Revealing the active ingredients and mechanism of P. sibiricumm in non-small-cell lung cancer based on UPLC-Q-TOF-MS/MS, network pharmacology, and molecular docking.

The alcohol extraction of P. sibiricum has exhibited significant inhibitory effects on the production of free radicals and the proliferation of non-small-cell lung carcinoma (NSCLC) A549 cells. Despite the diverse components found in alcohol extraction of P. sibiricum and its multiple targets, the active components and associated targets remain largely unidentified. Hence, there is a need for additional investigation into the pharmacodynamic elements and mechanisms of action. This study aimed to analyze and identify the components responsible for the anti-tumor activity of alcohol extraction from P. sibiricum using UPLC-Q-TOF-MS/MS for the first time. Subsequently, the targets of the active components were predicted using the SwissTargetPrediction database, whereas the targets for NSCLC were sourced from the Online Mendelian Inheritance in Man database (OMIM) and the GeneCards database. Next, the targets of chemical composition were integrated with disease targets via Venny online. GO and KEGG pathway enrichment analyses were performed utilizing DAVID. Subsequently, a network analysis of "components-targets-pathways" was established using Cytoscape 3.8.2 and assessed with the "network analyzer" plug-in. Molecular docking was conducted utilizing Autodock 1.5.6. The study aimed to examine the anti-proliferative impacts and underlying mechanisms of alcohol extraction from P. sibiricum on NSCLC through in vivo and in vitro investigations utilizing an animal model of transplanted tumor, CCK8 assay, cell scratch test, RT-qPCR, and western blotting. The study unveiled that 17 active components extracted from P. sibiricum alcohol demonstrated anti-non-small cell lung cancer (NSCLC) effects through the modulation of 191 targets and various significant signaling pathways. These pathways include Endocrine resistance, PI3K/AKT, Chemical carcinogenesis-receptor activation, Proteoglycans in cancer, EGFR tyrosine kinase inhibitor resistance, AMPK signaling pathway, and other related signaling pathways. Network analysis and molecular docking results indicated that specific compounds such as (25S)-26-O-(ß-d-glucopyranosyl)-furost-5-en3ß,22α,26-triol3-O-ß-d-glucopyranosyl-(1→2)-ß-d-glucopyranosyl-(1→4)-ß-d-glucopyranoside, Timosaponin H1, Deapi-platycodin D3, (3R)-5,7-dihydroxy-6,8-dimethyl-3-(4'-hydroxybenzyl)-chroman-4-one, Disporopsin, Funkioside F, Kingianoside E, Parisyunnanoside H, and Sibiricoside B primarily targeted 17 key proteins (BCL2, EGFR, ESR1, ESR2, GRB2, IGF1R, JUN, MAP2K1, MAPK14, MAPK8, MDM2, MMP9, mTOR, PIK3CA, RAF1, RPS6KB1, and SRC) collectively. In conclusion, the alcohol extraction of P. sibiricum demonstrated inhibitory effects on cell proliferation, induction of apoptosis, and inhibition of metastasis through various pathways.

[Chemical Speciation, Influencing Factors, and Regression Model of Heavy Metals in Farmland of Typical Carbonate Area with High Geological Background, Southwest China].

The speciation of heavy metals in soil is an important factor determining their bioavailability and toxicity, and it is crucial for the scientific assessment of ecological risks posed by heavy metals in soils of typical carbonate areas with high geological background in southwest China. In order to investigate the distribution of speciation of heavy metals in soils of carbonate rock with high geological background, we selected a typical carbonate rock distribution area in Guizhou Province and used the second national soil survey plots as sampling units. A total of 309 topsoil samples were collected from farmland. The improved Tessier seven-step sequential extraction method was used to analyze the seven chemical forms of heavy metals:water-soluble (F1); exchangeable (F2); carbonate-bound (F3); weakly organic-bound (F4); iron-manganese oxide-bound (F5); strongly organic-bound (F6); and residual (F7) forms of arsenic (As), cadmium (Cd), copper (Cu), mercury (Hg), nickel (Ni), lead (Pb), and zinc (Zn). The study found that the residual forms of heavy metals As, Cu, Hg, Ni, Pb, and Zn in the soil accounted for more than 50%, the effective components (F1-F3) accounted for less than 5%, and the potential biological effective components (F4-F6) were less than 45%, indicating low reactivity and low ecological risk. The effective and potentially bioavailable components of Cd accounted for 55.49% and 29.37%, respectively, which were much higher than those of other heavy metals. The ecological risk based on the speciation of heavy metals in the soil was much lower than that based on the total content of heavy metals. The stepwise regression equations could effectively establish the relationship between the bioavailable and potentially bioavailable fractions of Cd, Cu, and Pb and their influencing factors. Total heavy metal contents and pH value were important factors influencing the speciation of heavy metals in soils of carbonate rock with high geological background areas. The enrichment of heavy metal elements in the residual fraction was influenced by long-term zinc smelting activities and the weathering of carbonate rocks into soil. Soil organic matter (OM) and oxide content had a relatively small influence on the speciation of heavy metals in the soil.

