Proteomics Analysis of Serum Reveals Potential Biomarkers for Heart Failure Patients with Phlegm-Blood Stasis Syndrome.

Heart failure (HF), a complex clinical syndrome, has become a global burden on health and economics around the world. Phlegm-blood stasis syndrome, one of the Traditional Chinese Medicine (TCM) syndrome differentiation, is the core pathogenesis dynamically throughout the occurrence, development, and prognosis of HF. Biomarkers having high sensitivity and specificity are highly demanded to facilitate the accurate differentiation of HF patients with phlegm-blood stasis syndrome. In the present study, serum samples were collected from 20 healthy controls and 40 HF patients (20 with and 20 without phlegm-blood stasis syndrome). We implemented data-independent acquisition mass spectrometry (DIA-MS) for discovery and parallel reaction monitoring (PRM) for validation of biomarkers for heart failure with phlegm-blood stasis syndrome. A total of 84 different proteins were found in the HF with phlegm-blood stasis syndrome (HF-TY) group compared with healthy controls. 37 candidate proteins were selected for the PRM assay, and five validated proteins with high sensitivity and specificity, including insulin-like growth factor-binding protein 4 (IGFBP4), ß-2-microglobulin (B2M), dystroglycan (DAG1), immunoglobulin J chain (JCHAIN), and kallikrein B1 (KLKB1), were considered potential biomarkers for heart failure patients with phlegm-blood stasis syndrome. Newly identified biomarkers might provide insights into the diagnosis and treatment of HF with TCM syndrome differentiation.

Association between Mediterranean diet and periodontitis among US adults: The mediating roles of obesity indicators.

OBJECTIVE: This study aimed to assess the association between the Mediterranean diet (MedDiet) and periodontitis in US adults and to further explore the mediating roles of obesity indicators in this association. BACKGROUND DATA: The relationship between MedDiet and periodontitis is controversial. And it is unclear whether obesity indicators are potential mediators of this relationship. METHODS: Using data derived from the National Health and Nutrition Examination Survey (2009-2014). Weighted binary logistic regression and restricted cubic spline were used to assess the association between MedDiet and periodontitis. Weighted ordinal logistic regression was performed to evaluate the relationship between MedDiet and periodontitis severity. The mediating roles of body mass index (BMI) and waist circumference in the relationship between the MedDiet and periodontitis were explored. Association analyses were further performed using mean clinical attachment loss (CAL) or mean periodontal probing depth (PPD) as dependent variables. The false discovery rate method was used to correct the p-values in the regression analyses. RESULTS: A total of 8290 eligible participants (4159 participants with periodontitis and 4131 without periodontitis) were included. A negative association between the MedDiet adherence score and periodontitis was observed in the binary logistic regression model (adjusted odds ratio = 0.94, 95% confidence interval: 0.90-0.97, p = .001). Restricted cubic spline regression revealed a dose-response relationship between the MedDiet adherence score and periodontitis. BMI and waist circumference significantly mediate this association, with mediation proportions of 9.7% (p = .032) and 9.3% (p = .012), respectively. Multivariable ordinal logistic regression showed that the MedDiet adherence score was negatively associated with the severity of periodontitis (all p < .05). Additionally, the MedDiet adherence score was negatively associated with mean PPD or mean CAL (all p < .05). CONCLUSIONS: This study suggests a significant negative association between adherence to the MedDiet and periodontitis and a possible mediating role of obesity indicators in this association. Furthermore, studies are still warranted to confirm our findings.

Association between polycyclic aromatic hydrocarbons and periodontitis: Results from a large population-based study.

AIM: To explore the association between polycyclic aromatic hydrocarbons (PAHs) (measured using urinary metabolites) and periodontitis using data from the National Health and Nutrition Examination Survey 2009-2014. MATERIALS AND METHODS: Weighted binary logistic regression, Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regression were used to evaluate independent and joint associations between the six urinary monohydroxylated metabolites of PAHs (OH-PAHs) and periodontitis. RESULTS: In all, 3413 participants were included in this study. All six urinary OH-PAHs were present at higher levels in the periodontitis group compared with the non-periodontitis group (p < .001). Fully adjusted multivariable logistic regressions showed positive associations between the six urinary OH-PAHs and periodontitis (p < .05). Higher concentrations of OH-PAHs were also positively associated with attachment loss, periodontal pocket depth (PPD) and the number of tooth loss. BKMR and WQS regression yielded similar positive associations between OH-PAH mixtures and periodontitis. CONCLUSIONS: PAHs and their mixture are positively associated with periodontitis, which may provide novel insights into periodontitis prevention from an environmental exposure perspective.

