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Aims: Neutrophil elastase (NE) is a critical proteolytic enzyme that is involved in cancer. We previously reported high NE expression in peripheral blood neutrophils from acute promyelocytic leukemia (APL) patients. The present study aimed to elucidate the specific role and mechanisms of NE in APL development., Materials and Methods: NE expression was detected in APL bone marrow samples and analyzed in the BloodSpot database. CCK-8 assay and flow cytometry were used to assess cell proliferation and cell cycle distribution, respectively. The expression levels of proliferation and differentiation markers were measured by Western blotting and quantitative real-time PCR. The co-expression and interaction of NE and p200 cut-like homeobox 1 (CUX1) were evaluated by indirect immunofluorescence, co-immunoprecipitation, and in situ proximity ligation assay., Key Findings: NE was highly expressed in APL bone marrow and blood neutrophils. NE overexpression promoted the proliferation and inhibited the differentiation of NB4 cells, whereas NE downregulation achieved the opposite results in U937 cells. Mechanistically, NE interacted with and effectively hydrolyzed the tumor suppressor p200 CUX1. Rescue experiments revealed that p200 CUX1 upregulation reversed the functional influence of NE on APL cells., Significance: NE-mediated proteolysis of the tumor suppressor p200 CUX1 promotes APL progression. NE/p200 CUX1 axis is a novel and promising therapeutic target for APL treatment., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: To evaluate the association of relapse and healthcare resource utilization in patients with schizophrenia (SZ), bipolar disorder (BD), or major depressive disorder (MDD) who switched antipsychotic medication versus those who did not. Materials and methods: Medicaid claims from six US states spanning six years were retrospectively analyzed for antipsychotic switching versus non-switching. For all patients with SZ, BD, or MDD, and for the subset of patients who also had ≥1 extrapyramidal symptoms (EPS) diagnosis at baseline, times to the following outcomes were analyzed: underlying disease relapse, other psychiatric relapse, all-cause emergency room (ER) visit, all-cause inpatient (IP) admission, and EPS diagnosis. Results: Switchers ( N  = 10,548) had a shorter time to disease relapse, other psychiatric relapse, IP admissions, ER visits, and EPS diagnosis (all, log-rank p  < .001) than non-switchers ( N  = 31,644). Switchers reached the median for IP admission (21.50 months) vs non-switchers (not reached) and for ER visits (switchers, 9.07 months; non-switchers, 13.35 months). For disease relapse, other psychiatric relapse, and EPS diagnosis, <50% of patients had an event during the two-year study period. Subgroup analysis of those with ≥1 EPS diagnosis revealed similar associations. Limitations: Only association, not causation, may be inferred, and there may be differences between the patient groups in parameters not evaluated. Conclusions: These results show that disease and other psychiatric relapse, all-cause ER visits, IP admissions, and EPS diagnosis occurred earlier for patients who switched antipsychotics than for those who did not, suggesting that switching is associated with an increased risk of relapse in patients with SZ, BD, and MDD. This may be attributed to more-severely ill patients being less responsive than those with less-severe illness, which, in turn, may require more episodes of switching.

Objective: The purpose of this work was to investigate the bioactive compounds, core genes, and pharmacological mechanisms and to provide a further research orientation of Erzhi pill (EZP) on drug-induced liver injury (DILI)., Methods: At first, we collected information of bioactive compounds of EZP from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and previous studies. And then, the targets related to bioactive compounds and DILI were obtained from 4 public databases. At last, Cytoscape was used to establish a visual network. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and network analysis were performed to investigate potential mechanism of EZP against DILI., Results: A total of 23 bioactive compounds and 89 major proteins of EZP were screened out as potential players against DILI. Association for bioactive compounds, core targets, and related pathways was analyzed, implying that core targets related to these pathways are ALB, AKT1, MAPK1, EGFR, SRC, MAPK8, IGF1, CASP3, HSP90AA1, and MMP9, and potential mechanisms of EZP acting on DILI are closely related to negative regulation of apoptosis process, improvement of lipid metabolism, and positive regulation of liver regeneration process., Conclusion: This study demonstrated the multicompound, multitarget, and multichannel characteristics of EZP, which provided a novel approach for further research the mechanism of EZP in the treatment of DILI., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Shao-jie Huang et al.)

