Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma.

BACKGROUND AND AIMS: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS: We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.

Nanoscale Janus Z-Scheme Heterojunction for Boosting Artificial Photosynthesis.

Artificial photosynthesis for CO2 reduction coupled with water oxidation currently suffers from low efficiency due to inadequate interfacial charge separation of conventional Z-scheme heterojunctions. Herein, an unprecedented nanoscale Janus Z-scheme heterojunction of CsPbBr3 /TiOx is constructed for photocatalytic CO2 reduction. Benefitting from the short carrier transport distance and direct contact interface, CsPbBr3 /TiOx exhibits significantly accelerated interfacial charge transfer between CsPbBr3 and TiOx (8.90 × 108 s-1 ) compared with CsPbBr3 :TiOx counterpart (4.87 × 107 s-1 ) prepared by traditional electrostatic self-assembling. The electron consumption rate of cobalt doped CsPbBr3 /TiOx can reach as high as 405.2 ± 5.6 µmol g-1 h-1 for photocatalytic CO2 reduction to CO coupled with H2 O oxidation to O2 under AM1.5 sunlight (100 mW cm-2 ), over 11-fold higher than that of CsPbBr3 :TiOx , and surpassing the reported halide-perovskite-based photocatalysts under similar conditions. This work provides a novel strategy to boost charge transfer of photocatalysts for enhancing the performance of artificial photosynthesis.

Kidney-type glutaminase is a biomarker for the diagnosis and prognosis of hepatocellular carcinoma: a prospective study.

PURPOSE: The pathological diagnosis and prognosis prediction of hepatocellular carcinoma (HCC) is challenging due to the lack of specific biomarkers. This study aimed to validate the diagnostic and prognostic efficiency of Kidney-type glutaminase (GLS1) for HCC in prospective cohorts with a large sample size. METHODS: A total of 1140 HCC patients were enrolled in our prospective clinical trials. Control cases included 114 nontumour tissues. The registered clinical trial (ChiCTR-DDT-14,005,102, chictr.org.cn) was referred to for the exact protocol. GLS1 immunohistochemistry was performed on the whole tumour section. The diagnostic and prognostic performances of GLS1 was evaluated by the receiver operating characteristic curve and Cox regression model. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, Youden index, and area under the curve of GLS1 for the diagnosis of HCC were 0.746, 0.842, 0.979, 0.249, 0.588, and 0.814, respectively, which could be increased to 0.846, 0.886, 0.987,0.366, 0.732, and 0.921 when combined with glypican 3 (GPC3) and alpha-fetoprotein (AFP), indicating better diagnostic performance. Further, we developed a nomogram with GPC3 and GLS1 for identifying HCC which showed good discrimination and calibration. GLS1 expression was also related with age, T stage, TNM stage, Edmondson-Steiner grade, microvascular invasion, Ki67, VEGFR2, GPC3, and AFP expression in HCC. GLS1 expression was negatively correlated with disease-free survival (P < 0.001) probability of patients with HCC. CONCLUSIONS: It was validated that GLS1 was a sensitive and specific biomarker for pathological diagnosis of HCC and had prognostic value, thus having practical value for clinical application.

Population total and unbound pharmacokinetics and pharmacodynamics of ciprofol and M4 in subjects with various renal functions.

AIMS: The aim of this study was to develop a population pharmacokinetic (PK) model to simultaneously describe both total and unbound concentrations of ciprofol and its major glucuronide metabolite, M4, and to link it to the population pharmacodynamics (PD) model in subjects with various renal functions. METHODS: A total of 401 and 459 pairs of total and unbound plasma concentrations of ciprofol and M4, respectively, as well as 2190 bispectral index (BIS) data from 24 Chinese subjects with various renal functions were available. Covariates that may potentially contribute to the PK and PD variability of ciprofol were screened using a stepwise procedure. The optimal ciprofol induction dosing regimen was determined by model-based simulations. RESULTS: The PK of unbound ciprofol could best be described by a three-compartment model, while a two-compartment model could adequately describe unbound M4 PK. The concentrations of total and unbound ciprofol and M4 were linked using a linear protein binding model. The relationship between plasma concentrations of ciprofol and BIS data was best described by an inhibitory sigmoidal Emax model with a two-compartment biophase distribution compartment. Hemoglobin was the identified covariate determining the central compartment clearance of ciprofol; uric acid was a covariate affecting the central compartment clearance of M4 and protein binding rate, kB . The included covariates had no effect on the PD of ciprofol. Simulation results indicated that the label-recommended dose regimen was adequate for anaesthesia induction. CONCLUSIONS: The developed model fully characterized the population PK and PD profiles of ciprofol. No dose adjustment is required in patients with mild and moderate renal impairment.

