Correlation between NGS panel-based mutation results and clinical information in colorectal cancer patients.

Early mutation identification guides patients with colorectal cancer (CRC) toward targeted therapies. In the present study, 414 patients with CRC were enrolled, and amplicon-based targeted next-generation sequencing (NGS) was then performed to detect genomic alterations within the 73 cancer-related genes in the OncoAim panel. The overall mutation rate was 91.5 % (379/414). Gene mutations were detected in 38/73 genes tested. The most frequently mutated genes were TP53 (60.9 %), KRAS (46.6 %), APC (30.4 %), PIK3CA (15.9 %), FBXW7 (8.2 %), SMAD4 (6.8 %), BRAF (6.5 %), and NRAS (3.9 %). Compared with the wild type, TP53 mutations were associated with low microsatellite instability/microsatellite stability (MSI-L/MSS) (P = 0.007), tumor location (P = 0.043), and histological grade (P = 0.0009); KRAS mutations were associated with female gender (P = 0.026), distant metastasis (P = 0.023), TNM stage (P = 0.013), and histological grade (P = 0.004); APC mutations were associated with patients <64 years of age at diagnosis (P = 0.04); PIK3CA mutations were associated with tumor location (P = 4.97e-06) and female gender (P = 0.018); SMAD4 mutations were associated with tumor location (P = 0.033); BRAF mutations were associated with high MSI (MSI-H; P = 6.968e-07), tumor location (P = 1.58e-06), and histological grade (P = 0.04). Mutations in 164 individuals were found to be pathogenic or likely pathogenic. A total of 26 patients harbored MSI-H tumors and they all had at least one detected gene mutation. Mutated genes were enriched in signaling pathways associated with CRC. The present findings have important implications for improving the personalized treatment of patients with CRC in China.

Tetramethylpyrazine-loaded electroconductive hydrogels promote tissue repair after spinal cord injury by protecting the blood-spinal cord barrier and neurons.

Spinal cord injury (SCI) usually induces profound microvascular dysfunction. It disrupts the integrity of the blood-spinal cord barrier (BSCB), which could trigger a cascade of secondary pathological events that manifest as neuronal apoptosis and axonal demyelination. These events can further lead to irreversible neurological impairments. Thus, reducing the permeability of the BSCB and maintaining its substructural integrity are essential to promote neuronal survival following SCI. Tetramethylpyrazine (TMP) has emerged as a potential protective agent for treating the BSCB after SCI. However, its therapeutic potential is hindered by challenges in the administration route and suboptimal bioavailability, leading to attenuated clinical outcomes. To address this challenge, traditional Chinese medicine, TMP, was used in this study to construct a drug-loaded electroconductive hydrogel for synergistic treatment of SCI. A conductive hydrogel combined with TMP demonstrates good electrical and mechanical properties as well as superior biocompatibility. Furthermore, it also facilitates sustained local release of TMP at the implantation site. Furthermore, the TMP-loaded electroconductive hydrogel could suppress oxidative stress responses, thereby diminishing endothelial cell apoptosis and the breakdown of tight junction proteins. This concerted action repairs BSCB integrity. Concurrently, myelin-associated axons and neurons are protected against death, which meaningfully restore neurological functions post spinal cord injury. Hence, these findings indicate that combining the electroconductive hydrogel with TMP presents a promising avenue for potentiating drug efficacy and synergistic repair following SCI.

Marinobacter albus sp. nov., Isolated from Sand Sediment in a Coastal Intertidal Zone.

A Gram-stain-negative bacterium with a rod-to-ovoid shape, named strain M216T, was isolated from sand sediment from the coastal intertidal zone of Huludao, Liaoning Province, China. Growth was observed at 8-40 °C (optimal, 30 °C), pH 5.5-9.5 (optimal, pH 6.5) and 0.5-14.0% (w/v) NaCl (optimal, 6%). Strain M216T possessed ubiquinone-9 as its sole respiratory quinone and phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, one unidentified aminophosphoglycolipid, one unidentified aminophospholipid, two unidentified phosphoglycolipids, three unidentified phospholipids and three unidentified glycolipids as the main polar lipids. C12:0, C16:0, C12:0 3-OH, C16:1 ω9c, C18:1 ω9c and summed features 3 (C16:1 ω7c and/or C16:1 ω6c) were the major fatty acids (> 5%). The 16S rRNA gene sequence of strain M216T exhibited high similarity to those of 'Marinobacter arenosus' CAU 1620T and Marinobacter adhaerens HP15T (99.3% and 98.5%, respectively) and less than 98.5% similarity to those of the other type strains. The ANI and dDDH values between the strain M216T and 'Marinobacter arenosus' CAU 1620T were 87.4% and 33.3%, respectively; these values were the highest among the other type strains but lower than the species threshold. The G+C content of strain M216T was 58.3%. Genomic analysis revealed that strain M216T harbors the major CAZymes of GH13, GH23, GH73, and PL5, which are responsible for polysaccharide degradation and the potential ability to reduce nitrate to ammonia. Through phenotypic, genotypic, and chemotaxonomic analyses, we proposed the name Marinobacter albus sp. nov., a novel species in the genus Marinobacter, with its type strain M216T (= MCCC 1K08600T = KCTC 82894T).