Association of per- and polyfluoroalkyl substances (PFAS) with periodontitis: the mediating role of sex hormones.

OBJECTIVES: To investigate the association between serum per- and polyfluoroalkyl substances (PFAS) and periodontitis, and further explore the possible mediating role of sex hormones in this association. METHODS: We extracted data from National Health and Nutrition Examination Survey (NHANES) 2009-2014. Univariable and multivariable logistic regression models were performed to investigate the association between serum levels of seven PFASs and periodontitis. Bayesian kernel machine regression (BKMR) was conducted to assess the joint effect of PFASs in mixtures. Mediation analyses were used to explore the potential mediating role of sex hormones. RESULTS: Participants with periodontitis had higher concentrations of serum perfluorooctane sulfonate (PFOS) and perfluorononanoic acid (PFNA) than those without periodontitis (both P < 0.05). In fully adjusted models, high serum concentrations of PFOS and PFNA were positively associated with periodontitis (tertile 3 vs. tertile 1: prevalence ratio (PR) = 1.19 for PFOS, 95% CI: 1.01-1.39; PR = 1.17 for PFNA, 95% CI: 1.02-1.34). The results from the BKMR models consistently showed a positive association between PFAS mixtures and periodontitis. Of note, testosterone and the ratio of testosterone to estradiol significantly mediated the relationship between high level of PFOS and periodontitis, accounting for 16.5% and 31.7% of the total effect, respectively. Sensitivity analyses yielded similar results when using periodontal clinical indices (mean loss of attachment, mean periodontal probing depth, and the number of teeth) as dependent variables. CONCLUSIONS: These findings provide evidence to support a positive association between certain PFASs and periodontitis, which might be partially mediated by sex hormones.

Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia.

Anti-PD-1 monotherapy had limited clinical efficacy in relapsed/refractory (r/r) AML patients with higher PD-1 and PD-L1 expression. Hence, we investigated the efficacy and safety of PD-1 inhibitor with DNA hypomethylating agent (HMA) + CAG regimen in patients who had failed prior AML therapy. In this phase 2, single-arm study, r/r AML patients received azacitidine or decitabine plus CAG regimen with tislelizumab. Primary endpoints were efficacy (objective response rate [ORR]) and safety. Secondary endpoints included overall survival (OS), event-free survival (EFS) and duration of response (DOR). Statistical analyses were performed using Stata 14.0 and SPSS 20.0 software where P < 0.05 denoted significance. Twenty-seven patients were enrolled patients and completed 1 cycle, and 14 (51.9%) and 4 (14.8%) patients completed 2 and 3 cycles, respectively. ORR was 63% (14: complete remission [CR]/CR with incomplete hematologic recovery [CRi], 3: partial remission (PR), 10: no response [NR]). Median OS (mOS) and EFS were 9.7 and 9.2 months, respectively. With a median follow-up of 8.2 months (1.1-26.9), the mOS was not reached in responders (CR/CRi/PR) while it was 2.4 months (0.0-5.4) in nonresponders (P = 0.002). Grade 2-3 immune-related adverse events (irAEs) were observed in 4 (14.8%) patients and 3 nonresponders died of lung infection after treatment. Tislelizumab + HMA + CAG regimen showed improved outcomes in r/r AML patients with lower pretherapy leukemia burden. irAEs were mild and low-grade and higher pretherapy bone marrow CD4+ CD127+ PD-1+ T cells might serve as a predictor of treatment response.ClinicalTrials.gov identifier NCT04541277.

Assessment of the role and mechanism of Bifidobacterium animalis subsp. lactis isolated from neonates' feces in protecting neonatal rats from Salmonella infection.