Vacancy-Enhanced Self-Reduction of Eu in Pyrophosphate Phosphor.

The self-reduction mechanism in pyrophosphate phosphors is currently explained through nonequivalent substitution for charge compensation. Nevertheless, the impact of oxygen vacancies on the self-reduction enhancement requires further investigation. Herein, heterovalent Ba1-xZn1-yP2O7:xEu2+/3+, yMg phosphors with rigid structures were prepared through conventional solid-phase technology in air. The cation substitution strategy leads to different chemistry electronegativity and adjustable crystal field environments and creates vacancy defects. Crystal structure and component analysis indicate the gradual phase segregation change from BaZnP2O7 to BaMgP2O7 with increasing Mg2+ content. The CIE coordinates that are tuned from (0.514, 0.334) to (0.326, 0.152) and realize color-tunable emission from red-orange to blue-violet can be used as multicolor functional materials. Besides, the phosphor demonstrates its maximum Sa of 0.4725% K-1 (498 K) and Sr of 1.376% K-1 (423 K). These results demonstrate that the phosphors have the potential for contactless optical temperature measurement and anticounterfeiting. This work not only investigates the self-reduction of the Eu3+ → Eu2+ phenomenon but also provides a supplementary explanation and data support to complete the effect of the oxygen vacancy on self-reduction.

Transhepatectomy combined with arterial chemoembolization and transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a clinical prognostic analysis.

BACKGROUND: The prognosis of patients undergoing hepatectomy combined with transarterial chemoembolization (TACE) and TACE alone was examined in order to better understand the role of hepatectomy in the treatment of hepatocellular carcinoma (HCC). In this work, we also created a model and investigated the variables influencing overall survival (OS) in HCC patients. METHODS: Retrospective analysis of 1083 patients who received TACE alone as the control group and 188 patients who received TACE after surgery in a total of 1271 HCC patients treated with LR + TACE or TACE at three third-class hospitals in China. It was done using the Propensity Score Matching (PSM) technique. The differences in OS between the two groups were compared, and OS-influencing factors were looked at. The main endpoint is overall survival. In this study, the COX regression model was used to establish the nomogram. RESULTS: The median OS of the LR + TACE group was not attained after PSM. The median OS for the TACE group was 28.8 months (95% CI: 18.9-38.7). The median OS of the LR + TACE group was higher than that of the TACE group alone, indicating a significant difference between the two groups (χ2 = 16.75, P < 0.001). While it was not achieved in the LR + TACE group, the median OS for patients with lymph node metastases in the TACE group alone was 18.8 months. The two groups differed significantly from one another (χ2 = 4.105, P = 0.043). In patients with distant metastases, the median OS of the LR + TACE treatment group was not achieved, and the median OS of the TACE group alone was 12.0 months. The difference between the two groups was sizable (χ2 = 5.266, P = 0.022). The median OS for patients with PVTT following PSM was 30.1 months in the LR + TACE treatment group and 18.7 months in the TACE alone group, respectively. The two groups differed significantly from one another (χ2 = 5.178, P = 0.023); There was no discernible difference between the two groups in terms of median overall survival (OS), which was 30.1 months for patients with lymph node metastasis and 19.2 months for those without (P > 0.05); Regarding the median OS for patients with distant metastases, which was not achieved and 8.5 months, respectively, there was a significant difference between the two groups (χ2 = 5.759, P = 0.016). We created a new nomogram to predict 1-, 2-, and 3-year survival rates based on multiple independent predictors in COX multivariate analysis. The cohort's C-index is 0.705. The area under the curve (AUC value) for predicting 1-, 2-, and 3-year survival rates were shown by the subject operating characteristic (ROC) curve linked to the nomogram to be 0.730, 0.728, and 0.691, respectively. CONCLUSIONS: LR + TACE can increase OS, delay tumor recurrence, and improve prognosis in HCC patients when compared to TACE alone. Additionally, the nomogram we created does a good job of forecasting the 1-year survival rate of hepatocellular carcinoma.