Comparison of left- and right-sided colorectal cancer to explore prognostic signatures related to pyroptosis.

Background: Colorectal cancer (CRC) is one of the most common malignancies, and pyroptosis exerts an immunoregulatory role in CRC. Although the location of the primary tumor is a prognostic factor for patients with CRC, the mechanisms of pyroptosis in left- and right-sided CRC remain unclear. Methods: Expression and clinical data were collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Differences in clinical characteristics, immune cell infiltration, and somatic mutations between left- and right-sided CRC were then compared. After screening for differentially expressed genes, Pearson correlation analysis was performed to select pyroptosis-related genes, followed by a gene set enrichment analysis. Univariate and multivariate Cox regression analyses were used to construct and validate the prognostic model and nomogram for predicting prognosis. Collected left- and right-sided CRC samples were subjected to reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to validate the expression of key pyroptosis-related genes. Results: Left- and right-sided CRC exhibited significant differences in clinical features and immune cell infiltration. Five prognostic signatures were identified from among 134 pyroptosis-related differentially expressed genes to construct a risk score-based prognostic model, and adverse outcomes for high-risk patients were further verified using an external cohort. A nomogram was also generated based on three independent prognostic factors to predict survival probabilities, while calibration curves confirmed the consistency between the predicted and actual survival. Experiment data confirmed the significant differential expression of five genes between left- and right-sided CRC. Conclusion: The five identified pyroptosis-related gene signatures may be potential biomarkers for predicting prognosis in left- and right-sided CRC and may help improve the clinical outcomes of patients with CRC.

Comparison of Ba-Hao burn ointment gauze and petrolatum gauze in split graft donor site healing: A randomized, prospective, and self-control study.

Background and Aims: To assess patient comfort, wound healing, and scarring at the 6-month follow-up of split-skin graft donor sites treated with Ba-Hao burn ointment (BHBO) gauze, a compound preparation of traditional Chinese medicine since 1970s, compared with petrolatum gauze. Methods: Thirty patients admitted to the Department of Burns of the First Affiliated Hospital of Anhui Medical University between September 2021 and September 2022 participated in this randomized, prospective, self-control clinical study. After harvesting the split skin, donor sites were divided into two parts along the midline. BHBO gauze was applied to half of the donor wounds, and petrolatum gauze was applied to the other half. The wound healing time, pain scores on the postoperative Days 3, 6, and 9, and Vancouver Scar Scale (VSS) score at the 6-month follow-up were assessed. Results: The wound healing time was significantly shorter in the BHBO group than in the control group (10.07 ± 1.48 days vs. 11.50 ± 1.74 days, p < 0.001). On postoperative Days 3 and 6, the pain scores quantified by visual analog scores were significantly lower in the BHBO group than in the control group (5.33 ± 1.54 and 4.17 ± 1.51, respectively vs. 7.57 ± 1.41 and 5.20 ± 1.47, respectively). The difference in the visual analog scale score on postoperative Day 9 between the groups was not significant (p > 0.05). Microbiological assessment revealed the absence of bacterial contamination in both groups. At the 6-month follow up, the VSS score was significantly lower in the BHBO group (6.67 ± 1.92) than in the control group (9.57 ± 1.55). Conclusion: BHBO resulted in faster donor-site healing, reduced postoperative pain, and improved scar quality at the 6-month follow-up than petrolatum gauze alone.

Vegfc-expressing cells form heterotopic bone after musculoskeletal injury.