Continuous flow biocatalysis: synthesis of purine nucleoside esters catalyzed by lipase TL IM from Thermomyces lanuginosus.

Purine nucleoside ester is one of the derivatives of purine nucleoside, which has antiviral and anticancer activities. In this work, a continuous flow synthesis of purine nucleoside esters catalyzed by lipase TL IM from Thermomyces lanuginosus was successfully achieved. Various parameters including solvent, reaction temperature, reaction time/flow rate and substrate ratio were investigated. The best yields were obtained with a continuous flow microreactor for 35 min at 50 °C with the substrate ratio of 1 : 5 (nucleosides to vinyl esters) in the solvent of tert-amyl alcohol. 12 products were efficiently synthesized with yields of 78-93%. Here we reported for the first time the use of lipase TL IM from Thermomyces lanuginosus in the synthesis of purine nucleoside esters. The significant advantages of this methodology are a green solvent and mild conditions, a simple work-up procedure and the highly reusable biocatalyst. This research provides a new technique for rapid synthesis of anticancer and antiviral nucleoside drugs and is helpful for further screening of drug activity.

Development of a green, concise synthesis of nicotinamide derivatives catalysed by Novozym® 435 from Candida antarctica in sustainable continuous-flow microreactors.

An increasing number of studies have shown that many nicotinamide derivatives exhibited extensive biological activities, such as anti-inflammatory and antitumor activity. In this paper, a green, concise synthesis of nicotinamide derivatives in sustainable continuous-flow microreactors catalysed by Novozym® 435 from Candida antarctica has been developed. Application of an easily obtainable and reusable lipase in the synthesis of nicotinamide derivatives from methyl nicotinate and amines/benzylamines reacted for 35 min at 50 °C led to high product yields (81.6-88.5%). Environmentally friendly tert-amyl alcohol was applied as a reaction medium. Substantially shorter reaction times as well as a significant increase in the product yield were obtained as compared to the batch process. This innovative approach provides a promising green, efficient and rapid synthesis strategy for pharmaceutical synthesis and further activity research of novel nicotinamide derivatives.

Ultrafast removal of toxic Cr(VI) by the marine bacterium Vibrio natriegens.

The fastest-growing microbe Vibrio natriegens is an excellent platform for bioproduction processes. Until now, this marine bacterium has not been examined for bioremediation applications, where the production of substantial amounts of biomass would be beneficial. V. natriegens can perform extracellular electron transfer (EET) to Fe(III) via a single porin-cytochrome circuit conserved in Vibrionaceae. Electroactive microbes capable of EET to Fe(III) usually also reduce toxic metals such as carcinogenic Cr(VI), which is converted to Cr(III), thus decreasing its toxicity and mobility. Here, the performance of V. natriegens was explored for the bioremediation of Cr(VI). At a density of 100 mg/mL, V. natriegens removed 5-20 mg/L Cr(VI) within 30 s and 100 mg/L Cr(VI) within 10 min. In comparison, the model bacterium Escherichia coli grown to a comparable cell density removed Cr(VI) 36 times slower. To eliminate Cr(VI), V. natriegens had to be metabolically active, and functional outer-membrane c-type cytochromes were required. At the end of the Cr(VI) removal process, V. natriegens had reduced all of it into Cr(III) while adsorbing more than half of the metallic ions. These results demonstrate that V. natriegens, with its fast metabolism, is a viable option for the rapid treatment of aqueous pollution with Cr.