Construction and validation of a nomogram for HBV-related hepatocellular carcinoma: A large, multicenter study.

INTRODUCTION AND OBJECTIVES: We initiated this multicenter study to integrate important risk factors to create a nomogram for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) for clinician decision-making. PATIENTS AND METHODS: Between April 2011 and March 2022, 2281 HCC patients with an HBV-related diagnosis were included. All patients were randomly divided into two groups in a ratio of 7:3 (training cohort, n = 1597; validation cohort, n = 684). The nomogram was built in the training cohort via Cox regression model and validated in the validation cohort. RESULTS: Multivariate Cox analyses revealed that the portal vein tumor thrombus, Child-Pugh class, tumor diameter, alanine aminotransferase level, tumor number, extrahepatic metastases, and therapy were independent predictive variables impacting overall survival. We constructed a new nomogram to predict 1-, 2-, and 3-year survival rates based on these factors. The nomogram-related receiver operating characteristics (ROC) curves indicated that the area under the curve (AUC) values were 0.809, 0.806, and 0.764 in predicting 1-, 2-, and 3-year survival rates, respectively. Furthermore, the calibration curves revealed good agreement between real measurements and nomogram predictions. The decision curve analyses (DCA) curves demonstrated excellent therapeutic application potential. In addition, stratified by risk scores, low-risk groups had longer median OS than medium-high-risk groups (p < 0.001). CONCLUSIONS: The nomogram we constructed showed good performance in predicting the 1-year survival rate for HBV- related HCC.

Clinical features and markers to identify pulmonary lesions caused by infection or vasculitis in AAV patients.

OBJECTIVES: Pulmonary lesion is frequently seen in ANCA-associated vasculitis (AAV) patients primarily due to AAV lung involvement or infection, which are hard to differentiate due to their high similarity in clinical manifestations. We aimed to analyze the clinical features of pulmonary lesions consequent to AAV involvement or infection in AAV patients and further identify the markers for differential diagnosis. METHODS: 140 AAV patients who admitted to the Renmin Hospital of Wuhan University from January 2016 to July 2021 were included in this study. According to the nature of lung conditions, these patients were divided into the non-pulmonary lesion group, the lung infection group and the non-pulmonary infection group, and their demographics, clinical symptoms, imaging features, as well as laboratory findings were compared. A receiver operating characteristic (ROC) curve was drawn, and the diagnostic efficacy of single biomarker and composite biomarkers on pulmonary infection was then evaluated. RESULTS: The patients in the lung infection group were significantly older than those in the no lesion group (63.19 ± 14.55 vs 54.82 ± 15.08, p = 0.022). Patients in the lung infection group presented more frequent symptoms and more obvious pulmonary image findings. Compared with patients in the non-pulmonary infection group, patients in the lung infection group showed a higher symptom incidence of fever, chest tightness, cough and expectoration, and hemoptysis (52.94% vs 16.00%, 61.76% vs 40.00%, 72.06% vs 46.00%, 27.94% vs 8.00%, p < 0.05, respectively), and more changes in pulmonary CT scanning images in terms of patched/striped compact opacity, alveolar hemorrhage, bronchiectasis, pleural effusion, as well as mediastinal lymphadenopathy (89.71% vs 52.00%, 11.76% vs 2.00%, 22.06% vs 8.00%, 50.00% vs 20.00%, 48.53% vs 24.00%, p < 0.05, respectively). In addition, patients in the lung infection group had significantly higher levels of serum pro-calcitonin (PCT), C-reactive protein (CRP), amyloid A (SAA), blood neutrophil-to-lymphocyte ratio (NLCR), erythrocyte sedimentation rate (ESR), as well as Birmingham vasculitis activity score (BVAS) than patients in the other two groups (p < 0.05). Among all biomarkers, PCT exhibited the highest diagnostic efficacy (0.928; 95%CI 0.89-0.97) for pulmonary infected AAV patients at a cut-off score of 0.235 ng/ml with 85.3% sensitivity and 84% specificity. Moreover, the composite biomarker of PCT-CRP-NLCR showed more diagnostic efficacy (0.979; 95% CI 0.95-1.00) in distinguishing the infectious and non-infectious lung injuries in AAV patients. CONCLUSIONS: AAV patients with lung infection manifested more clinical symptoms and prominent lung image changes. The PCT and composite biomarker PCT-CRP-NLCR showed high diagnostic efficacy for a lung infection in AAV patients. Pulmonary lesion caused by either infection or AAV involvement is commonly seen and difficult to distinguish. We aim to identify the biomarkers that can be applied in the differentiation diagnosis of pulmonary lesions in AAV patients.