Heterotopic ossification (HO) is a challenging condition that occurs after musculoskeletal injury and is characterized by the formation of bone in non-skeletal tissues. While the effect of HO on blood vessels is well established, little is known about its impact on lymphatic vessels. Here, we use a mouse model of traumatic HO to investigate the relationship between HO and lymphatic vessels. We show that injury triggers lymphangiogenesis at the injury site, which is associated with elevated vascular endothelial growth factor C (VEGF-C) levels. Through single-cell transcriptomic analyses, we identify mesenchymal progenitor cells and tenocytes as sources of Vegfc. We demonstrate by lineage tracing that Vegfc-expressing cells undergo osteochondral differentiation and contribute to the formation of HO. Last, we show that Vegfc haploinsufficiency results in a nearly 50% reduction in lymphangiogenesis and HO formation. These findings shed light on the complex mechanisms underlying HO formation and its impact on lymphatic vessels.

Assessing NGS-based computational methods for predicting transcriptional regulators with query gene sets.

This article provides an in-depth review of computational methods for predicting transcriptional regulators with query gene sets. Identification of transcriptional regulators is of utmost importance in many biological applications, including but not limited to elucidating biological development mechanisms, identifying key disease genes, and predicting therapeutic targets. Various computational methods based on next-generation sequencing (NGS) data have been developed in the past decade, yet no systematic evaluation of NGS-based methods has been offered. We classified these methods into two categories based on shared characteristics, namely library-based and region-based methods. We further conducted benchmark studies to evaluate the accuracy, sensitivity, coverage, and usability of NGS-based methods with molecular experimental datasets. Results show that BART, ChIP-Atlas, and Lisa have relatively better performance. Besides, we point out the limitations of NGS-based methods and explore potential directions for further improvement. Key points: An introduction to available computational methods for predicting functional TRs from a query gene set.A detailed walk-through along with practical concerns and limitations.A systematic benchmark of NGS-based methods in terms of accuracy, sensitivity, coverage, and usability, using 570 TR perturbation-derived gene sets.NGS-based methods outperform motif-based methods. Among NGS methods, those utilizing larger databases and adopting region-centric approaches demonstrate favorable performance. BART, ChIP-Atlas, and Lisa are recommended as these methods have overall better performance in evaluated scenarios.

Causal associations of antioxidants with Alzheimer's disease and cognitive function: a Mendelian randomisation study.

BACKGROUND: Circulating antioxidants are associated with a lower risk of Alzheimer's disease (AD) in observational studies, suggesting potential target areas for intervention. However, whether the associations are causal remains unclear. Here, we studied the causality between antioxidants and AD or cognitive function using two-sample Mendelian randomisation (MR). METHODS: Single nucleotide polymorphisms strongly (p<5×10-8) associated with antioxidants (vitamin A, vitamin C, zinc, selenium, ß-carotene and urate) and outcomes (AD, cognitive performance and reaction time) were obtained from the largest and most recent genome-wide association studies (GWAS). MR inverse variance weighting (IVW) and MR pleiotropy residual sum and outlier test (MR-PRESSO) were used for data analysis. RESULTS: Higher genetically determined selenium level was associated with 5% higher risk of AD (OR 1.047, 95% CI 1.005 to 1.091, p=0.028) using IVW. Higher genetically determined urate level was associated with worse cognitive performance (ß=-0.026, 95% CI -0.044 to -0.008, p=0.005) using MR-PRESSO. No association between the other antioxidants and AD, cognitive performance and reaction time was found. Similar results were found in the sensitivity analyses. CONCLUSION: Our results suggest that lifelong exposure to higher selenium may be associated with a higher risk of AD, and higher urate levels could be associated with worse cognitive performance. Further analyses using larger GWAS of antioxidants are warranted to confirm these observations. Our results suggest that caution is needed in the interpretation of traditional observational evidence on the neuroprotective effects of antioxidants.

Deciphering the complex relationship between type 2 diabetes and fracture risk with both genetic and observational evidence.

The 'diabetic bone paradox' suggested that type 2 diabetes (T2D) patients would have higher areal bone mineral density (BMD) but higher fracture risk than individuals without T2D. In this study, we found that the genetically predicted T2D was associated with higher BMD and lower risk of fracture in both weighted genetic risk score (wGRS) and two-sample Mendelian randomization (MR) analyses. We also identified ten genomic loci shared between T2D and fracture, with the top signal at SNP rs4580892 in the intron of gene RSPO3. And the higher expression in adipose subcutaneous and higher protein level in plasma of RSPO3 were associated with increased risk of T2D, but decreased risk of fracture. In the prospective study, T2D was observed to be associated with higher risk of fracture, but BMI mediated 30.2% of the protective effect. However, when stratified by the T2D-related risk factors for fracture, we observed that the effect of T2D on the risk of fracture decreased when the number of T2D-related risk factors decreased, and the association became non-significant if the T2D patients carried none of the risk factors. In conclusion, the genetically determined T2D might not be associated with higher risk of fracture. And the shared genetic architecture between T2D and fracture suggested a top signal around RSPO3 gene. The observed effect size of T2D on fracture risk decreased if the T2D-related risk factors could be eliminated. Therefore, it is important to manage the complications of T2D to prevent the risk of fracture.

