independent risk factors were then included in the logistic regression for multivariable analysis. The optimal cutoff value of Comprehensive Risk Score (CRS) was identified by a receiver operating characteristic (ROC) curve. Based on this value, the patients were divided into two groups to investigate the relation between CRS with postoperative complications. The relation between CRS and overall survival (OS) or recurrence-free survival (RFS) was analyzed further in these two groups. Results: Postoperative complications occurred in 79 patients. Multivariable analysis suggested that CRS was independent factor for predicting postoperative complications (P<0.001). The optimal CRS cutoff value in our study was 0.126. Patients with high Preoperative Risk Score (PRS) had a higher rate of postoperative complications occurrence, both major and mild complications (P<0.001). Our study showed that HCC patients with higher CRS had poorer survival prognosis [hazard ratio (HR): 3.735, 95% confidence interval (CI): 1.200-11.631, P=0.023]. The 3-year OS rate of high CRS group (CRS ≥0.126) and low CRS group (CRS <0.126) were 66.2% vs. 84.8% (P<0.001), respectively. Conclusions: For HCC patients after liver resection, E-PASS was an effective predictive system for evaluating the risks of postoperative complications and may can predict prognosis in long term.

Target residence of Cas9-sgRNA influences DNA double-strand break repair pathway choices in CRISPR/Cas9 genome editing.

BACKGROUND: Due to post-cleavage residence of the Cas9-sgRNA complex at its target, Cas9-induced DNA double-strand breaks (DSBs) have to be exposed to engage DSB repair pathways. Target interaction of Cas9-sgRNA determines its target binding affinity and modulates its post-cleavage target residence duration and exposure of Cas9-induced DSBs. This exposure, via different mechanisms, may initiate variable DNA damage responses, influencing DSB repair pathway choices and contributing to mutational heterogeneity in genome editing. However, this regulation of DSB repair pathway choices is poorly understood. RESULTS: In repair of Cas9-induced DSBs, repair pathway choices vary widely at different target sites and classical nonhomologous end joining (c-NHEJ) is not even engaged at some sites. In mouse embryonic stem cells, weakening the target interaction of Cas9-sgRNA promotes bias towards c-NHEJ and increases target dissociation and reduces target residence of Cas9-sgRNAs in vitro. As an important strategy for enhancing homology-directed repair, inactivation of c-NHEJ aggravates off-target activities of Cas9-sgRNA due to its weak interaction with off-target sites. By dislodging Cas9-sgRNA from its cleaved targets, DNA replication alters DSB end configurations and suppresses c-NHEJ in favor of other repair pathways, whereas transcription has little effect on c-NHEJ engagement. Dissociation of Cas9-sgRNA from its cleaved target by DNA replication may generate three-ended DSBs, resulting in palindromic fusion of sister chromatids, a potential source for CRISPR/Cas9-induced on-target chromosomal rearrangements. CONCLUSIONS: Target residence of Cas9-sgRNA modulates DSB repair pathway choices likely through varying dissociation of Cas9-sgRNA from cleaved DNA, thus widening on-target and off-target mutational spectra in CRISPR/Cas9 genome editing.

Prediction of tannin profile in grape (Vitis vinifera L.) skins during berry maturation using a rapid mechanical puncture approach.

Tannin structure and composition are variable during grape maturation, and crucially determine perceived astringency, body structure and aging capacity of red wines. This study investigated the evolution of condensed tannins (CTs) in grape skins as maturation progressed and the feasibility of using a rapid mechanical puncture approach for assessing the CTs profile. The results showed that the mean degree of polymerization (mDP), molecular mass (MM), and proportions of (-)-epigallocatechin in extension subunits (EGC_ext) and (-)-epicatechin-3-O-gallate in terminal subunits (ECG_term) of skins increased during grape maturation, while CTs content and the proportion of (-)-epicatechin-3-O-gallate in extension subunits decreased. The predictive models built by random forest for CTs content based on skin weight, mDP, MM_subunit, EGC_ext, and ECG_term obtained good results with high squared correlation coefficients of prediction and calibration (R2_P > 0.85 and R2_C ≈ 0.95). In addition, the classifications of CTs characteristics obtained from ripe and unripe samples were observed in different principal component spaces. This study indicated that the mechanical properties were useful for predicting skin CTs profile, estimating tannin maturity stages, and providing information for optimal harvesting and winemaking protocols.