Performance of the European Society of Cardiology 0/1-Hour, 0/2-Hour, and 0/3-Hour Algorithms for Rapid Triage of Acute Myocardial Infarction : An International Collaborative Meta-analysis.

BACKGROUND: The 2020 European Society of Cardiology (ESC) guidelines recommend using the 0/1-hour and 0/2-hour algorithms over the 0/3-hour algorithm as the first and second choices of high-sensitivity cardiac troponin (hs-cTn)-based strategies for triage of patients with suspected acute myocardial infarction (AMI). PURPOSE: To evaluate the diagnostic accuracies of the ESC 0/1-hour, 0/2-hour, and 0/3-hour algorithms. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus from 1 January 2011 to 31 December 2020. (PROSPERO: CRD42020216479). STUDY SELECTION: Prospective studies that evaluated the ESC 0/1-hour, 0/2-hour, or 0/3-hour algorithms in adult patients presenting with suspected AMI. DATA EXTRACTION: The primary outcome was index AMI. Twenty unique cohorts were identified. Primary data were obtained from investigators of 16 cohorts and aggregate data were extracted from 4 cohorts. Two independent authors assessed each study for methodological quality. DATA SYNTHESIS: A total of 32 studies (20 cohorts) with 30 066 patients were analyzed. The 0/1-hour algorithm had a pooled sensitivity of 99.1% (95% CI, 98.5% to 99.5%) and negative predictive value (NPV) of 99.8% (CI, 99.6% to 99.9%) for ruling out AMI. The 0/2-hour algorithm had a pooled sensitivity of 98.6% (CI, 97.2% to 99.3%) and NPV of 99.6% (CI, 99.4% to 99.8%). The 0/3-hour algorithm had a pooled sensitivity of 93.7% (CI, 87.4% to 97.0%) and NPV of 98.7% (CI, 97.7% to 99.3%). Sensitivity of the 0/3-hour algorithm was attenuated in studies that did not use clinical criteria (GRACE score <140 and pain-free) compared with studies that used clinical criteria (90.2% [CI, 82.9 to 94.6] vs. 98.4% [CI, 88.6 to 99.8]). All 3 algorithms had similar specificities and positive predictive values for ruling in AMI, but heterogeneity across studies was substantial. Diagnostic performance was similar across the hs-cTnT (Elecsys; Roche), hs-cTnI (Architect; Abbott), and hs-cTnI (Centaur/Atellica; Siemens) assays. LIMITATION: Diagnostic accuracy, inclusion and exclusion criteria, and cardiac troponin sampling time varied among studies. CONCLUSION: The ESC 0/1-hour and 0/2-hour algorithms have higher sensitivities and NPVs than the 0/3-hour algorithm for index AMI. PRIMARY FUNDING SOURCE: National Taiwan University Hospital.