Association of Cantonese dietary patterns with mortality risk in older Chinese: a 16-year follow-up of a Guangzhou Biobank cohort study.

Background: Evidence about the associations between Cantonese dietary patterns and mortality is scarce. We examined the prospective association of the dietary pattern with all-cause, cancer and cardiovascular disease (CVD) mortality in older Chinese. Methods: We included 19 598 participants of a Guangzhou Biobank cohort study aged 50+ years, who were recruited from 2003 to 2006 and followed up until July, 2022. The diet was assessed by using a 300-item validated food frequency questionnaire. The food items were collapsed into 27 food groups. Factor analysis (FA) was used to identify dietary patterns. Multivariable Cox regression produced hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality. Results: During 305 410 person-years, 4966 deaths including 1971 CVD, 1565 cancer and 1436 other-causes occurred. Four dietary patterns were identified by FA. No association of the vegetable-based dietary pattern with all-cause, CVD and cancer mortality was found. Compared with the lowest quartile of the healthy Cantonese dietary pattern score, the highest quartile showed lower risks of all-cause (HR 0.86, 95% CI 0.80-0.94) and CVD mortality (HR 0.84, 95% CI 0.72-0.97). The highest quartile of the nut and fruit dietary pattern showed lower risks of all-cause (HR 0.92, 95% CI 0.85-0.99) and CVD mortality (HR 0.82, 95% CI 0.72-0.93), while the unhealthy western dietary pattern was associated with a higher risk of all-cause (HR 1.10, 95% CI 1.01-1.19) and cerebrovascular disease mortality (HR 1.28, 95% CI 1.03-1.58). Conclusion: We have first identified four dietary patterns based on the Cantonese cuisine and found that healthy Cantonese and nut and fruit dietary patterns were associated with lower risks of all-cause and CVD mortality, whereas the unhealthy western dietary pattern was associated with a higher risk of all-cause and cerebrovascular disease mortality.

A comprehensive single-cell breast tumor atlas defines epithelial and immune heterogeneity and interactions predicting anti-PD-1 therapy response.

We present an integrated single-cell RNA sequencing atlas of the primary breast tumor microenvironment (TME) containing 236,363 cells from 119 biopsy samples across eight datasets. In this study, we leverage this resource for multiple analyses of immune and cancer epithelial cell heterogeneity. We define natural killer (NK) cell heterogeneity through six subsets in the breast TME. Because NK cell heterogeneity correlates with epithelial cell heterogeneity, we characterize epithelial cells at the level of single-gene expression, molecular subtype, and 10 categories reflecting intratumoral transcriptional heterogeneity. We develop InteractPrint, which considers how cancer epithelial cell heterogeneity influences cancer-immune interactions. We use T cell InteractPrint to predict response to immune checkpoint inhibition (ICI) in two breast cancer clinical trials testing neoadjuvant anti-PD-1 therapy. T cell InteractPrint was predictive of response in both trials versus PD-L1 (AUC = 0.82, 0.83 vs. 0.50, 0.72). This resource enables additional high-resolution investigations of the breast TME.

Distraction-aware hierarchical learning for vascular structure segmentation in intravascular ultrasound images.