OBJECTIVES: It is now well known that Bifidobacterium animalis subsp. lactis (B. lactis), an important early-life colonizer of the gut, provides immune-related benefits to infants. The aim of the work is to explore the intraspecific resistance to Salmonella infection of B. lactis isolated from neonatal feces, and to learn more insights into how B. lactis mediates beneficial roles in early-life infection resistance. METHODS: Five strains of B. lactis (NFBAL11/NFBAL23/NFBAL44/NFBAL63/NFBAL92) were screened from fecal samples of neonates born within fifteen days and pretreated neonatal rats prior to infection with Salmonella typhimurium (S. typhimurium) SL1344. The survival rate, fecal occult blood, diarrhea and hepatosplenomegaly were detected to assess the ability of B. lactis to prevent S. typhimurium infection. Furthermore, the structure of mucus layer, gene expression, cytokine levels, antioxidant levels and intestinal microflora composition were detected to explore the mechanism. RESULTS: All strains showed activity against S. typhimurium, with B. lactis NFBAL23 being the most active, followed by NFBAL63 and NFBAL92. And these advantages weren't attained by enhancing physical growth and development. Mechanistically, the neonatal rats treated with B. lactis (NFBAL23/NFBAL63/NFBAL92) had improved intestinal barrier function involving physical, chemical, immune and biological barriers in the face of challenges posed by S. typhimurium. CONCLUSIONS: These findings revealed the intraspecific difference, beneficial roles and mechanisms of action of B. lactis against Salmonella infection early in life, which highlighted the necessity of supplementing appropriate B. lactis, and provided several potential B. lactis candidates for Salmonella infection treatment.

ß-Arrestin 2 Regulates Inflammatory Responses against Mycobacterium tuberculosis Infection through ERK1/2 Signaling.

Mycobacterium tuberculosis, the pathogen that causes tuberculosis, exhibits complex host-pathogen interactions. Pattern recognition receptors and their downstream signaling pathways play crucial roles in determining the outcome of infection. In particular, the scaffold protein ß-arrestin 2 mediates downstream signaling of G protein-coupled receptors. However, the role of ß-arrestin 2 in conferring immunity against M. tuberculosis has not yet been explored. We found that ß-arrestin 2 was upregulated in the lesioned regions of lung tissues in patients with tuberculosis. M. tuberculosis infection upregulated ß-arrestin 2 expression in human macrophages, and silencing of ß-arrestin 2 significantly enhanced bactericidal activity by enhancing the expression of proinflammatory cytokines such as TNF-α. ß-Arrestin 2 was shown to inhibit the activation of the TLR2/ERK1/2 pathway and its transcriptional regulation activity upon M. tuberculosis infection. Furthermore, ß-arrestin 2 transcriptionally regulates TNF-α by binding to CREB1. These observations revealed that the upregulation of ß-arrestin 2 is critical for M. tuberculosis to escape immune surveillance through an unknown mechanism. Our research offers a novel interference modality to enhance the immune response against tuberculosis by targeting ß-arrestin 2 to modulate the TLR2-ß-arrestin 2-ERK1/2-CREB1-TNF-α regulatory axis.

Nanosilicate-functionalized nanofibrous membrane facilitated periodontal regeneration potential by harnessing periodontal ligament cell-mediated osteogenesis and immunomodulation.