Background: Teduglutide reduces or eliminates parenteral support (PS) dependency in patients with short bowel syndrome (SBS). Recent post hoc analyses demonstrated that effects are correlated with baseline PS volume. We assessed the SBS-related quality-of-life (QoL) impact of teduglutide, particularly whether improvements are greater among subgroups achieving more PS volume reduction., Methods: Using phase 3 trial data of teduglutide in patients with SBS (NCT00798967), change in Short Bowel Syndrome-Quality of Life (SBS-QoL) scores from baseline were compared between teduglutide vs placebo in the overall population and subgroups classified by baseline PS volume requirement, disease etiology, and bowel anatomy. Generalized estimating equation models were fitted to assess impact of teduglutide on SBS-related QoL using data from all visits, adjusted for baseline characteristics., Results: Of 86 patients, 43 each were randomized to teduglutide or placebo (mean age: 51 vs 50 years, respectively). In adjusted analyses, teduglutide had a nonsignificant reduction (improvement) of -8.6 points (95% CI: 2.6 to -19.8) in SBS-QoL sum score from baseline to Week-24 vs placebo. The impact of teduglutide varied by subgroup. Patients treated with teduglutide experienced significantly greater reductions in SBS-QoL sum score at Week-24 vs placebo in 2 subgroups, ie, the third (highest) tertile baseline PS volume (-27.3, 95% CI: -50.8 to -3.7) and inflammatory bowel disease (IBD; -29.6, 95% CI: -46.3 to -12.9). Results were similar for SBS-QoL subscale and item scores., Conclusions: The impact of teduglutide treatment on SBS-related QoL vs placebo varied among subgroups and was significant and most pronounced among patients with highest baseline PS volume requirement or IBD., (© 2019 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals, Inc. on behalf of American Society for Parenteral and Enteral Nutrition.)

Objective: This study was performed to explore the efficacy and safety of different surgical interventions in patients with spontaneous supratentorial intracranial hemorrhage (SSICH) and determine which intervention is most suitable for such patients., Patients and Methods: We searched the PubMed, Medline, OVID, Embase, and Cochrane Library databases. The quality of the included studies was assessed. Statistical analyses were performed using the software Stata 13.0 and RevMan 5.3., Results: Endoscopic surgery (ES), minimally invasive surgery combined with urokinase (MIS + UK), minimally invasive surgery combined with recombinant tissue plasminogen activator (MIS + rt-PA), and craniotomy were associated with higher survival rates and a lower risk of intracranial rebleeding than standard medical care (SMC) in patients with SSICH, especially in younger patients with few comorbidities. The order from highest to lowest survival rate was ES, MIS + UK, MIS + rt-PA, craniotomy, and SMC. The order from lowest to highest intracranial rebleeding risk was ES, MIS + UK, craniotomy, MIS + rt-PA, and SMC. Additionally, compared with SMC, all four surgical interventions (ES, MIS + rt-PA, MIS + UK, and craniotomy) improved the prognosis and reduced the proportion of patients with serious disability. The order from most to least favorable prognosis was MIS + rt-PA, ES, MIS + UK, craniotomy, and SMC. The order from highest to lowest proportion of patients with serious disability was ES, MIS + rt-PA, MIS + UK, craniotomy, and SMC., Conclusions: This study revealed that the efficacy and safety of different surgical interventions (ES, MIS + UK, MIS + rt-PA, craniotomy) were superior to those of SMC in the patients with SSICH, especially in younger patients with few comorbidities. Among them, ES was the most reasonable and effective intervention. ES was found not only to improve the survival rate and prognosis but also to have the lowest risk of intracranial rebleeding and the lowest proportion of patients with serious disability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Salvia miltiorrhiza-Dalbergia odorifera coupled-herbs (SMDOCH) has been used to treat coronary heart disease (CHD) for thousands of years, but its unclear bioactive components and mechanisms greatly limit its clinical application. In this study, for the first time, we used network pharmacology to elucidate the mechanisms of action of SMDOCH on CHD. We collected 270 SMDOCH-related targets from 74 bioactive components and 375 CHD-related targets, with 58 overlapping common targets. Next, we performed enrichment analysis for common-target network and protein-protein interaction (PPI) network. The results showed that SMDOCH affected CHD mainly through 10 significant signaling pathways in three biological processes: 'vascular endothelial function regulation', 'inflammatory response', and 'lipid metabolism'. Six pathways belonged to the 'vascular endothelial function regulation' model, which primarily regulated hormone (renin, angiotensin, oestrogen) activity, and included three key upstream pathways that influence vascular endothelial function, namely KEGG:04933, KEGG:05418, and KEGG:04066. Three pathways, namely KEGG:04668, KEGG:04064, and KEGG:04620, belonged to the 'inflammatory response' model. One pathway (KEGG:04920) belonged to the 'lipid metabolism' model. To some extent, this study revealed the potential bioactive components and pharmacological mechanisms of SMDOCH on CHD, and provided a new direction for the development of new drugs for the treatment of CHD.