Identification of BRD7 by whole-exome sequencing as a predictor for intermediate-stage hepatocellular carcinoma in patients undergoing TACE.

OBJECTIVE: In the present study, we aimed to identify potential predictors of intermediate-stage hepatocellular carcinoma (HCC) using whole-exome sequencing (WES) in patients undergoing transarterial chemoembolization (TACE). MATERIALS AND METHODS: In A total of 51 patients, newly diagnosed with intermediate-stage HCC between January 2013 and December 2020, were enrolled. Prior to treatment, histological samples were collected for western blotting and immunohistochemistry. The predictive roles of clinical indicators and genes in patient prognosis were analyzed using univariate and multivariate analyses. Finally, the correlation between imaging features and gene signatures was examined. RESULTS: Using WES, we identified that bromodomain-containing protein 7 (BRD7) was significantly mutated in patients with different TACE responses. No significant difference in BRD7 expression was observed between patients with and without BRD7 mutations. HCC tumors exhibited higher BRD7 than normal liver tissues. Multivariate analysis revealed that alpha-fetoprotein (AFP), BRD7 expression, and BRD7 mutations were independent risk factors for progression-free survival (PFS). In addition, Child-Pugh class, BRD7 expression, and BRD7 mutations were independent risk factors for overall survival (OS). Patients with wild-type BRD7 and high BRD7 expression had worse PFS and OS, whereas those with mutated BRD7 and low BRD7 expression exhibited the best PFS and OS. The Kruskal-Wallis test revealed that wash-in enhancement on computed tomography might be an independent risk factor for high BRD7 expression. CONCLUSION: BRD7 expression may be an independent risk factor for prognosis in patients with HCC undergoing TACE. Imaging features such as wash-in enhancement are closely related to BRD7 expression.

Laboratory risk factors for coexistent primary biliary cholangitis in patients with Sjögren's syndrome: a retrospective study.

BACKGROUND: Limited research exists on the laboratory characteristics of coexistent primary biliary cholangitis (PBC) and Sjögren's syndrome (SS). This study aimed to investigate the laboratory risk factors for the coexistence of PBC in patients with SS. METHODS: Eighty-two patients with coexistent SS and PBC (median age 52.50 years) and 82 age- and sex-matched SS controls were retrospectively enrolled between July 2015 and July 2021. The clinical and laboratory characteristics of the two groups were compared. Laboratory risk factors for the coexistence of PBC in patients with SS were analyzed using logistic regression analysis. RESULTS: Both groups had a similar prevalence of hypertension, diabetes, thyroid disease, and interstitial lung disease. Compared with the SS group, patients in the SS + PBC group had higher levels of liver enzymes, immunoglobulins M (IgM), G2, and G3 (P < 0.05). The percentage of patients with an antinuclear antibody (ANA) titre > 1:10000 in the SS + PBC group was 56.1%, higher than that in the SS group (19.5%, P < 0.05). Additionally, cytoplasmic, centromeric, and nuclear membranous patterns of ANA and positive anti-centromere antibody (ACA) were observed more frequently in the SS + PBC group (P < 0.05). Logistic regression analysis showed that elevated IgM levels, high ANA titre, cytoplasmic pattern, and ACA were independent risk factors for PBC coexistence in SS. CONCLUSIONS: In addition to established risk factors, elevated IgM levels, positive ACA, and high ANA titre with cytoplasmic pattern provide clues to clinicians for the early screening and diagnosis of PBC in patients with SS.

Chronological changes of viral shedding in adult inpatients with Omicron infection in Shanghai, China.