[Clinical application of Chaihu Jia Longgu Muli Decoction based on modern pathophysiology mechanism].

Chaihu Jia Longgu Muli Decoction was firstly recorded in Treatise on Cold Damage(ZHANG Zhong-jing, Eastern Han dynasty). According to this medical classic, it is originally used in the treatment of the Shaoyang and Yangming syndrome. Based on the modern pathophysiological mechanism, this study interpreted the classic provisions of Chaihu Jia Longgu Muli Decoction. Original records of "chest fullness" "annoyance" "shock" "difficult urination" "delirium" "heavy body and failing to turn over" all have profound pathophysiological basis, involving disorders in cardiovascular, respiratory, nervous, and mental systems. This formula is widely used, which can be applied to treat epilepsy, cerebral arteriosclerosis, cerebral infarction, and other cerebrovascular diseases, hypertension, arrhythmia, and other cardiovascular diseases, insomnia, constipation, anxiety, depression, cardiac neurosis and other acute and chronic diseases as well as diseases in psychosomatic medicine. The clinical indications include Bupleuri Radix-targeted syndrome such as fullness and discomfort in chest and hypochondrium, bitter taste mouth, dry throat, and dizziness, the insomnia, anxiety, depression, susceptibility to fright, upset, dreamfulness and other psychiatric symptoms, red tongue, thick and yellow tongue coating, and wiry hard and powerful pulse. This formula was found to be used in combination with other formulas, such as Gualou Xiebai Decoction, Wendan Decoction, Zhizhu Pills, Juzhijiang Decoction, Suanzaoren Decoction, and Banxia Baizhu Tianma Decoction.

Regulation mechanisms of flavonoids biosynthesis of Hancheng Dahongpao peels (Zanthoxylum bungeanum Maxim) at different development stages by integrated metabolomics and transcriptomics analysis.

BACKGROUND: Flavonoids have strong free radical scavenging and antioxidant capacity. The high abundance of flavonoids in Chinese prickly ash peels have many benefits to human health. In this study, 'Hancheng Dahongpao', a main cultivar, was taken as materials to investigate the flavonoids biosynthesis mechanism of Zanthoxylum bungeanum Maxim at three key development stages by integration of metabolomics and transcriptomics analysis. RESULTS: A total of 19 differentially accumulated metabolites were identified, the key flavonoids compounds were kaempferol, quercetin and their glycoside derivatives, and two major anthocyanins (peonidin O-hexoside and peonidin 3-O-glucoside). 5 gene networks/modules including 15 important candidate genes were identified, which was highly correlated with flavonoids. Among these genes, ZM-163828 and ZM-184209 were strongly correlated with kaempferol and quercetin, and ZM-125833 and ZM-97481 were controlled the anthocyanins biosynthesis. Moreover, it was shown that MYB-ZM1, MYB-ZM3, MYB-ZM5, MYB-ZM6 and MYB-ZM7 coordinately controlled flavonoids accumulation through regulating the structural genes. CONCLUSIONS: Generally, this study systematically revealed the flavonoids metabolic pathways and candidate genes involved in flavonoids biosynthesis and laid a foundation for the potential targets for the breeding of new valuable Chinese prickly ash cultivars.

Genome-wide association study of primary dysmenorrhea in the Taiwan Biobank validates associations near the NGF and IL1 gene loci.