Three patients with nasopharyngeal carcinoma developed binaural secretory otitis media 12, 2, and 0.5 years after radiotherapy, respectively. The secretions subsided after conventional drug and drainage treatments, but hearing continued to deteriorate until severe loss was documented in both ears. After examination of the eardrum and tympanum, patients were enrolled in a clinical trial in the first half of 2019 (ClinicalTrials.gov: NCT03818347). After 0.5, 1 and 2 months of continuous hydrogen-oxygen therapy, our first three patients reported different levels of improvement in binaural hearing. This is the first report to show that, after treatment for nasopharyngeal carcinoma, hearing loss can be alleviated using hydrogen-oxygen therapy.

Objectives: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by autoantibody production. This study aims to identify biomarkers involving citrullinated peptides that can be used for SLE diagnosis., Methods: After a negative selection step with serum from healthy controls (HCs), a phage library of 12 peptides was used for three rounds of screening with sera from 30 SLE patients. After four rounds of biopanning, 21 positive peptides were sequenced. We produced 37-feature arrays containing 16 recombinant citrullinated peptides. The microarrays were tested with an independent validation set of serum samples from 50 HCs, 60 SLE patients, and 60 rheumatoid arthritis (RA) patients., Results: Microarray analysis showed that the positive rates of 13S1212Cit3-IgM (60.0%), 13S1210-IgG (43.33%), and 13S1212Cit3-IgG (41.67%) were increased in SLE patients compared with HCs and RA patients. The area under the receiver operating characteristic curve (AUC) was 0.770, 0.687 and 0.698, respectively. The combination of 13S1212Cit3-IgM and 13S1210-IgG (termed COPSLE, for combination of peptides for SLE) was more efficient for SLE diagnosis, with a larger AUC (0.830) and a positive rate of 73.33%. COPSLE could be used to identify 80.0% of SLE patients who were negative for anti-Smith (Sm), anti-double-stranded DNA (ds-DNA), and anticardiolipin (ACA). The Spearman rank correlation indicated that COPSLE increased with albumin, serum level of C3 and platelet distribution width, but had negative correlations with decreased C3 and discoid lupus., Conclusions: A citrullinated/non-citrullinated peptide panel is a valuable diagnostic marker of SLE, even for patients who are negative for anti-Sm, anti-ds-DNA and ACA.

Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene lead to cystic fibrosis (CF). The most common mutation F508del inhibits folding and processing of CFTR protein. FDA-approved correctors rescue the biosynthetic processing of F508del-CFTR protein, while potentiators improve the rescued CFTR channel function. Transforming growth factor (TGF-β1), overexpressed in many CF patients, blocks corrector/potentiator rescue by inhibiting CFTR mRNA in vitro. Increased TGF-β1 signaling and acquired CFTR dysfunction are present in other lung diseases. To study the mechanism of TGF-β1 repression of CFTR, we used molecular, biochemical, and functional approaches in primary human bronchial epithelial cells from over 50 donors. TGF-β1 destabilized CFTR mRNA in cells from lungs with chronic disease, including CF, and impaired F508del-CFTR rescue by new-generation correctors. TGF-β1 increased the active pool of selected micro(mi)RNAs validated as CFTR inhibitors, recruiting them to the RNA-induced silencing complex (RISC). Expression of F508del-CFTR globally modulated TGF-β1-induced changes in the miRNA landscape, creating a permissive environment required for degradation of F508del-CFTR mRNA. In conclusion, TGF-β1 may impede the full benefit of corrector/potentiator therapy in CF patients. Studying miRNA recruitment to RISC under disease-specific conditions may help to better characterize the miRNAs utilized by TGF-β1 to destabilize CFTR mRNA.