Deficit irrigation and leaf removal modulate anthocyanin and proanthocyanidin repartitioning of Cabernet Sauvignon (Vitis vinifera L.) grape and resulting wine profile.

BACKGROUND: In monsoonal climates, grape anthocyanin and proanthocyanidin (PA) accumulations are unsatisfactory for producing optimal wine. Agronomical practices are often considered to be effective means for regulating fruit components. However, there is a lack of quantitative information on the effects of deficit irrigation (DI), basal leaf removal (LR) or their combination of deficit irrigation and leaf removal (DILR) on the characteristics of anthocyanin and PA compositions and their implications on the resulting wine quality. In this study, the dynamics of grape anthocyanin and PA accumulation were investigated in DI, LR and DILR during grape ripening, and the resulting wine profile was assessed. RESULTS: The contents of reducing sugar and total anthocyanins in Cabernet Sauvignon berries were significantly increased by DI, LR and DILR, while titratable acidity, total flavan-3-ols and tannins levels were generally decreased. Notably, the levels of 3'5'-substituted anthocyanins, such as malvidin and its derivatives significantly increased, and 3'-substituted anthocyanins decreased in both grape and wine under DI and DILR strategies. Skin PAs were sensitive to water deficits, whereas they were insensitive to LR. In resulting wine, PAs content and the proportion of 3'-hydroxylated PAs, such as (+)-catechin, (-)-epicatechin and (-)-epicatechin-3-O-gallate units were significantly decreased under DI and DILR, while molecular mass and the proportion of 3'5'-hydroxylated units of PAs were increased in response to DILR. CONCLUSION: The DILR was the most favorable for the repartitioning of anthocyanin and PA metabolites, and promoted the accumulation of tri-substituted forms contributing a higher color intensity, mouthfeel persistence, structure, and astringency of wine. This information provides an important strategy for modulating the anthocyanin and PA compositions by agricultural practices and achieving the desired quality of grapes and wines in monsoonal climates. © 2021 Society of Chemical Industry.

The Estimation of Physiologic Ability and Surgical Stress (E-PASS) model as a predictor of postoperative complications and mortality after digestive surgeries: a meta-analysis and systematic review.

BACKGROUND: Conflicting results exist about the usefulness of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) model in patients undergoing digestive surgeries. Thus, this study aims to analyze and evaluate the E-PASS model for predicting postoperative complications and mortality. METHODS: A literature search strategy for "E-PASS" was carried out in PubMed, Embase, Google Scholar, Ovid, and Cochrane databases for studies published before November 2020. "E-PASS" or "Estimation of Physiologic Ability and Surgical Stress" were used as the search terms in all databases, and a total of 20 published English language studies with available data relating to digestive surgery were selected for this study. Clinical data and indices including preoperative risk score (PRS), surgical stress score (SSS), comprehensive risk score (CRS), postoperative complications, mortality, and overall survival (OS) were collected. Meta-analyses of heterogeneity were performed using Review Manager version 5.3 and STATA 14.0. RESULTS: Twenty studies with 9,136 patients were included in our meta-analysis. Using a random-effects model, the indices of the E-PASS model in patients with postoperative complications were significantly greater than those in patients without complications [PRS: 95% confidence interval (CI): 0.14-1.50; SSS: 95% CI: 0.28-1.06; CRS: 95% CI: 048-1.49]. Moreover, patient morbidity and mortality were associated with a higher CRS (morbidity: 95% CI: 2.17-6.29; mortality: 95% CI: 1.57-4.78), while subgroup analyses showed that a high CRS in the elderly was related to increased morbidity (95% CI: 1.57-4.78) without heterogeneity. In addition, we found that a high E-PASS CRS was significantly associated with shorter OS after digestive surgery (95% CI: 1.24-5.41). DISCUSSION: The higher CRS score in the E-PASS model accompanies with many postoperative complications, increased mortality and shorter OS. Collectively, the E-PASS model is a convenient and effective risk assessment for patients undergoing digestive surgeries. More stringently designed studies are expected to develop better estimates of the application value of this model in digestive surgeries.