Using the Taiwan Biobank, we aimed to identify traits and genetic variations that could predispose Han Chinese women to primary dysmenorrhea. Cases of primary dysmenorrhea included those who self-reported "frequent dysmenorrhea" in a dysmenorrhea-related Taiwan Biobank questionnaire, and those who have been diagnosed with severe dysmenorrhea by a physician. Controls were those without self-reported dysmenorrhea. Customized Axiom-Taiwan Biobank Array Plates were used to perform whole-genome genotyping, PLINK was used to perform association tests, and HaploReg was used to conduct functional annotations of SNPs and bioinformatic analyses. The GWAS analysis included 1186 cases and 24,020 controls. We identified 53 SNPs that achieved genome-wide significance (P < 5 × 10-8, which clustered in 2 regions. The first SNP cluster was on chromosome 1, and included 24 high LD (R2 > 0.88) variants around the NGF gene (lowest P value of 3.83 × 10-13 for rs2982742). Most SNPs occurred within NGF introns, and were predicted to alter regulatory binding motifs. The second SNP cluster was on chromosome 2, including 7 high LD (R2 > 0.94) variants around the IL1A and IL1B loci (lowest P value of 7.43 × 10-10 for rs11676014) and 22 SNPs that did not reach significance after conditional analysis. Most of these SNPs resided within IL1A and IL1B introns, while 2 SNPs may be in the promoter histone marks or promoter flanking regions of IL1B. To conclude, data from this study suggest that NGF, IL1A, and IL1B may be involved in the pathogenesis of primary dysmenorrhea in the Han Chinese in Taiwan.

Temporal Trends in the Microbiological Characteristics of Sepsis in the United States: A Population Based Study.

BACKGROUND: Epidemiologic studies are needed for monitoring population-level trends in sepsis. This study examines sepsis-causing microorganisms from 2006 to 2014 in the United States using data from the Nationwide Inpatient Sample database. METHODS: 7 860 686 adults hospitalized with sepsis were identified using a validated ICD-9 coding approach. Associated microorganisms were identified by ICD-9 code and classified by major groups (Gram-positive, Gram-negative, fungi, anaerobes) and specific species for analysis of their incidence and mortality. RESULTS: The rate of sepsis incidence has increased for all four major categories of pathogens, while the mortality rate decreased. In 2014, Gram-negative pathogens had a higher incidence than Gram-positives. Anaerobes increased the fastest with an average annual increase of 20.17% (p < 0.001). Fungi had the highest mortality (19.28%) and the slowest annual decrease of mortality (-2.31%, p = 0.006) in 2013, while anaerobic sepsis had the highest hazard of mortality (adjusted HR 1.60, 95% CI 1.53-1.66). CONCLUSIONS: Gram-negative pathogens have replaced Gram-positives as the leading cause of sepsis in the United States in 2014 during the study period (2006-2014). The incidence of anaerobic sepsis has an annual increase of 20%, while the mortality of fungal sepsis has not decreased at the same rate as other microorganisms. These findings should inform the diagnosis and management of septic patients, as well as the implementation of public health programs.

Dihydroartemisinin suppresses renal fibrosis in mice by inhibiting DNA-methyltransferase 1 and increasing Klotho.

Renal fibrosis is an unavoidable end result of all forms of progressive chronic kidney diseases (CKD). Discovery of efficacious drugs against renal fibrosis is in crucial need. In a preliminary study we found that a derivative of artemisinin, dihydroartemisinin (DHA), exerted strong renoprotection, and reversed renal fibrosis in adenine-induced CKD mouse model. In this study we investigated the anti-fibrotic mechanisms of DHA, particularly its specific target in renal cells. Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) or oral administration of adenine (80 mg · kg-1), the mice received DHA (30 mg · kg-1 · d-1, i.g.) for 14 or 21 days, respectively. We showed that DHA administration markedly attenuated the inflammation and fibrotic responses in the kidneys and significantly improved the renal function in both the renal fibrosis mouse models. In adenine-treated mice, DHA was more effective than 5-azacytidine against renal fibrosis. The anti-fibrotic effects of DHA were also observed in TGF-ß1-treated HK-2 cells. In order to determine the target protein of DHA, we conducted pull-down technology coupled with shotgun proteomics using a small-molecule probe based on the structure of DHA (biotin-DHA). As a results, DNA methyltransferase 1 (DNMT1) was identified as the anti-fibrotic target of DHA in 3 different types of renal cell lines (HK-2, HEK293 and 3T3). We demonstrated that DHA directly bound to Asn 1529 and Thr 1528 of DNMT1 with a Kd value of 8.18 µM. In primary mouse renal tubular cells, we showed that DHA (10 µM) promoted DNMT1 degradation via the ubiquitin-proteasome pathway. DHA-reduced DNMT1 expression effectively reversed Klotho promoter hypermethylation, which led to the reversal of Klotho protein loss in the kidney of UUO mice. This subsequently resulted in inhibition of the Wnt/ß-catenin and TGF-ß/Smad signaling pathways and consequently conferred renoprotection in the animals. Knockdown of Klotho abolished the renoprotective effect of DHA in UUO mice. Our study reveals a novel pharmacological activity for DHA, i.e., renoprotection. DHA exhibits this effect by targeting DNMT1 to reverse Klotho repression. This study provides an evidence for the possible clinical application of DHA in the treatment of renal fibrosis.