Although various new biomaterials have enriched the methods for periodontal regeneration, their efficacy is still controversial, and the regeneration of damaged support tissue in the periodontium remains challenging. Laponite (LAP) nanosilicate is a layered two-dimensional nanoscale, ultrathin nanomaterial with a unique structure and brilliant biocompatibility and bioactivity. This study aimed to investigate the effects of nanosilicate-incorporated PCL (PCL/LAP) nanofibrous membranes on periodontal ligament cells (PDLCs) in vitro and periodontal regeneration in vivo. A PCL/LAP nanofibrous membrane was fabricated by an electrospinning method. The characterization of PCL/LAP nanofibrous membrane were determined by scanning electron microscopy (SEM), energy dispersive spectrum of X-ray (EDS), inductively coupled plasma mass spectrometry (ICP-MS) and tensile test. The proliferation and osteogenic differentiation of PDLCs on the PCL/LAP nanofibrous membrane were evaluated. A PDLCs and macrophage coculture system was used to explore the immunomodulatory effects of the PCL/LAP nanofibrous membrane. PCL/LAP nanofibrous membrane was implanted into rat calvarial and periodontal defects, and the regenerative potential was evaluated by microcomputed topography (micro-CT) and histological analysis. The PCL/LAP nanofibrous membrane showed good biocompatibility and bioactivity. It enhanced the proliferation and osteogenic differentiation of PDLCs. The PCL/LAP nanofibrous membrane also stimulated anti-inflammatory and pro-remodeling N2 neutrophil formation, regulated inflammatory responses and induced M2 macrophage polarization by orchestrating the immunomodulatory effects of PDLCs. The PCL/LAP nanofibrous membrane promoted rat calvarial defect repair and periodontal regeneration in vivo. LAP nanosilicate-incorporated PCL membrane is capable of mediating osteogenesis and immunomodulation of PDLCs in vitro and accelerating periodontal regeneration in vivo. It could be a promising biomaterial for periodontal regeneration therapy.

A novel approach on designing ultrahigh burnup metallic TWR fuels: Upsetting the current technological limits.

Abstract: The grand challenge of "net-zero carbon" emission calls for technological breakthroughs in energy production. The traveling wave reactor (TWR) is designed to provide economical and safe nuclear power and solve imminent problems, including limited uranium resources and radiotoxicity burdens from back-end fuel reprocessing/disposal. However, qualification of fuels and materials for TWR remains challenging and it sets an "end of the road" mark on the route of R&D of this technology. In this article, a novel approach is proposed to maneuver reactor operations and utilize high-temperature transients to mitigate the challenges raised by envisioned TWR service environment. Annular U-50Zr fuel and oxidation dispersion strengthened (ODS) steels are proposed to be used instead of the current U-10Zr and HT-9 ferritic/martensitic steels. In addition, irradiation-accelerated transport of Mn and Cr to the cladding surface to form a protective oxide layer as a self-repairing mechanism was discovered and is believed capable of mitigating long-term corrosion. This work represents an attempt to disruptively overcome current technological limits in the TWR fuels. Impact statement: After the Fukushima accident in 2011, the entire nuclear industry calls for a major technological breakthrough that addresses the following three fundamental issues: (1) Reducing spent nuclear fuel reprocessing demands, (2) reducing the probability of a severe accident, and (3) reducing the energy production cost per kilowatt-hour. An inherently safe and ultralong life fast neutron reactor fuel form can be such one stone that kills the three birds. In light of the recent development findings on U-50Zr fuels, we hereby propose a disruptive, conceptual metallic fuel design that can serve the following purposes at the same time: (1) Reaching ultrahigh burnup of above 40% FIMA, (2) possessing strong inherent safety features, and (3) extending current limits on fast neutron irradiation dose to be far beyond 200 dpa. We believe that this technology will be able to bring about revolutionary changes to the nuclear industry by significantly lowering the operational costs as well as improving the reactor system safety to a large extent. Supplementary information: The online version contains supplementary material available at 10.1557/s43577-022-00420-4.

A novel prognostic score based on systemic inflammatory biomarkers for patients with oral squamous cell carcinoma.

OBJECTIVE: To explore the prognostic value of systemic inflammatory biomarkers (albumin/globulin ratio [AGR], neutrophil/lymphocyte ratio [NLR], and platelet/lymphocyte ratio [PLR]) in patients with oral squamous cell carcinoma (OSCC), and further develop a novel prognostic score (AGR-NLR). METHODS: A large-scale prospective study enrolling 792 eligible patients from December 2002 to June 2018 was carried out at the First Affiliated Hospital of Fujian Medical University. Three multivariate Cox regression models were performed to assess the association of overall survival (OS) with systemic inflammatory biomarkers, quantified by Akaike information criterion (AIC). Then, a novel AGR-NLR score was established and incorporated into a prognostic nomogram. RESULTS: In the univariate analysis, the increased AGR was associated with a reduced risk of death. Conversely, the higher NLR and PLR, the worse the OS. In the multivariate Cox regression models, AGR and NLR were stably independent prognostic indicators in all models, with Model 2 showing a lowest AIC (AGR: HR = 0.56, 95%CI: 0.41-0.78; NLR: HR = 1.80, 95%CI: 1.07-3.04). Then, a novel AGR-NLR score was established, which showed a more excellent performance than either AGR or NLR alone (area under curve [AUC]: 0.589, 0.559, and 0.556, respectively). The C-index of the nomogram based on AGR-NLR was superior to that of traditional TNM staging system (C-index: 0.658 versus. 0.596, p < .001). Similar results were also showed by decision curve analysis, indicating the nomogram had more positive net benefit compared to TNM staging system. CONCLUSION: The novel AGR-NLR score is strongly associated with outcome in patients with OSCC and could be serve as a useful tool to accurately predict the OS of OSCC patients.