Wafer bonding of a silicon carbide (SiC) diaphragm to a patterned SiC substrate coated with aluminum nitride (AlN) film as an insulating layer is a promising choice to fabricate an all-SiC capacitive pressure sensor. To demonstrate the bonding feasibility, a crystalline AlN film with a root-mean-square (RMS) surface roughness less than ~0.70 nm was deposited on a SiC wafer by a pulsed direct current magnetron sputtering method. Room temperature wafer bonding of SiC-AlN by two surface activated bonding (SAB) methods (standard SAB and modified SAB with Si nano-layer sputtering deposition) was studied. Standard SAB failed in the bonding, while the modified SAB achieved the bonding with a bonding energy of ~1.6 J/m 2 . Both the microstructure and composition of the interface were investigated to understand the bonding mechanisms. Additionally, the surface analyses were employed to confirm the interface investigation. Clear oxidation of the AlN film was found, which is assumed to be the failure reason of direct bonding by standard SAB.

High-power GaN-based electronics are limited by high channel temperatures induced by self-heating, which degrades device performance and reliability. Increasing the thermal boundary conductance (TBC) between GaN and SiC will aid in the heat dissipation of GaN-on-SiC devices by taking advantage of the high thermal conductivity of SiC substrates. For the typical growth method, there are issues concerning the transition layer at the interface and low-quality GaN adjacent to the interface, which impedes heat flow. In this work, a room-temperature bonding method is used to bond high-quality GaN to SiC directly, which allows for the direct integration of high-quality GaN with SiC to create a high TBC interface. Time-domain thermoreflectance is used to measure the GaN thermal conductivity and GaN-SiC TBC. The measured GaN thermal conductivity is larger than that of grown GaN-on-SiC by molecular beam epitaxy. High TBC is observed for the bonded GaN-SiC interfaces, especially for the annealed interface (∼230 MW m -2 K -1 , close to the highest value ever reported). Thus, this work provides the benefit of both a high TBC and higher GaN thermal conductivity, which will impact the GaN-device integration with substrates in which thermal dissipation always plays an important role. Additionally, simultaneous thermal and structural characterizations of heterogeneous bonded interfaces are performed to understand the structure-thermal property relation across this new type of interface.

The present study investigated the potential effects of seawater acidification on the taxonomic structure and diversity of nematode communities using a microcosm experiment. Nematode samples for the microcosm experiment were collected from the low tidal zone of two sandy beaches with different sediment compositions (medium sand vs. very fine sand) in Qingdao (China). In the microcosm, nematode communities were exposed to nine experimental treatments comprising two pH levels for 56 days: 8.0 (ambient control) and 7.3. Communities were exposed for 0, 7, 14, 28, or 56 days. Results showed that the most distinguishable differences in nematode community structure and diversity indices were caused by sediment type. Reduced pH changed the taxonomic structure of nematode communities in medium sand sediments. An increase in species with higher tolerance to lowered pH occurred as a response and resulted in increased diversity in medium sand sediments. Nematode communities in finer sediments appeared less sensitive to reduced pH., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Infection by diverse mycoviruses is a common phenomenon in Sclerotinia sclerotiorum. In this study, the full genome of a single-stranded RNA mycovirus, tentatively named Hubei sclerotinia RNA virus 1 (HuSRV1), was determined in the hypovirulent strain 277 of S. sclerotiorum. The HuSRV1 genome is 4492 nucleotides (nt) long and lacks a poly (A) tail at the 3'- terminus. Sequence analyses showed that the HuSRV1 genome contains four putative open reading frames (ORFs). ORF1a was presumed to encode a protein with a conserved protease domain and a transmembrane domain. This protein is 27% identical to the P2a protein encoded by the subterranean clover mottle virus. ORF1b encodes a protein containing a conserved RNA-dependent RNA polymerase (RdRp) domain, which may be translated into a fusion protein by a -1 ribosome frameshift. This protein is 45.9% identical to P2b encoded by the sowbane mosaic virus. ORF2 was found to encode a putative coat protein, which shares 23% identical to the coat protein encoded by the olive mild mosaic virus. ORF3 was presumed to encode a putative protein with an unknown function. Evolutionary relation analyses indicated that HuSRV1 is related to members within Sobemovirus, but forms a unique phylogenetic branch, suggesting that HuSRV1 represents a new member within Solemoviridae. HuSRV1 virions, approximately 30 nm in diameter, were purified from strain 277. The purified virions were successfully introduced into virulent strain Ep-1PNA367, resulting in a new hypovirulent strain, which confirmed that HuSRV1 confers hypovirulence on S. sclerotiorum., Competing Interests: The authors declare no conflict of interest.