Background: Coronavirus disease 2019 (COVID-19) caused by the Omicron variant occurred in Shanghai, China, but its clinical characteristics and virology have not been comprehensively described. Methods: This retrospective cohort study included adult inpatients (≥18 years) diagnosed with COVID-19 at Changhai Hospital. Laboratory and clinical data were obtained from electronic medical records to investigate the clinical characteristics of COVID-19 and the variations in the patients' laboratory indexes were examined. Results: The symptoms of COVID-19 caused by the Omicron variant were relatively mild. Upper respiratory tract specimens yielded higher positive detection rates than lower respiratory tract and intestinal specimens. Peak COVID-19 viral load was reached at the time of admission; quantification cycle (Cq) values increased to approximately 35 after 8.54 days. In vivo viral shedding duration correlated with age and disease severity (p<0.05). The older the patient and the more severe the disease, the longer the duration of viral shedding was. Portion parameters of blood routine, coagulative function, clinical chemistry, and inflammatory factor showed a certain correlation with the SARS-CoV-2 viral load. Conclusions: Virus replication and shedding are rapid in Omicron-positive patients; COVID-19 in these patients is characterized by acute onset, mild symptoms, and fast recovery. Older patients and those with more severe disease demonstrate prolonged virus shedding. Routine hematological indexes can reveal disease severity and help clinically evaluate the patient's condition.

Identifying optimal candidates for post-TIPS patients with HCC undergoing TACE: a multicenter observational study.

OBJECTIVE: To develop a prognostic model for post-transjugular intrahepatic portosystemic shunt (TIPS) patients with hepatocellular carcinoma (HCC) beyond the Milan criteria treated by transarterial chemoembolization (TACE). DESIGN: Between January 2013 and January 2020, 512 patients with HCC beyond the Milan criteria who underwent TACE after TIPS were retrospectively recruited from 15 tertiary centers. Patients were randomly sorted into a training set (n = 382) and a validation set (n = 130). Medical data and overall survival were assessed. A prediction model was developed using multivariate Cox regression analyses. Predictive performance and discrimination were evaluated and compared with other prognostic models. RESULTS: Vascular invasion, log10(AFP), 1/creatinine, extrahepatic spread, and log10(ALT) were the most significant prognostic factors of survival. These five parameters were included in a new VACEA score. This score was able to stratify patients in the training set into four distinct risk grades whose median overall survival were 25.2, 15.1, 8.9, and 6.2 months, respectively. The 6-month, 1-year, 2-year, and 3-year AUROC values and C-index of the VACEA model were 0.819, 0.806, 0.779, 0.825, and 0.735, respectively, and higher than those of other seven currently available models in both the training and validation sets, as well as in different subgroups. CONCLUSION: The VACEA score could stratify post-TIPS patients with HCC beyond the Milan criteria treated by TACE and help to identify candidates who benefit from this treatment. KEY POINTS: • Vascular invasion, AFP, creatinine, extrahepatic spread, and ALT were independent significant prognostic factors of survival for HCC patients who underwent TACE after TIPS. • Our new model, named VACEA score, can accurately predict prognosis at the individual level and stratify patients into four distinct risk grades. • The VACEA model showed better prognostic discrimination and calibration than other current TACE-/TIPS-specific models Graphical abstract.

Sorafenib plus drug-eluting bead transarterial chemoembolization for early intrahepatic stage-progressed advanced hepatocellular carcinoma refractory to conventional transarterial chemoembolization.

PURPOSE: To investigate the effectiveness and safety of the combination of sorafenib and drug-eluting bead transarterial chemoembolization (DEB-TACE) in the treatment of early intrahepatic stage-progressed advanced hepatocellular carcinoma (ISPA-HCC). METHODS: This study was approved by the ethics committees of six tertiary medical centers in China. Between October 2017 and October 2020, 213 patients with advanced HCC received either sorafenib combined with on-demand DEB-TACE (DTS group, n = 103) or sorafenib monotherapy (S group, n = 110). Overall survival (OS), time to progression (TTP), local tumor response, and adverse events (AEs) were compared between the two groups. RESULTS: The incidences of nause/vomiting, abdonimal pain, hyperbilirubinemia, fever and ALT/AST increasing were higher in the DTS group. The post-treatment partial response, objective response, and disease control rates were significantly higher in the DTS group than in the S group (51.5% vs. 23.6%; 56.3% vs. 25.5%; 77.7% vs. 56.4%, respectively). The median OS was significantly longer in the DTS group than in the S group [16.3 vs. 10.0 months; hazard ratio (HR) = 0.43; P < 0.001], as was the TTP (6.7 vs. 4.3 months; HR = 0.60; P = 0.001). In the DTS group, patients who received ≥ 2 sessions of DEB-TACE benefited more than those who received two sessions of DEB-TACE. Multivariate analysis revealed that the α-fetoprotein level and treatment allocation were independent predictors of OS and TTP. CONCLUSION: The combination of sorafenib and DEB-TACE is safe and effective for the treatment of early ISPA-HCC.