Clinical efficacy and safety of external radiotherapy combined with sorafenib in the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Both external radiotherapy and sorafenib are promising treatments for hepatocellular carcinoma (HCC). Nevertheless, the combined treatment of external radiotherapy and sorafenib has not been widely applied clinically due to potentially adverse effects. This meta-analysis aimed to evaluate the clinical efficacy and safety of external radiotherapy combined with sorafenib in the treatment of HCC. METHODS: Pubmed, MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were searched. The primary and secondary observation endpoints were the end of survival and incidence of adverse events, respectively. 11 studies involving 664 patients were included in this meta-analysis. RESULTS: The results demonstrated that median overall survival (mOS) and median progression-free survival (mPFS) of the external radiotherapy combined with sorafenib (RS) group were 19.45 months and 8.20 months. The one- and two-year survival rates were 0.65 (95%CI: 0.55-0.76) and 0.40 (95%CI: 0.24-0.56). The incidence of adverse events was 0.34 (95%CI: 0.25-0.44). CONCLUSIONS: The findings demonstrated that the survival of the RS group was significantly improved and few severe adverse events were observed. Hence, it can be concluded that external radiotherapy combined with sorafenib is a safe, effective, and promising therapeutic option for HCC.

Gram-scale synthesis of nitrogen-doped carbon dots from locusts for selective determination of sunset yellow in food samples.

Locust powder was converted into water-soluble fluorescent nitrogen-doped carbon dots (N-CDs) with gram-scale yield through a self-exothermic reaction between nitric acid and diethylenetriamine (DETA) within 10 min. The morphology, elemental information, and optical properties of the N-CDs were characterized using high-resolution transmission electron microscopy, X-ray photoelectron spectroscopy, and Fourier-transform infrared, ultraviolet-visible and fluorescence spectroscopy. Spectroscopic investigation indicated that the fluorescence emission behaviour of N-CDs is excitation wavelength dependent, with the strongest emission peak at 470 nm using a 390 nm excitation wavelength. The strong absorption peak of sunset yellow (SY) at 482 nm overlaps substantially with the blue emission peak (470 nm) of N-CDs. This enables the fluorescence emission of N-CDs to be obviously quenched by SY through the inner filter effect. There was a good linear relationship between the fluorescence quenching degree and the concentrations of SY within the range 0.5-40 µM. The detection limit of developed fluorescence assay for SY is 28 nM, and the relative standard deviation is 2.3% (c = 10 µM). The N-CDs derived from locusts by the self-exothermic reaction are highly selective and sensitive fluorescent probes for SY, which were applied to the fluorescence sensing of SY in different food samples with satisfactory results.

Quality Evaluation of Wild Germplasm of Chinese Prickly Ash (Zanthoxylum bungeanum Maxim) from Qinling Mountains at Different Elevations Based on HPLC-Fingerprint.