Nanoprobes-Assisted Multichannel NIR-II Fluorescence Imaging-Guided Resection and Photothermal Ablation of Lymph Nodes.

Lymph node metastasis is a major metastatic route of cancer and significantly influences the prognosis of cancer patients. Radical lymphadenectomy is crucial for a successful surgery. However, iatrogenic normal organ injury during lymphadenectomy is a troublesome complication. Here, this paper reports a kind of organic nanoprobes (IDSe-IC2F nanoparticles (NPs)) with excellent second near-infrared (NIR-II) fluorescence and photothermal properties. IDSe-IC2F NPs can effectively label lymph nodes and helped achieve high-contrast lymphatic imaging. More importantly, by jointly using IDSe-IC2F nanoparticles and other kinds of nanoparticles with different excitation/emission properties, a multichannel NIR-II fluorescence imaging modality and imaging-guided lymphadenectomy is proposed. With the help of this navigation system, the iatrogenic injury can be largely avoided. In addition, NIR-II fluorescence imaging-guided photothermal treatment ("hot" strategy) can ablate those metastatic lymph nodes which are difficult to deal with during resection ("cold" strategy). Nanoprobes-assisted and multichannel NIR-II fluorescence imaging-guided "cold" and "hot" treatment strategy provides a general new basis for the future precision surgery.

Immunotherapy for Hepatocellular Carcinoma: Current Limits and Prospects.

Although many approaches have been used to treat hepatocellular carcinoma (HCC), the clinical benefits remain limited, particularly for late stage HCC. In recent years, studies have focused on immunotherapy for HCC. Immunotherapies have shown promising clinical outcomes in several types of cancers and potential therapeutic effects for advanced HCC. In this review, we summarize the immune tolerance and immunotherapeutic strategies for HCC as well as the main challenges of current therapeutic approaches. We also present alternative strategies for overcoming these limitations.

Cancer and COVID-19 Susceptibility and Severity: A Two-Sample Mendelian Randomization and Bioinformatic Analysis.

The clinical management of patients with COVID-19 and cancer is a Gordian knot that has been discussed widely but has not reached a consensus. We introduced two-sample Mendelian randomization to investigate the causal association between a genetic predisposition to cancers and COVID-19 susceptibility and severity. Moreover, we also explored the mutation landscape, expression pattern, and prognostic implications of genes involved with COVID-19 in distinct cancers. Among all of the cancer types we analyzed, only the genetic predisposition to lung adenocarcinoma was causally associated with increased COVID-19 severity (OR = 2.93, ß = 1.074, se = 0.411, p = 0.009) with no obvious heterogeneity (Q = 17.29, p = 0.24) or symmetry of the funnel plot. In addition, the results of the pleiotropy test demonstrated that instrument SNPs were less likely to affect COVID-19 severity via approaches other than lung adenocarcinoma cancer susceptibility (p = 0.96). Leave-one-out analysis showed no outliers in instrument SNPs, whose elimination rendered alterations in statistical significance, which further supported the reliability of the MR results. Broad mutation and differential expression of these genes were also found in cancers, which may provide valuable information for developing new treatment modalities for patients with both cancer and COVID-19. For example, ERAP2, a risk factor for COVID-19-associated death, is upregulated in lung squamous cancer and negatively associated with patient prognosis. Hence, ERAP2-targeted treatment may simultaneously reduce COVID-19 disease severity and restrain cancer progression. Our results highlighted the importance of strengthening medical surveillance for COVID-19 deterioration in patients with lung adenocarcinoma by showing their causal genetic association. For these patients, a delay in anticancer treatment, such as chemotherapy and surgery, should be considered.

1-Aminocyclopropane-1-Carboxylate Deaminase-Producing Plant Growth-Promoting Rhizobacteria Improve Drought Stress Tolerance in Grapevine (Vitis vinifera L.).