Factors influencing self-management among patients diagnosed with anxiety disorders in China: A cross-sectional study.

WHAT IS KNOWN ON THE SUBJECT?: Self-management comprises five core skills: "Problem Solving, Decision-Making, Resource Utilization, Forming a Patient/Healthcare Provider Partnership and Taking Action." Effective self-management among patients diagnosed with anxiety can reduce the number of relapses and improve treatment outcomes. Knowledge of the impact of the family atmosphere, well-being and illness symptoms on self-management in patients diagnosed with anxiety disorders is limited. WHAT DOES THE PAPER ADD TO THE EXISTING KNOWLEDGE?: This is the first study in China to explore whether family atmosphere and well-being of patients diagnosed with anxiety disorders affects self-management. This paper adds to the list of factors influencing self-management among patients diagnosed with anxiety disorders. SAS scores are a major factor influencing self-management among patients diagnosed with anxiety disorders. The subjective well-being of patients diagnosed with anxiety disorders can influence their self-management behaviour. Patients who experienced family harmony had significantly higher self-management scores than those who experienced family disharmony. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Nurses should encourage patients diagnosed with anxiety disorders to manage their condition while receiving treatment at home. Nurses should focus on patients diagnosed with anxiety disorders who have significant anxiety symptoms and low well-being. Nurses should emphasize the importance of the home environment in family self-management and affirm that a good home environment promotes patient self-management. ABSTRACT: INTRODUCTION: Better self-management can improve treatment outcomes and reduce the number of relapses for patients diagnosed with anxiety disorders. However, the impact of well-being and the home environment on self-management among patients diagnosed with anxiety disorders is unclear in China. AIM: This study sought to determine the impact of the home environment, well-being and illness symptoms on self-management during home treatment for patients diagnosed with anxiety disorders. METHOD: This cross-sectional study was conducted with patients diagnosed with anxiety disorders. Data were collected with SAS, Self-Management Scale for People with Anxiety Disorders and Index of Well-being. Frequency, percentage, analysis of variance, Kruskal-Wallis and multiple linear regression analyses were used. RESULTS: Home environment (p < .001), self-perceived quality of life (p = .015), well-being index (p = .002) and SAS total score (p = .033) had a major impact on self-management in patients diagnosed with anxiety disorders (n = 245). DISCUSSION: Family disharmony, poor self-perceived quality of life, high SAS scores and low levels of well-being were significant influences on self-management among people diagnosed with anxiety disorders. IMPLICATIONS FOR PRACTICE: Nurses should focus on the self-management of patients diagnosed with significant anxiety symptoms and low well-being and value the importance of the home environment in facilitating self-management among patients diagnosed with anxiety disorders.

Idarubicin-Loaded DEB-TACE plus Lenvatinib versus Lenvatinib for patients with advanced hepatocellular carcinoma: A propensity score-matching analysis.

AIMS: To investigate the efficacy and safety of lenvatinib and idarubicin-loaded drug-eluting beads transarterial chemoembolization (IDADEB-TACE) in primary advanced hepatocellular carcinoma (HCC). METHODS: This retrospective study included patients with primary advanced HCC who received either lenvatinib monotherapy or lenvatinib plus IDADEB-TACE as first-line treatment from September 2019 to September 2020 at three institutes. Overall survival (OS), time to progression (TTP), objective response rate (ORR), and adverse events were compared. Propensity score-matching was used to reduce the influence of confounding factors on the outcomes. RESULTS: The study reviewed 118 patients who received lenvatinib plus IDADEB-TACE (LIDA group) and 182 who received lenvatinib alone (LEN group). After propensity score-matching, 78 pairs of patients remained. Compared to patients in the LEN group, those in the LIDA group had better post-treatment ORR (57.7% vs. 25.6%, p < 0.001, respectively), median OS and TTP (15.7 vs. 11.3 months, hazard ratio [HR] = 0.50, p < 0.001; 8.0 vs. 5.0 months, HR = 0.60, p = 0.003, respectively), 6- and 12-month OS rates (88.5% vs. 71.4%; 67.6% vs. 43.4%, respectively), and progression-free rates at 6 and 12 months (60.3% vs. 42.3%; 21.1% vs. 10.3%, respectively). Vascular invasion, α-fetoprotein level, and treatment type were independent OS predictors, and vascular invasion and treatment type were independent TTP predictors. Incidences of nausea/vomiting, fever, abdominal pain, and increased ALT/AST were higher in the LIDA group than in the LEN group. CONCLUSIONS: Lenvatinib plus IDADEB-TACE is well-tolerated and more effective than lenvatinib monotherapy in patients with advanced HCC.