Wild Chinese prickly ash resources provide a valuable genetic resource for Zanthoxylum bungeanum Maxim improvement and breeding. The Qinling Mountains was an abundant source for wild Chinese prickly ash. In this study, the phenolic and flavonoid compounds of wild germplasm resources from different altitudes and six cultivated varieties were analyzed by high performance liquid chromatography (HPLC). The chromatograms of them were essentially consistent, although their chemical composition contents were greatly different. The thirty samples were divided into three categories through the hierarchical clustering analysis. Catechin, hyperoside and quercitrin were considered to be key compounds for the quality evaluation, and by contrast, the wild samples with an altitude of 2300±50 m (Group IV) had the highest content of key compounds, and presented stronger antioxidant activity and antibacterial ability, indicating that these wild samples could be identified as the excellent breeding resources. This is the first time to evaluate the quality of wild Chinese prickly ash at different altitudes in Qinling Mountains. These excellent wild germplasm resources provided substantial potential accessions for use directly in Chinese prickly ash breeding programs.

Multi-GNSS Precise Point Positioning with UWB Tightly Coupled Integration.

Global Navigation Satellite Systems (GNSSs) can provide high-precision positioning services, which can be applied to fields including navigation and positioning, autonomous driving, unmanned aerial vehicles and so on. However, GNSS signals are easily disrupted in complex environments, which results in a positioning performance with a significantly inferior accuracy and lengthier convergence time, particularly for the single GNSS system. In this paper, multi-GNSS precise point positioning (PPP) with tightly integrating ultra-wide band (UWB) technology is presented to implement fast and precise navigation and positioning. The validity of the algorithm is evaluated by a set of GNSS and UWB data. The statistics indicate that multi-GNSS/UWB integration can significantly improve positioning performance in terms of the positioning accuracy and convergence time. The improvement of the positioning performance for the GNSS/UWB tightly coupled integration mainly concerns the north and east directions, and to a lesser extent, the vertical direction. Furthermore, the convergence performance of GNSS/UWB solution is analyzed by simulating GNSS signal interruption. The reliability and robustness of GNSS/UWB solution during GNSS signal interruption is verified. The results show that multi-GNSS/UWB solution can significantly improve the accuracy and convergence speed of PPP.

Tumor-Promoting Actions of HNRNP A1 in HCC Are Associated with Cell Cycle, Mitochondrial Dynamics, and Necroptosis.

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies in the world. Although increasing evidence supports the role of heterogeneous ribonucleoprotein particle A1 (HNRNP A1) in tumor progression, the function of HNRNP A1 in HCC remains unclear. Here, we focused on the role of HNRNP A1 in the development of HCC. In this study, we found HNRNP A1 participates in many aspects of HCC, such as progression and prognosis. Our results showed that HNRNP A1 is upregulated in human HCC tissues and cell lines. High expression of HNRNP A1 can promote the proliferation, migration, and invasion in HCC cells and accelerate tumor progression in mice. Moreover, we found that HNRNP A1 prevents the senescence process of HCC cells. Knocking down of HNRNP A1 promotes the expression of P16INK4, which arrests the cell cycle and then induces the senescence phenotype in HCC cells. Furthermore, we found that HNRNP A1 regulated necroptosis and mitochondrial dynamics. In summary, our study indicates that HNRNP A1 promotes the development of HCC, which suggests a potential therapeutic target for HCC.

Glycine-Functionalized CsPbBr3 Nanocrystals for Efficient Visible-Light Photocatalysis of CO2 Reduction.

Capping ligands are indispensable for the preparation of metal-halide-perovskite (MHP) nanocrystals (NCs) with good stability; however, the long alkyl-chain capping ligands in conventional MHP NCs will be unfavorable for CO2 adsorption and hinder the efficient carrier separation on the surface of MHP NCs, leading to inferior catalytic activity in artificial photosynthesis. Herein, CsPbBr3 nanocrystals with short-chain glycine as ligand are constructed through a facile ligand-exchange strategy. Owing to the reduced hindrance of glycine and the presence of the amine group in glycine, the photogenerated carrier separation and CO2 uptake capacity are noticeably improved without compromising the stability of the MHP NCs. The CsPbBr3 nanocrystals with glycine ligands exhibit a significantly increased yield of 27.7 µmol g-1 h-1 for photocatalytic CO2 -to-CO conversion without any organic sacrificial reagents, which is over five times higher than that of control CsPbBr3 NCs with conventional long alkyl-chain capping ligands.