To investigate the effect of gentiopicrin on the expressions of inflammatory factors in human fibroblast-like synoviocytes (HFLS) and the underlying mechanism. Human fibroblast-like synoviocytes (HFLS) were cultured in vitro at 37 °C in Dulbecco's modified Eagle's medium (DMEM) supplemented with 5 % fetal bovine serum (FBS) in a humidified incubator containing 5 % CO2. Cell viability was determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-tetrazolium bromide (MTT) assay, while real-time quantitative polymerase chain reaction (qRT-PCR) was used to determine the expressions of interleukin 1β (IL-1β) and interleukin 6 (IL-6) mRNAs. The expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) were determined using Western blotting. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of IL-1β and IL-6 in cell lysate. Treatment with 5-25 μM gentiopicrin did not significantly affect the number of viable cells, when compared with control group (p &gt; 0.05). However, at 50 and 100 μM gentiopicrin, the number of viable cells were significantly increased, relative to control group (p &lt; 0.05). Results of qRT-PCR showed that the expression levels of IL-1β and IL-6 mRNAs were significantly higher in TNF-α group than in control group (p &lt; 0.05). However, treatment with gentiopicrin significantly and dose-dependently decreased their expression levels compared with TNF-α group (p &lt; 0.05). Western blotting results showed that the expressions of p-p38MAPK and NF-κB-p65 proteins were significantly upregulated in TNF-α group, when compared with control group (p &lt; 0.05). However, treatment with gentiopicrin significantly and dose-dependently down-regulated the expression of these proteins compared with TNF-α group (p &lt; 0.05). The levels of IL-1β and IL-6 in cell lysate were significantly higher in TNF-α group than in control group (p &lt; 0.05). However, treatment with gentiopicrin, and p38MAPK/NF-κB pathway inhibitors (SB203580 and BAY11-7082) significantly reduced the levels of these inflammatory factors compared with TNF-α group (p &lt; 0.05).  Gentiopicrin has therapeutic potential for Rheumatoid arthritis (RA  ) through a mechanism involving the inhibition of p38MAPK/NF-κB pathway.