Plant growth-promoting rhizobacteria (PGPRs) that produce 1-aminocyclopropane-1-carboxylate (ACC) deaminase are capable of reducing limits to plant growth due to water-deficient conditions. Here, seven PGPR strains that can produce ACC deaminase were successfully obtained from the rhizosphere soil of grapevine (Vitis vinifera L.) in arid regions of China. The strains belonged to three different genera: Pseudomonas, Enterobacter, and Achromobacter, according to their 16S rDNA sequencing analysis. A drought tolerance experiment revealed two PGPR strains (DR3 and DR6) with exceptionally high phosphate solubilization, nitrogen fixation, indoleacetic acid (IAA), and exopolysaccharides secretion potential. Both strains were selected for use in a pot experiment to evaluate their growth-promoting effects on grapevines under drought conditions. Each of these two PGPRs and their mixed inoculation into grapevines were expected to alleviate the comprehensive growth inhibition of grapevines caused by drought stress. The mixed inoculation was hypothesized to elicit the best growth-promoting effects. Inoculation with the PGPRs not only enhanced the root-adhering soil/root tissue ratios and soil aggregate stability, but it also increased the nitrogen and phosphorus levels in the soil and plant leaves. Further, inoculation with PGPRs significantly altered the plant height, biomass of shoot and root organs, relative water contents, and net photosynthetic rate of leaves, enabling grapevines to better cope with drought. Moreover, the contents of IAA, abscisic acid, and malondialdehyde in these grapevines under drought stress were significantly changed by PGPRs. They indirectly affected biochemical and physiological properties of grapevines to alleviate their drought stress. Taken together, these results demonstrate that the DR3 and DR6 PGPRs might be useful for effectively weakening the growth inhibition caused by drought in grapevines. The strains might also be applied as effective bioinoculants to maintain the quality of wine grapes.

The Preoperative Prognostic Nutritional Index in Hepatocellular Carcinoma After Curative Hepatectomy: A Retrospective Cohort Study and Meta-Analysis.

OBJECTIVE: Conflicting results existed about the role of prognostic nutritional index (PNI) for hepatocellular carcinoma (HCC) patients who received curative hepatectomy. The aim of this study is to identify the predictive capacity of PNI for survival after hepatectomy. METHODS: Preoperative PNI, neutrophil-to-lymphocyte ratio (NLR), tumor feature and clinical information of 187 patients with HCC from Sir Run Run Shaw hospital were evaluated. We also conducted a meta-analysis of seven cohort studies. RESULTS: Our study showed that HCC patients with a low PNI of <45 had a poor recurrence-free survival (RFS) rate (hazard ratio [HR] 1.762, 95% confidence interval [CI] 1.066-2.911, p = 0.027, respectively). The 5-year OS and RFS rates of the high PNI (≥45) vs low PNI (<45) were 76.7% vs 50.1% (p = 0.001) and 47.0% vs 28.9% (p = 0.001), respectively. In HCC TNM I patients (n = 144), a low PNI remained an independent prognostic factor of OS and RFS (HR 2.305, 95% CI 1.008-5.268, p = 0.048; HR 2.122, 95% CI 1.149-3.920, p = 0.016). The 5-year OS and RFS rates of the high PNI vs low PNI were 81.3% vs 62.4% (p = 0.041) and 53.4% vs 45.6% (p = 0.013), respectively. In the pooled analysis, the data showed that a low PNI was significantly associated with poor OS and RFS (HR 2.27, 95% CI 1.03-4.07, p < 0.001 and HR 1.68, 95% CI 1.45-1.94, p < 0.001, respectively). CONCLUSIONS: The preoperative PNI was an independent prognostic factor for OS and RFS rates in HCC patients who received hepatectomy.

Epigenome-wide DNA methylation profiling of portal vein tumor thrombosis (PVTT) tissues in hepatocellular carcinoma patients.