Vascular structure segmentation in intravascular ultrasound (IVUS) images plays an important role in pre-procedural evaluation of percutaneous coronary intervention (PCI). However, vascular structure segmentation in IVUS images has the challenge of structure-dependent distractions. Structure-dependent distractions are categorized into two cases, structural intrinsic distractions and inter-structural distractions. Traditional machine learning methods often rely solely on low-level features, overlooking high-level features. This way limits the generalization of these methods. The existing semantic segmentation methods integrate low-level and high-level features to enhance generalization performance. But these methods also introduce additional interference, which is harmful to solving structural intrinsic distractions. Distraction cue methods attempt to address structural intrinsic distractions by removing interference from the features through a unique decoder. However, they tend to overlook the problem of inter-structural distractions. In this paper, we propose distraction-aware hierarchical learning (DHL) for vascular structure segmentation in IVUS images. Inspired by distraction cue methods for removing interference in a decoder, the DHL is designed as a hierarchical decoder that gradually removes structure-dependent distractions. The DHL includes global perception process, distraction perception process and structural perception process. The global perception process and distraction perception process remove structural intrinsic distractions then the structural perception process removes inter-structural distractions. In the global perception process, the DHL searches for the coarse structural region of the vascular structures on the slice of IVUS sequence. In the distraction perception process, the DHL progressively refines the coarse structural region of the vascular structures to remove structural distractions. In the structural perception process, the DHL detects regions of inter-structural distractions in fused structure features then separates them. Extensive experiments on 361 subjects show that the DHL is effective (e.g., the average Dice is greater than 0.95), and superior to ten state-of-the-art IVUS vascular structure segmentation methods.

Thermally Activated Delayed Fluorescence with Nanosecond Emission Lifetimes and Minor Concentration Quenching: Achieving High-Performance Nondoped and Doped Blue OLEDs.

Simultaneously achieving a high photoluminescence quantum yield (PLQY), ultrashort exciton lifetime, and suppressed concentration quenching in thermally activated delayed fluorescence (TADF) materials is desirable yet challenging. Here, a novel acceptor-donor-acceptor type TADF emitter, namely, 2BO-sQA, wherein two oxygen-bridged triarylboron (BO) acceptors are arranged with cofacial alignment and positioned nearly orthogonal to the rigid dispirofluorene-quinolinoacridine (sQA) donor is reported. This molecular design enables the compound to achieve highly efficient (PLQYs up to 99%) and short-lived (nanosecond-scale) blue TADF with effectively suppressed concentration quenching in films. Consequently, the doped organic light-emitting diodes (OLEDs) base on 2BO-sQA achieve exceptional electroluminescence performance across a broad range of doping concentrations, maintaining maximum external quantum efficiencies (EQEs) at over 30% for doping concentrations ranging from 10 to 70 wt%. Remarkably, the nondoped blue OLED achieves a record-high maximum EQE of 26.6% with a small efficiency roll-off of 14.0% at 1000 candelas per square meter. By using 2BO-sQA as the sensitizer for the multiresonance TADF emitter ν-DABNA, TADF-sensitized fluorescence OLEDs achieve high-efficiency deep-blue emission. These results demonstrate the feasibility of this molecular design in developing TADF emitters with high efficiency, ultrashort exciton lifetime, and minimal concentration quenching.

Impact of health education on promoting influenza vaccination health literacy in primary school students: a cluster randomised controlled trial protocol.

INTRODUCTION: Influenza is a major public health threat, and vaccination is the most effective prevention method. However, vaccination coverage remains suboptimal. Low health literacy regarding influenza vaccination may contribute to vaccine hesitancy. This study aims to evaluate the effect of health education interventions on influenza vaccination rates and health literacy. METHODS AND ANALYSIS: This cluster randomised controlled trial will enrol 3036 students in grades 4-5 from 20 primary schools in Dongguan City, China. Schools will be randomised to an intervention group receiving influenza vaccination health education or a control group receiving routine health education. The primary outcome is the influenza vaccination rate. Secondary outcomes include health literacy levels, influenza diagnosis rate, influenza-like illness incidence and vaccine protection rate. Data will be collected through questionnaires, influenza surveillance and self-reports at baseline and study conclusion. ETHICS AND DISSEMINATION: Ethical approval has been sought from the Ethics Committee of the School of Public Health, Sun Yat-sen University. Findings from the study will be made accessible to both peer-reviewed journals and key stakeholders. TRIAL REGISTRATION NUMBER: NCT06048406.

Nitrogen-Based Gas Molecule Adsorption on a ReSe2 Monolayer via Single-Atom Doping: A First-Principles Study.