Bacteria are ubiquitous throughout the earth's lower atmosphere. Bacteria, especially pathogenic bacteria, play an important role in human health. The diversity, composition, and dynamics of airborne bacteria has been widely studied; however, the characteristics of pathogenic bacteria remain poorly understood. In this study, a high throughput sequencing method was used to explore the airborne opportunistic pathogenic bacteria during autumn and winter in Xi'an, China. An aggregated boosted tree (ABT) was developed to determine the relative influence of environmental factors on the proportions of opportunistic pathogenic bacteria. Results showed that significantly more opportunistic pathogenic bacteria were found in winter than in autumn, and more opportunistic pathogenic bacteria were found in fine particulate matters (<2.5 μm) than in PM 10 (<10 μm). However, the composition of opportunistic pathogenic bacteria varied in autumn and winter. PM was the main factor affecting the proportions of opportunistic pathogenic bacteria, and air contaminants (PM, sulfur dioxide, nitrogen oxide, carbon monoxide, and ozone) influenced the proportion of opportunistic pathogenic bacteria more than meteorological factors (relative humidity, temperature, and wind speed). Different factors may be responsible for the variances in opportunistic pathogenic bacterial communities in different seasons. This study may provide a reference to support the control of pathogenic bacteria in urban environments during haze events., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Hidradenitis suppurativa (HS), a chronic cutaneous disease, can negatively affect work life., Objectives: This retrospective cohort study evaluates the indirect burden among employed patients with HS in the U.S.A., Methods: Newly diagnosed and general patients with HS, who were employees (age 18-64 years) from a large claims database (Q1 1999 to Q1 2015), were matched 1 : 5 to controls. Income growth and risk of leaving the workforce were assessed among the newly diagnosed HS and control cohorts in the 5-year study period. Income, work loss days and indirect costs (absenteeism and disability) were assessed among the general HS and control cohorts in the 1-year study period., Results: Newly diagnosed (n = 1003, mean age 39·5 years, 66·3% female) and general patients with HS (n = 1204, mean age 39·9 years, 69·1% female) were matched to 5015 and 6020 controls, respectively. Newly diagnosed patients with HS had significantly slower income growth ($324 per year) and higher risk of leaving the workforce (adjusted hazard ratio 1·65, 95% confidence interval 1·45-1·88) compared with controls (all P < 0·05). General patients with HS had more total days of work loss (18·4 vs. 7·7), higher annual total indirect costs ($2925 vs. $1483) and lower annual income ($54 925 vs. $62 357) than controls (all P < 0·001)., Conclusions: Patients with newly diagnosed HS and general patients with HS experienced a greater indirect burden than matched controls., (© 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Advanced cancer treatment is a huge challenge and new ideas and strategies are required. Hydrogen exerts antioxidant and anti-inflammatory effects that may be exploited to control cancer, the occurrence and progression of which is closely related to peroxidation and inflammation. We conducted a prospective follow-up study of 82 patients with stage III and IV cancer treated with hydrogen inhalation using the "real world evidence" method. After 3-46 months of follow-up, 12 patients died in stage IV. After 4 weeks of hydrogen inhalation, patients reported significant improvements in fatigue, insomnia, anorexia and pain. Furthermore, 41.5% of patients had improved physical status, with the best effect achieved in lung cancer patients and the poorest in patients with pancreatic and gynecologic cancers. Of the 58 cases with one or more abnormal tumor markers elevated, the markers were decreased at 13-45 days (median 23 days) after hydrogen inhalation in 36.2%. The greatest marker decrease was in achieved lung cancer and the lowest in pancreatic and hepatic malignancies. Of the 80 cases with tumors visible in imaging, the total disease control rate was 57.5%, with complete and partial remission appearing at 21-80 days (median 55 days) after hydrogen inhalation. The disease control rate was significantly higher in stage III patients than in stage IV patients (83.0% and 47.7%, respectively), with the lowest disease control rate in pancreatic cancer patients. No hematological toxicity was observed although minor adverse reactions that resolved spontaneously were seen in individual cases. In patients with advanced cancer, inhaled hydrogen can improve patients' quality-of-life and control cancer progression. Hydrogen inhalation is a simple, low-cost treatment with few adverse reactions that warrants further investigation as a strategy for clinical rehabilitation of patients with advanced cancer. The study protocol received ethical approval from the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval number: Fuda20181207).

Fibrosis is the major pathological feature of chronic kidney disease (CKD). Aloe-emodin (AE), one of the main active compounds in Rhubarb, is widely used for renal protection. However, mechanisms implied in the modulation of kidney fibrosis after AE treatment for CKD remain elusive. Here, we explored the protective effects of AE for renal fibrosis and the involved mechanisms in vivo and in vitro . The renal fibrosis mice model was established by unilateral ureteral obstruction (UUO). We found that AE administration significantly ameliorated UUO-induced impairment of kidney, evidenced by improved histopathological abnormalities, body weight, and abnormal renal function in mice model. Immunohistochemical staining showed that TGF-β1 and Fibronectin expressions were significantly decreased in UUO mice compared with sham group. Meanwhile, we found that AE suppressed the activation of the PI3K/Akt/mTOR pathway induced by TGF-β1 in vivo . AE improved cell survival and decreased the level of fibrosis-related proteins under TGF-β1-induced fibrosis in HK-2 cells as well as in vitro . Furthermore, both wortmannin, an inhibitor of PI3K, and short-hairpin RNAs of PI3K knockdown abrogated TGF-β1-induced phosphorylation of Akt and mTOR, and decreased the suppression of fibrosis. These findings indicated that AE alleviated fibrosis by inhibiting PI3K/Akt/mTOR pathway in vivo and in vitro , which may provide a potential therapeutic option for CKD.