SLC18A3 promoted renal cancer development through acetylcholine/cAMP signaling.

Renal cancer displays a high metastatic potential and a poor response to chemotherapy. However, the critical contributors to renal cancer development remain elusive. This study focused on acetylcholine (ACh) signaling. We identified the vesicular acetylcholine transporter (SLC18A3) that upregulates in patients with renal cancer. We further discovered that SLC18A3 enhanced the uptake of ACh, a classical neurotransmitter mediating synaptic transmission. The elevated ACh activated the protein kinase A (PKA)/cAMP-response element binding protein (CREB) pathway, which contributed to renal cancer cell proliferation and invasive migration. Consistently, SLC18A3 overexpression caused sustained tumor growth and increased lung metastases in A489-bearing mice. In summary, our study demonstrated that SLC18A3 contributed to cancer spread in an ACh/PKA/CREB-dependent manner, which may drive the design of efficacious treatment strategies.

Fast-growing cyanobacteria bio-embedded into bacterial cellulose for toxic metal bioremediation.

Cyanobacterial biomass and cellulose-based materials have been used separately as green bio-adsorbents for the removal of toxic metals from water. Hybrid materials made of living microbial cells encased in a solid matrix have shown good potential for bioremediation. Here, the fast-growing cyanobacterium Synechococcus elongatus UTEX 2973 was embedded in situ into bacterial cellulose (BC), a robust biopolymer rich in hydroxyl groups with excellent water holding capacity. The living material was obtained by injecting S. elongatus into a Komagataeibacter sucrofermentans culture producing BC. Several types of BC/S. elongatus (BC/SE) materials were developed including small spheroids and flat films with different cyanobacteria loads via simple adjustments of the biosynthesis process parameters. BC/SE spheroids were evaluated for toxic copper removal and exhibited excellent adsorption properties compared to pure BC with a maximum capacity of 156.25 mg g-1. Thus, this simple bio-embedding approach holds promises in the development of living materials for environmental applications.

Non-Apoptotic Programmed Cell Death-Related Gene Signature Correlates With Stemness and Immune Status and Predicts the Responsiveness of Transarterial Chemoembolization in Hepatocellular Carcinoma.

Background: Non-apoptotic programmed cell death, including autophagy, ferroptosis, and pyroptosis, newly discovered in recent years, plays an important role in hepatocellular carcinoma (HCC). So, this study attempted to explore the relationship between non-apoptotic programmed cell death-related genes and the molecular characteristics, tumor microenvironment, and prognosis in HCC patients. Methods: The transcriptomic and clinical data of HCC samples were downloaded from various public datasets, followed by acquiring non-apoptotic programmed cell death-related genes from the database. A gene signature model was then constructed using univariate and multivariate Cox regression analyses and validated in other cohorts as well as our institution sequencing data. Kaplan-Meier survival curves and time-dependent receiver operating characteristic curves were generated to evaluate the model's predictive capability. Furthermore, the relationships among the gene signature, TP53 mutation, stemness, immune status, and responsiveness of transarterial chemoembolization (TACE) were analyzed. Results: The gene signature model was constructed based on five autophagy-, three ferroptosis-, and two pyroptosis-related differentially expressed genes. The model accurately predicted that patients classified as low risk would have better overall survival than high-risk patients, which was robustly consistent with data from other cohorts as well as our institution sequencing data. The comprehensive results indicated that a high-risk index was correlated with a high TP53 mutation rate, high cancer cell stemness, high infiltration of immunosuppressive cells and low immunophenoscore, and low TACE responsiveness of HCC patients. Conclusion: Collectively, the established non-apoptotic programmed cell death-related gene signature was shown to accurately predict prognosis, associated with the TP53 mutation and liver cancer cell stemness, reflect the tumor immune microenvironment, and predict TACE responsiveness in HCC patients.