Two-dimensional materials have shown immense promise for gas-sensing applications due to their remarkable surface-to-volume ratios and tunable chemical properties. However, despite their potential, the utilization of ReSe2 as a gas-sensing material for nitrogen-containing molecules, including NO2, NO, and NH3, has remained unexplored. The choice of doping atoms in ReSe2 plays a pivotal role in enhancing the gas adsorption and gas-sensing capabilities. Herein, the adsorption properties of nitrogen-containing gas molecules on metal and non-metal single-atom (Au, Pt, Ni, P, and S)-doped ReSe2 monolayers have been evaluated systematically via ab initio calculations based on density functional theory. The findings strongly suggest that intrinsic ReSe2 has better selectivity toward NO2 than toward NO and NH3. Moreover, our results provide compelling evidence that all of the dopants, with the exception of S, significantly enhance both the adsorption strength and charge transfer between ReSe2 and the investigated molecules. Notably, P-decorated ReSe2 showed the highest adsorption energy for NO2 and NO (-1.93 and -1.52 eV, respectively) with charge transfer above 0.5e, while Ni-decorated ReSe2 exhibited the highest adsorption energy for NH3 (-0.76 eV). In addition, on the basis of transition theory, we found that only Au-ReSe2 and Ni-ReSe2 can serve as reusable chemiresisitve gas sensors for reliable detection of NO and NH3, respectively. Hence, our findings indicate that gas-sensing applications can be significantly improved by utilizing a single-atom-doped ReSe2 monolayer.

H4K20me3, H3K4me2 and H3K9me2 mediate the effect of ER on prognosis in breast cancer.

Previous studies have indicated that histone methylations act as mediators in the relationship between oestrogen receptor (ER) and breast cancer prognosis, yet the mediating role has never been assessed. Therefore, we investigated seven histone methylations (H3K4me2, H3K4me3, H3K9me1, H3K9me2, H3K9me3, H3K27me3 and H4K20me3) to determine whether they mediate the prognostic impact of ER on breast cancer. Tissue microarrays were constructed from 1045 primary invasive breast tumours, and the expressions of histone methylations were examined by immunohistochemistry. Multifactorial logistic regression was used to analyse the associations between ER and histone methylations. Cox proportional hazard model was performed to assess the relationship between histone methylations and breast cancer prognosis. The mediation effects of histone methylations were evaluated by model-based causal mediation analysis. High expressions of H3K9me1, H3K9me2, H3K4me2, H3K27me3, H4K20me3 were associated with ER positivity, while high expression of H3K9me3 was associated ER negativity. Higher H3K9me2, H3K4me2 and H4K20me3 levels were associated with better prognosis. The association between ER and breast cancer prognosis was most strongly mediated by H4K20me3 (29.07% for OS; 22.42% for PFS), followed by H3K4me2 (11.5% for OS; 10.82% for PFS) and least by H3K9me2 (9.35% for OS; 7.34% for PFS). H4K20me3, H3K4me2 and H3K9me2 mediated the relationship between ER and breast cancer prognosis, which would help to further elucidate the impact of ER on breast cancer prognosis from an epigenetic perspective and provide new ideas for breast cancer treatment.

Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC.

BACKGROUND AND AIMS: Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. MATERIALS AND METHODS: A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. RESULTS: CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. CONCLUSION: Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

Associations of soy product intake with all-cause, cardiovascular disease and cancer mortality: Guangzhou Biobank Cohort Study and updated meta-analyses.

PURPOSE: We examined the associations of soy product intake with all-cause, cardiovascular disease (CVD), and cancer mortality and mediations through CVD risk factors based on the Guangzhou Biobank Cohort Study (GBCS), and conducted updated meta-analyses. METHODS: A total of 29,825 participants aged 50 + years were included. Causes of death were identified through record linkage. Soy product intake was assessed by food frequency questionnaire. Cox proportional hazards regression was used to analyze the associations between soy product intake and mortality, yielding hazard ratios (HRs) and 95% confidence intervals (CIs). Mediation analyses with CVD risk factors as mediators, and updated meta-analyses were conducted. RESULTS: During 454,689 person-years of follow-up, 6899 deaths occurred, including 2694 CVD and 2236 cancer. Participants who consumed soy product of 1-6 portions/week, versus no consumption, had significantly lower risks of all-cause and CVD mortality (adjusted HR (95% CI) 0.91 (0.86, 0.97) and 0.87 (0.79, 0.96), respectively). In participants who consumed soy product of ≥ 7 portions/week, the association of higher intake with lower CVD mortality was modestly mediated by total cholesterol (4.2%, 95% CI 1.0-16.6%). Updated meta-analyses showed that the highest level of soy product intake, versus the lowest, was associated with lower risks of all-cause and CVD mortality (pooled HR (95% CI) 0.92 (0.88, 0.96) and 0.92 (0.87, 0.98), respectively). CONCLUSION: Moderate and high soy product intake were associated with lower risks of all-cause and CVD mortality. Our findings provide support for current dietary guidelines recommending moderate soy product intake, and contribute additional evidence regarding the potential protective effects of high soy product intake.