Aberrant methylation is a hallmark of hepatocellular carcinoma and plays an important role in tumor initiation and progression. However, the epigenome-wide methylation patterns of portal vein tumor thrombosis (PVTTs) have not been fully explored. Here, we performed epigenome-wide DNA methylation of adjacent normal tissues (ANTs), paired tumor tissues and paired PVTTs using an Infinium HumanMethylation450 array (n = 11) and conducted the Sequenom EpiTYPER assays to confirm the aberrantly methylated genes. MTS and apoptosis assay were used to assess the synergistic effect of two drugs on the HCC cell lines. We found the mean global methylation levels of HCC tissues and PVTTs were significantly lower than ANTs (P < 0.01). A total of 864 differentially methylated CpG sites annotated in 532 genes were identified between HCC tissues and paired PVTTs (|mean methylation difference|>10%, P < 0.005). The pathway analysis based on hypermethylated genes in PVTT tissues was interestingly enriched in regulation of actin cytoskeleton pathway (P = 4.48E-5). We found 23 genes whose methylation levels were gradually alternated in HCC tissues and PVTTs. Aberrant methylation status of TNFRSF10A, ZC3H3 and SLC9A3R2 were confirmed in a validation cohort (n = 48). The functional experiments demonstrated the combination of decitabine (DAC) and tumor necrosis factor-related apoptosis-inducing ligand (rh-TRAIL) could synergistically suppress the proliferation and induce apoptosis in SK-Hep-1 and Huh7 cell lines. Together, our findings indicated that DNA methylation plays an important role in the PVTT formation through regulating the metastasis-related pathways. The combination of DAC and rh-TRAIL might be a promising treatment strategy for HCC.

ROS-Mediated Selective Killing Effect of Black Phosphorus: Mechanistic Understanding and Its Guidance for Safe Biomedical Applications.

Black phosphorus (BP)-based nanomaterials have distinguished advantages and potential applications in various biomedical fields. However, their biological effects in physiological systems remain largely unexplored. Here, we systematically revealed a reactive oxygen species (ROS)-mediated mechanism for the selective killing of cancer cells by BP-based nanosheets. The treatment with BP-based materials can induce higher levels of ROS in cancer cells than in normal cells, leading to significant changes in the cytoskeleton, cell cycle arrest, DNA damage, and apoptosis in tumor cell lines. We revealed that the decreased superoxide dismutase activity by lipid peroxides could be an essential mechanism of the selectively higher ROS generation induced by BP-based nanosheets in cancer cells. In addition, the selective killing effect only occurred within a certain dosage range (named "SK range" in this study). Once exceeding the SK range, BP-based materials could also induce a high ROS production in normal tissues, leading to detectable DNA damage and pathological characteristics in normal organs and raising safety concerns. These findings not only shed light on a new mechanism for the selective killing of cancer cells by BP-based materials but also provide deep insights into the safe use of BP-based therapies.

Promoter aberrant methylation status of ADRA1A is associated with hepatocellular carcinoma.

The aim of our study was to explore the relationship between the methylation status of the alpha-1A adrenergic receptor (ADRA1A) gene and hepatocellular carcinoma (HCC). We combined our in-house data-set with the Cancer Genome Atlas (TCGA) data-set to screen and identify the methylation status and expression of adrenergic receptor (AR) genes in HCC. Immunohistochemistry and western blot were performed to assess the expression of ADRA1A in HCC cell lines and tissues. We further evaluated the methylation levels of the ADRA1A promoter region in 160 HCC patients using the Sequenom MassARRAY® platform and investigated the association between methylation of ADRA1A and clinical characteristics. The expression levels of ADRA1A mRNA and protein were significantly decreased in HCC tissues. Compared with that in paired normal tissues, the mean methylation level of the ADRA1A promoter region was significantly increased in tumour tissues from 160 HCC patients (25.2% vs. 17.0%, P < 0.0001). We found that a DNA methyltransferase inhibitor (decitabine) could increase the expression of ADRA1A mRNA in HCC cell lines. Moreover, hypermethylation of the ADRA1A gene in HCC samples was associated with clinical characteristics, including alcohol intake (P = 0.0097) and alpha-fetoprotein (P = 0.0411). Receiver operator characteristic (ROC) curve analysis demonstrated that the mean methylation levels of ADRA1A could discriminate between HCC tissues and adjacent non-cancerous tissues (AUC = 0.700, P < 0.0001). mRNA sequencing indicated that the main enriched pathways were pathways in cancer, cytokine-cytokine receptor interaction and metabolic pathways (P < 0.01). ADRA1A gene hypermethylation might contribute to HCC initiation and is a promising biomarker for the diagnosis of HCC.