Anti-phospholipase A2 receptor antibodies directly induced podocyte damage in vitro.

BACKGROUND: The pathogenesis of primary membranous nephropathy (MN) involves the antibodies against antigens on the cell surface of podocytes, with the majority of M-type phospholipase A2 receptor (PLA2R), and a profound podocyte dysfunction. The effects of anti-PLA2R antibodies directly to the podocytes remain unclear. METHODS: Anti-PLA2R antibodies from patients with PLA2R-associated MN were affinity-purified using a column coupled with recombinant human PLA2R protein. Their effects on conditionally immortalized human podocytes were assessed by apoptosis assays, cellular calcium detection, wound healing assay, and immunofluorescent staining. Proteomics analysis was performed by LC-MS/MS and on PANTHER database. RESULTS: The stimulation by anti-PLA2R antibodies could induce early-stage apoptosis of podocytes (MFI of Annexin V = 104.3 ± 19.2 vs. 36.7 ± 7.6, p = 0.004). The increase of calcium concentration in podocytes (MFI = 3309.3 ± 363.6 vs. 1776.3 ± 212.7, p = 0.015) might attribute to the endoplasmic reticulum calcium efflux. The expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) was also increased (MFI = 134.4 ± 9.8 vs. 105.3 ± 10.1, p = 0.011). Proteomics results suggested that anti-PLA2R antibody treatment led to damage on cellular structure, and produced functional disorders on protein binding, actin filament binding, and microtubule motor activity. The staining of F-actin on foot process was reduced (MFI = 27.3 ± 2.8 vs. 47.5 ± 1.0, p = 0.001) and the motility and adherence capacity of podocytes were reduced (number of migrated cells = 44.7 ± 3.1 vs. 53.3 ± 4.9, p = 0.001) after incubation with anti-PLA2R antibodies. CONCLUSION: These data indicate that anti-PLA2R antibodies may directly induce podocyte damage independent of the complement system, which expands the mechanism of anti-PLA2R antibodies on MN.

Vision-Based Defect Inspection and Condition Assessment for Sewer Pipes: A Comprehensive Survey.

Due to the advantages of economics, safety, and efficiency, vision-based analysis techniques have recently gained conspicuous advancements, enabling them to be extensively applied for autonomous constructions. Although numerous studies regarding the defect inspection and condition assessment in underground sewer pipelines have presently emerged, we still lack a thorough and comprehensive survey of the latest developments. This survey presents a systematical taxonomy of diverse sewer inspection algorithms, which are sorted into three categories that include defect classification, defect detection, and defect segmentation. After reviewing the related sewer defect inspection studies for the past 22 years, the main research trends are organized and discussed in detail according to the proposed technical taxonomy. In addition, different datasets and the evaluation metrics used in the cited literature are described and explained. Furthermore, the performances of the state-of-the-art methods are reported from the aspects of processing accuracy and speed.

IL-36γ Promotes Killing of Mycobacterium tuberculosis by Macrophages via WNT5A-Induced Noncanonical WNT Signaling.