Circulating tumor DNA (ctDNA) has been frequently investigated to monitor tumor dynamics and measure tumor burden. This non-invasive method concerning ctDNA has been recognized as a promising biomarker. Recently, next generation sequencing has been used in ctDNA detection by researchers. However, those reports have been limited by modest sensitivity, and only a minority of patients with cancer were applicable. Additionally, a limited number of cases of liver cancer have been analyzed. A more precise method is required to be established to evaluate ctDNA noninvasively. In the present study, a novel method to design a liver cancer-associated chip region (spanning 211 kb, containing 159 genes) was performed with high specificity using International Cancer Genome Consortium datasets. Following evaluation with datasets from The Cancer Genome Atlas and data from 3 patients with liver cancer, the selected regions were demonstrated to be beneficial to locate specific somatic mutations associated with liver cancer therapy and to monitor cancer dynamics in the plasma samples of the patients. In addition to establishing performance benchmarks supporting direct clinical use, the chip designed and the high-resolution sequencing analyses pipeline would allow the development a set of patient specific markers that could monitor the process of cancer with high accuracy and low cost. Furthermore, the present study is essential to understanding the dynamics and providing insight into the basic mechanisms of liver cancer.

The miR-17-92 cluster is involved in animal development and homeostasis, and its dysregulation leads to human diseases such as cancer. In the present study, we investigated the functional link between miR-17-92 cluster and Wnt/β-catenin signaling pathway in ICP2 and DF1 cells. We demonstrated that ectopic expression of either LEF1 or β-catenin increased the promoter activity of the miR-17-92 cluster host gene (MIR17HG) and combined ectopic expression of LEF1 and β-catenin further enhanced the promoter activity; while knockdown of either LEF1 or β-catenin reduced the MIR17HG promoter activity. Both LEF1 and β-catenin could directly bind to the MIR17HG promoter. Furthermore, we demonstrated that low doses of lithium chloride (LiCl), an activator of Wnt/β-catenin signaling pathway, increased MIR17HG promoter activity and the endogenous expression of the miR-17-92 cluster, while high doses of LiCl had the opposite effects. Treatment with XAV-939, an inactivator of the Wnt/β-catenin pathway, reduced the endogenous expression of miR-17-92 cluster. Finally, we found that low doses of LiCl promoted the proliferation of ICP2 and DF1 cells, while high doses of LiCl inhibited the proliferation of ICP2 and DF1 cells. Taken together, our results reveal that MIR17HG is a target of LEF1 and the Wnt/β-catenin pathway and suggest that the miR-17-92 cluster may, at least in part, mediate the proliferation-promoting effect of the Wnt/β-catenin pathway in cell proliferation.