Preoperative C-reactive protein/albumin ratio to predict mortality and recurrence of patients with hepatocellular carcinoma after curative resection / Relación proteína C reactiva/albúmina preoperatoria para predecir la mortalidad y la recurrencia de los pacientes después de la resección curativa de carcinoma hepatocelular

Background & objectives: Recent studies have shown that the C-reactive protein-to-albumin ratio (CAR) can predict the mortality in patients with hepatocellular carcinoma (HCC). The aim of the present study was to investigate the utility of preoperative CAR for predicting postoperative overall and tumor free survival among HCC patients after radical surgery. Methods: Preoperative neutrophil-to-lymphocyte ratio (NLR), clinicopathological parameters, laboratory data and patient demographics of 187 patients with HCC receiving initial radical liver resection from Sir Run Run Shaw hospital were evaluated. Multivariate analyses were performed to identify clinical characteristics associated with overall survival (OS) and tumor free survival (TFS). Subsequently, the prognostic value of CAR was evaluated using the area under the curve (AUC) compared with other systemic inflammation-based prognostic scores. Results: Multivariate analysis revealed that the tumor number [hazard ratio (HR)=2.668; p=0.018] was independently associated with OS. While, the CRP/Alb ratio [HR=0.477; p=0.006] and the tumor number [HR=2.458; p=0.006] were significantly associated with TFS. The AUC values of the CRP/Alb ratio (6 months: 0.868; 12 months: 0.787; 36 months: 0.680) were higher than those of the GPS, mGPS and NLR at all time points in OS. Conclusion: Preoperative CRP/Alb ratio is an independent prognostic marker with tumor free survival in patients with HCC after curative resection and the prognostic ability was comparable to other applied inflammation-based prognostic scores in both overall and tumor-free survival, especially at the early stage

Antecedentes y objetivos: Estudios recientes han demostrado que la relación proteína C reactiva/albúmina (CAR) puede predecir la mortalidad en pacientes con carcinoma hepatocelular (HCC). El objetivo del presente estudio fue investigar la utilidad de la CAR preoperatoria para predecir la supervivencia postoperatoria general y libre de tumores entre los pacientes con HCC después de la cirugía radical. Métodos: Se evaluaron la relación preoperatoria de neutrófilos a linfocitos (NLR), los parámetros clínico-patológicos, los datos de laboratorio y los datos demográficos de 187 pacientes con HCC que recibieron resección hepática radical inicial en el Hospital Sir Run Run Shaw. Se realizaron análisis multivariables para identificar las características clínicas asociadas con la supervivencia general (SG) y la supervivencia libre de tumor (SST). Posteriormente, se evaluó el valor pronóstico de la CAR utilizando el área bajo la curva (AUC) en comparación con otras puntuaciones de pronóstico basadas en la inflamación sistémica. Resultados: El análisis multivariado reveló que el número de tumores (cociente de riesgos instantáneos [CRI]: 2,668; p=0,018) se asoció de manera independiente con la SG. Mientras, la relación CRP/Alb (hazard ratio [HR]: 0,477; p=0,006) y el número de tumores (HR: 2,458; p=0,006) se asociaron significativamente con SST. Los valores de AUC de la relación CRP/Alb (6 meses: 0,868; 12 meses: 0,787 y 36 meses: 0,680) fueron superiores a los del GPS, mGPS y NLR en todos los puntos temporales en SG. Conclusión: La proporción preoperatoria de CRP/Alb no solo puede predecir la supervivencia general en pacientes con HCC después de la resección curativa, sino que también tiene un rendimiento favorable en la predicción de recidiva tumoral, especialmente en las primeras etapas