Mycobacterium tuberculosis, which primarily infects mononuclear phagocytes, remains the leading bacterial cause of enormous morbidity and mortality because of bacterial infections in humans throughout the world. The IL-1 family of cytokines is critical for host resistance to M. tuberculosis As a newly discovered subgroup of the IL-1 family, although IL-36 cytokines have been proven to play roles in protection against M. tuberculosis infection, the antibacterial mechanisms are poorly understood. In this study, we demonstrated that IL-36γ conferred to human monocyte-derived macrophages bacterial resistance through activation of autophagy as well as induction of WNT5A, a reported downstream effector of IL-1 involved in several inflammatory diseases. Further studies showed that WNT5A could enhance autophagy of monocyte-derived macrophages by inducing cyclooxygenase-2 (COX-2) expression and in turn decrease phosphorylation of AKT/mTOR via noncanonical WNT signaling. Consistently, the underlying molecular mechanisms of IL-36γ function are also mediated by the COX-2/AKT/mTOR signaling axis. Altogether, our findings reveal a novel activity for IL-36γ as an inducer of autophagy, which represents a critical inflammatory cytokine that control the outcome of M. tuberculosis infection in human macrophages.

Robust Korean License Plate Recognition Based on Deep Neural Networks.

With the rapid rise of private vehicles around the world, License Plate Recognition (LPR) plays a vital role in supporting the government to manage vehicles effectively. However, an introduction of new types of license plate (LP) or slight changes in the LP format can break previous LPR systems, as they fail to recognize the LP. Moreover, the LPR system is extremely sensitive to the conditions of the surrounding environment. Thus, this paper introduces a novel deep learning-based Korean LPR system that can effectively deal with existing challenges. The main contributions of this study include (1) a robust LPR system with the integration of three pre-processing techniques (defogging, low-light enhancement, and super-resolution) that can effectively recognize the LP under various conditions, (2) the establishment of two original Korean LPR approaches for different scenarios, including whole license plate recognition (W-LPR) and single-character license plate recognition (SC-LPR), and (3) the introduction of two Korean LPR datasets (synthetic data and real data) involving a new type of LP introduced by the Korean government. Through several experiments, the proposed LPR framework achieved the highest recognition accuracy of 98.94%.

Pharmacokinetics of gallic acid and protocatechuic acid in humans after dosing with Relinqing (RLQ) and the potential for RLQ-perpetrated drug-drug interactions on organic anion transporter (OAT) 1/3.

CONTEXT: Relinqing granules (RLQ) are being used alone or in combination with antibacterial drugs to treat urological disorders. OBJECTIVE: This study investigates the pharmacokinetics of RLQ in humans and the potential for RLQ-perpetrated interactions on transporters. MATERIALS AND METHODS: Twelve healthy subjects (six women and six men) participated to compare single- and multiple-dose pharmacokinetics of RLQ. In the single-dose study, all 12 subjects received 8 g of RLQ orally. After a 7-d washout period, the subjects received 8 g of RLQ for seven consecutive days (t.i.d.) and then a single dose. Gallic acid (GA) and protocatechuic acid (PCA) in plasma and urine samples were analysed using LC-MS/MS. The transfected cells were used to study the inhibitory effect of GA (50-5000 µg/L) and PCA (10-1000 µg/L) on transporters OAT1, OAT3, OCT2, OATP1B1, P-gp and BCRP. RESULTS: GA and PCA were absorbed into the blood within 1 h after administration and rapidly eliminated with a half-life of less than 2 h. The mean peak concentrations of GA (102 and 176 µg/L) and PCA (4.54 and 7.58 µg/L) were lower in males than females, respectively. The 24 h urine recovery rates of GA and PCA were about 10% and 5%, respectively. The steady-state was reached in 7 d without accumulation. GA was a potent inhibitor of OAT1 (IC50 = 3.73 µM) and OAT3 (IC50 = 29.41 µM), but not OCT2, OATP1B1, P-gp or BCRP. DISCUSSION AND CONCLUSIONS: GA and PCA are recommended as PK-markers in RLQ-related pharmacokinetic and drug interaction studies. We should pay more attention to the potential for RLQ-perpetrated interactions on transporters.

Vitamin B6 prevents excessive inflammation by reducing accumulation of sphingosine-1-phosphate in a sphingosine-1-phosphate lyase-dependent manner.