Anti-HMGB1 antibody is a potential characteristic autoantibody for Sjögren's syndrome.

Sjögren's syndrome (SS) is a common chronic inflammatory autoimmune disease that affects about 0.33-0.77% population in China. The positive for antinuclear antibodies (ANA) is one of the key features of SS, which shows a nuclear fine speckled (AC-4) pattern in an indirect immunofluorescent antibody test (IIFT). About 70% of ANA-positive SS patients have detectable anti-SS-A and/or SS-B antibodies, which indicates that other autoantibodies may present in SS patients. The anti-HMGB1 antibodies in 93 SS patients and 96 healthy controls were investigated with in-house developed ELISA and immunoblotting, and the locations of HMGB1 and fluorescent pattern of anti-HMGB1 antibody were investigated with IIFT. The contribution of anti-HMGB1 antibody in ANA-IF was evaluated with Cas9-induce HMGB1 knockout B16 cells. The anti-HMGB1 antibody level is higher in SS patients (9.96 ± 5.55 RU/ml) than in healthy controls (4.9 ± 1.4 RU/ml). With ROC curve analysis, when taking 8 RU/ml as the cutoff value, the sensitivity, specificity, and the area under the curve were 64.5%, 96.9%, and 0.83, respectively. A total of 18 patients (20.7%) with nuclear fine speckled (AC-4) pattern in ANA-IF test were anti-HMGB1 antibody positive only. With commercial antibody, anti-HMGB1 antibody showed the same nuclear fine speckled (AC-4) pattern. The serum from ANA-IF (+), SS-A (-), and SS-B (-) SS patients showed nuclear fine speckled (AC-4) pattern in wildtype B16 cells, but no fluorescence in HMGB1 knockout B16 cells. Anti-HMGB1 antibody may be one of the characteristic autoantibodies of SS in addition to anti-SS-A and SS-B. The detection of anti-HMGB1 antibody can provide more laboratory evidence for clinical diagnosis of SS.

Fumarate disproportionation by Geobacter sulfurreducens and its involvement in biocorrosion and interspecies electron transfer.

The model electroactive bacterium Geobacter sulfurreducens can acquire electrons directly from solid donors including metals and other species. Reports on this physiology concluding that solid donors are the only electron sources were conducted with fumarate believed to serve exclusively as the terminal electron acceptor (TEA). Here, G. sulfurreducens was repeatedly transferred for adaptation within a growth medium containing only fumarate and no other solid or soluble substrate. The resulting evolved strain grew efficiently with either the C4-dicarboxylate fumarate or malate acting simultaneously as electron donor, carbon source, and electron acceptor via disproportionation. Whole-genome sequencing identified 38 mutations including one in the regulator PilR known to repress the expression of the C4-dicarboxylate antiporter DcuB essential to G. sulfurreducens when growing with fumarate. Futhermore, the PilR mutation was identical to the sole mutation previously reported in an evolved G. sulfurreducens grown in a co-culture assumed to derive energy solely from direct interspecies electron transfer, but cultivated with fumarate as the TEA. When cultivating the fumarate-adapted strain in the presence of stainless steel and fumarate, biocorrosion was observed and bacterial growth was accelerated 2.3 times. These results suggest that G. sulfurreducens can conserve energy concomitantly from C4-dicarboxylate disproportionation and the oxidation of a solid electron donor. This co-metabolic capacity confers an advantage to Geobacter for survival and colonization and explains in part why these microbes are omnipresent in different anaerobic ecosystems.

Clinical Significance of Peripheral Blood Lymphocyte Subtypes and Cytokines in Patients with Hepatocellular Carcinoma Treated with TACE.