Vitamin B6 is necessary to maintain normal metabolism and immune response, especially the anti-inflammatory immune response. However, the exact mechanism by which vitamin B6 plays the anti-inflammatory role is still unclear. Here, we report a novel mechanism of preventing excessive inflammation by vitamin B6 via reduction in the accumulation of sphingosine-1-phosphate (S1P) in a S1P lyase (SPL)-dependent manner in macrophages. Vitamin B6 supplementation decreased the expression of pro-inflammatory cytokines by suppressing nuclear factor-κB and mitogen-activated protein kinases signalling pathways. Furthermore, vitamin B6-reduced accumulation of S1P by promoting SPL activity. The anti-inflammatory effects of vitamin B6 were inhibited by S1P supplementation or SPL deficiency. Importantly, vitamin B6 supplementation protected mice from lethal endotoxic shock and attenuated experimental autoimmune encephalomyelitis progression. Collectively, these findings revealed a novel anti-inflammatory mechanism of vitamin B6 and provided guidance on its clinical use.

Detection of EP300-ZNF384 fusion in patients with acute lymphoblastic leukemia using RNA fusion gene panel sequencing.

EP300-ZNF384 fusion is a rare recurrent cytogenetic abnormality associated with B cell acute lymphoblastic leukemia (B-ALL), which was rarely studied in Chinese patient cohort. Here, we used a customized RNA fusion gene panel to investigate gene fusions in 56 selected acute leukemia patients without conventional genetic abnormalities. Two EP300-ZNF384 fusion forms were detected in ten cases, which were in-frame fusions of EP300 exon 6 fused with exon 3 or 2 of ZNF384. The fusions led to the lack of most functional domains of EP300. We firstly reported EP300-ZNF384 fusion in a mixed-phenotype acute leukemia (MPAL) patient whose CD33 and CD13 were negative. The rest nine B-ALL patients with EP300-ZNF384 fusion expressed CD33 and/or CD13. Fifty-six percent of B-ALL patients (5/9) with EP300-ZNF384 fusion were positive with CD10. After the diagnosis of EP300-ZNF384 fusion, 70% of the patients achieved remission after chemotherapy. Our observations indicated that EP300-ZNF384 fusion consists of a distinct subgroup of B-ALL with a characteristic immunophenotype. These patients are sensitive to current chemotherapy regimen and have an excellent outcome.

Effect of glutamine on the immune function of paclitaxel intervention in ovarian cancer mice.

To analyze the effect of amide Valley on the immune function of ovarian cancer mice treated with paclitaxel. Fifty SPF female BALB/c mice were selected as experimental subjects, and the mice were divided into five groups, namely normal control group, tumor control group, paclitaxel group, glutamine group and combined intervention group, with 10 mice in each group. Except for the normal control group, the other 40 mice were all subjected to ovarian cancer modeling. After modeling, the tumor control group mice were injected with saline at a dose of 25 mg/kg; the mice in the paclitaxel group were given a dose of 25 mg/kg. Intraperitoneal injection of paclitaxel; mice in the glutamine group were intraperitoneally injected with glutamine at a dose of 25 mg/kg; mice in the joint intervention group were intraperitoneally injected with glutamine and paclitaxel at a dose of 25 mg/kg once daily. The normal control mice did not receive any treatment. Observe and compare the status of the five groups of mice and regularly measure the quality of the mice; after 2 weeks of treatment, the CD3+, CD4, CD4+, CD8, CD8+ of the T lymphocyte subsets of each group of mice were detected by flow cytometry calculate the ratio of CD4 / CD8. The tumor formation rate of mouse ovarian cancer was 95% (38/40). The hair color, diet, excretion and activity of mice in the normal control group were normal, while the hair of the remaining four groups of ovarian cancer mice was sparse and dull compared with those in the normal control group, and the diet was decreased and the action was retarded. By measuring the body mass of mice at a regular time, we found that before treatment, the body mass of the other four groups of ovarian cancer mice increased significantly (P< 0.05) because of the tumor body compared with the normal control group mice; after treatment, compared with the other ovarian cancer mice group, the body mass of the combined intervention group mice decreased significantly, the difference was statistically significant (P< 0.05), suggesting that the tumor body was reduced. Compare with normal control mice, CD3+, CD4, and CD4 / CD8 of other ovarian cancer mice groups were significantly decreased, and CD8+ was significantly increased, the differences were statistically significant (P< 0.05); There was no significant difference in the levels of CD3+, CD4+, CD4 / CD8, and CD8+ between the tumor control group and the paclitaxel group (P> 0.05). Paclitaxel does not improve the immunity of patients during the treatment of ovarian cancer. Glutamine is effective immunomodulation. By regulating paclitaxel-treated ovarian cancer mice, it can simultaneously treat ovarian cancer, significantly improve the immune function of ovarian cancer mice, thereby improving the anti-tumor ability, and provide the possibility of significantly improving the body's immunity of ovarian cancer patients. Clinical research and long-term prognosis still need to be confirmed by further studies.

Inhibitory effects of lappaconitine on the neuronal isoforms of voltage-gated sodium channels.

Lappaconitine (LA) has been widely used for postoperative and cancer pain control. LA exhibits excellent analgesic activity with a longer effective time than common local anesthetics such as tetracaine and bupivacaine. However, the mechanisms underlying the featured analgesic activity of LA remain largely unknown. Here, we report that LA is an inhibitor of voltage-gated sodium channel 1.7 (Nav1.7) stably expressed in human embryonic kidney (HEK293) cells. LA inhibited Nav1.7 in a voltage-dependent manner with an IC50 value (with 95% confidence limits) of 27.67 (15.68-39.66) µmol/L when the cell was clamped at -70 mV. In comparison with the quick and reversible inhibition of Nav1.7 by tetracaine and bupivacaine, the inhibitory effect of LA was rather slow and irreversible. It took more than 10 min to achieve steady-state inhibition when LA (300 µmol/L) was administered. Unlike tetracaine and bupivacaine, LA affected neither the voltage-dependent activation nor the inactivation of the channels. Five residues in domain III and domain IV have been reported to be critical for the effects of the two local anesthetics on Nav channels. But our mutant study revealed that only two residues (F1737, N1742) located in domain IV were necessary for the inhibitory activity of LA. The slow onset, irreversibility, and lack of influence on channel activation and inactivation accompanied with the different molecular determinants suggest that LA may inhibit Nav1.7 channels in a manner different from local anesthetics. These results may help to understand the featured analgesic activity of LA, thus benefiting its application in the clinic and future drug development.

Intravenous formulation of Panax notoginseng root extract: human pharmacokinetics of ginsenosides and potential for perpetrating drug interactions.

XueShuanTong, a lyophilized extract of Panax notoginseng roots (Sanqi) for intravenous administration, is extensively used as add-on therapy in the treatment of ischemic heart and cerebrovascular diseases and comprises therapeutically active ginsenosides. Potential for XueShuanTong-drug interactions was determined; the investigation focused on cytochrome P450 (CYP)3A induction and organic anion-transporting polypeptide (OATP)1B inhibition. Ginsenosides considerably bioavailable for drug interactions were identified by dosing XueShuanTong in human subjects and their interaction-related pharmacokinetics were determined. The CYP3A induction potential was determined by repeatedly dosing XueShuanTong for 15 days in human subjects and by treating cryopreserved human hepatocytes with circulating ginsenosides; midazolam served as a probe substrate. Joint inhibition of OATP1B by XueShuanTong ginsenosides was assessed in vitro, and the data were processed using the Chou-Talalay method. Samples were analyzed by liquid chromatography/mass spectrometry. Ginsenosides Rb1, Rd, and Rg1 and notoginsenoside R1 were the major circulating XueShuanTong compounds; their interaction-related pharmacokinetics comprised compound dose-dependent levels of systemic exposure and, for ginsenosides Rb1 and Rd, long terminal half-lives (32‒57 and 58‒307 h, respectively) and low unbound fractions in plasma (0.8%‒2.9% and 0.4%‒3.0%, respectively). Dosing XueShuanTong did not induce CYP3A. Based on the pharmacokinetics and inhibitory potency of the ginsenosides, XueShuanTong was predicted to have high potential for OATP1B3-mediated drug interactions (attributed chiefly to ginsenoside Rb1) suggesting the need for further model-based determination of the interaction potential for XueShuanTong and, if necessary, a clinical drug interaction study. Increased awareness of ginsenosides' pharmacokinetics and XueShuanTong-drug interaction potential will help ensure the safe use of XueShuanTong and coadministered synthetic drugs.