PURPOSE: To examine the clinical significance of circulating lymphocyte subtypes and cytokines in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). PATIENTS AND METHODS: We enrolled 53 patients and assessed lymphocyte subsets (CD4+ T cells, CD8+ T cells, CD4+/CD8+ cell ratio, natural killer cells, and regulatory T cells) and cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, and interferon [IFN]-γ) on the day before TACE, and 1 day and 4-8 weeks thereafter. The correlation between baseline inflammatory markers and IL-6, the differences between clinical subgroups, and the prognostic baseline inflammatory values and changes therein were analyzed. RESULTS: We found that baseline IL-6 was positively correlated with IL-10 and IFN-γ. Univariate analysis revealed that patients with higher baseline IL-6, IL-10, and IFN-γ levels had worse liver function and greater tumor burden, suggesting a poor prognosis. Multivariate analysis showed that higher baseline IFN-γ levels were associated with a shorter time to tumor progression (hazard ratio [HR] = 1.912; 95% confidence interval [CI] = 1.013-3.607; p = 0.045), and higher IL-10 levels were associated with poor overall survival (HR = 2.576; 95% CI = 1.237-5.364; p = 0.011). Baseline lymphocyte subtypes and changes therein did not have any significant association with prognosis. CONCLUSION: This study confirmed the association between inflammation and poor prognosis. The prognostic significance of IFN-γ was different from previous studies, while the prognostic significance of lymphocyte subtypes remains to be verified.

A 10-Gene Signature Identified by Machine Learning for Predicting the Response to Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) is recommended for intermediate-stage HCC patients. Owing to substantial variation in its efficacy, indicators of patient responses to TACE need to be determined. METHODS: A Gene Expression Omnibus (GEO) dataset consisting of patients of different TACE-response status was retrieved. Differentially expressed genes (DEGs) were calculated and variable gene ontology analyses were conducted. Potential drugs and response to immunotherapy were predicted using multiple bioinformatic algorithms. We built and compared 5 machine-learning models with finite genes to predict patients' response to TACE. The model was also externally validated to discern different survival outcomes after TACE. Tumor-infiltrating lymphocytes (TILs) and tumor stemness index were evaluated to explore potential mechanism of our model. RESULTS: The gene set variation analysis revealed enhanced pathways related to G2/M checkpoint, E2F, mTORC1, and myc in TACE nonresponders. TACE responders had better immunotherapy response too. 373 DEGs were detected and the upregulated DEGs in nonresponders were enriched in IL-17 signal pathway. 5 machine-learning models were constructed and evaluated, and a linear support vector machine (SVM)-based model with 10 genes was selected (AQP1, FABP4, HERC6, LOX, PEG10, S100A8, SPARCL1, TIAM1, TSPAN8, and TYRO3). The model achieved an AUC and accuracy of 0.944 and 0.844, respectively, in the development cohort. In the external validation cohort comprised of patients receiving adjuvant TACE and postrecurrence TACE treatment, the predicted response group significantly outlived the predicted nonresponse counterparts. TACE nonresponders tend to have more macrophage M0 cells and lower resting mast cells in the tumor tissue and the stemness index is also higher than responders. Those characteristics were successfully captured by our model. CONCLUSION: The model based on expression data of 10 genes could potentially predict HCC patients' response and prognosis after TACE treatment. The discriminating power was TACE-specific.

[Effect of heavy metal lead on anticoagulant activity of leech based on label-free quantitative proteomics].

Whitmania pigra is the most widely distributed species of leeches in the market. In this study, the effect of heavy metal lead pollution on the anticoagulant activity of Wh. pigra was studied and the potential mechanism was explored. Pb(NO_3)_2 was used to contaminate the breeding soil which was then used to rear Wh. pigra for 50 days(lead-contaminated group, LC group), and meanwhile the blank control group(CG group) was set. Proteins were extracted from the obtained leech samples, and the differentially expressed proteins between LC and CG groups were analyzed by label-free proteomics technology. In this study, a total of 152 differentially expressed proteins were screened out, of which 93 proteins were up-regulated and 59 proteins were down-regulated in LC group. Bioinformatics analysis showed that the biological processes enriched with the differentially expressed proteins were mainly vesicle-mediated transport and transport positive regulation; the enriched cell components were mainly endocytosis vesicles and apical plasma membrane; the enriched molecular functions mainly included carbohydrate binding. The differentially expressed proteins were enriched in 76 KEGG pathways, which mainly involved metabolic pathways, biosynthesis of secondary metabolites, and bacterial invasion of epithelial cells. In this study, two differentially expressed proteins with Antistasin domain were presumed, which provides reference for further exploring the regulatory mechanism and signal transduction underlying the effect of lead pollution on the anticoagulant activity of leech.