Neutrophils participate in the regulation of pathogens by phagocytosis as well as by generating neutrophil extracellular traps (NETs). Antiphospholipid antibodies, particularly those targeting beta-2-glycoprotein I (β2GPI), stimulate monocytes, platelets, and endothelial cells with prothrombotic participation. This study aimed to explore NET generation in response to anti-β2GPI/β2GPI. A series of experiments involving the separation of primary human leukocytes, NETosis quantification using propidium iodide, exploration of NETosis by fluorescence microscopy, western blotting, examination of free Zn 2+ using FluoZin-3, and reactive oxygen species (ROS) examination with dihydrorhodamine 123 were performed in this study. We found that anti-β2GPI/β2GPI triggered NETosis, resembling phorbol 12-myristate 13-acetate (PMA)-induced NETosis in magnitude and morphology. The anti-β 2 GPI/β 2 GPI complex in isolation stimulated NETs without relying on p38, protein kinase B (AKT), extracellular signal-related kinase (ERK) 1/2, and zinc signals. NET generation was unaffected by the NADPH oxidase suppressor DP1. The anti-β 2 GPI/β 2 GPI complex stimulated ROS generation without relying on NADPH oxidase, which may participate in NET generation triggered via the anti-β 2 GPI/β 2 GPI complex. In summary, our results indicate that the anti-β 2 GPI/β 2 GPI complex reinforced NET generation by relying on ROS. THE SIGNIFICANCE OF THE PAPER IN THE CONTEXT OF CURRENT KNOWLEDGE: Neutrophils as one of the first lines of defence and essential in the response to pathogen invasion. They eradicate bacteria via phagocytosis or by releasing antimicrobial proteins in degranulation. In this study, we explored the capability of anti-β 2 GPI/β 2 GPI to stimulate NETosis, demonstrating that anti-β 2 GPI/β 2 GPI is a promising method for triggering NET. Anti-β 2 GPI/β 2 GPI induced ROS generation without relying on NADPH oxidase, which contributes to NETosis independently of ERK1/2, Zn 2+ , or AKT. Our results showed that anti-β2GPI/β2GPI triggered NETosis, resembling PMA-induced NETosis in magnitude as well as morphology. The anti-β 2 GPI/β 2 GPI complex in isolation stimulated NETs without relying on p38, AKT, ERK1/2, or zinc signals. The anti-β 2 GPI/β 2 GPI complex stimulated ROS generation without relying on NADPH oxidase, which may participate in NET generation triggered via the anti-β 2 GPI/β 2 GPI complex., (© 2019 The Authors Cell Biochemistry and Function Published by John Wiley & Sons Ltd.)

Background: Parkinson's disease is a progressive, disabling neurodegenerative disorder associated with significant economic burden for patients and caregivers. The objective of this study was to compare the direct and indirect economic burden of Parkinson's patients' caregivers with demographically matched controls in the United States, in the 5 years after first diagnosis of Parkinson's disease., Methods: Policyholders (18-64 years old) linked to a Parkinson's disease patient (≥2 diagnoses of Parkinson's disease; first diagnosis is the index date) from January 1, 1998 to March 31, 2014, were selected from a private-insurer claims database and categorized as Parkinson's caregivers. Eligible Parkinson's caregivers were matched 1:5 to policyholders with a non-Parkinson's dependent (controls). Multivariable regression adjusted for baseline characteristics estimated direct costs (all-cause insurer cost [medical and prescription] and comorbidity-related medical costs; patient out-of-pocket costs) and indirect costs (disability and medically related absenteeism costs). Income progression was also compared between cohorts., Results: A total of 1211 eligible Parkinson's caregivers (mean age, 56 years; 54% female) were matched to 6055 controls. In adjusted analyses, Parkinson's caregivers incurred significantly higher year 1 total all-cause insurer costs ($8999 vs $7117) and medical costs ($7081 vs $5568) (both P < 0.01) and higher prescription costs (range for years 1-5, $2506-2573 vs $1405-$1687) and total out-of-pocket costs ($1259-1585 vs $902-$1192) in years 1-5 (all P < 0.01). Parkinson's caregivers had significantly higher adjusted indirect costs in years 1-3 (range for years 1-3, $2054-$2464 vs $1681-$1857; all P < 0.05) and higher cumulative income loss over 5 years ($5967 vs $2634 by year 5; P for interaction = 0.03)., Conclusions: Parkinson's caregivers exhibited higher direct and indirect costs and greater income loss compared with matched controls. © 2018 International Parkinson and Movement Disorder Society © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Purpose: This study aimed to investigate the safety and short-term efficacy of irreversible electroporation (IRE) combined with allogenic natural killer (NK) cell immunotherapy in the treatment of patients with unresectable primary liver cancer., Materials and Methods: Between October 2015 and December 2016, 40 patients were enrolled and randomly allocated to either the IRE group (n = 22) or the IRE-NK group (n = 18). All adverse events experienced by the patients were recorded; the changes in tumor biomarkers [AFP, CA 19-9, circulating tumor cells (CTCs)], lymphocyte number and function, quality of life, clinical response, progression-free survival (PFS) and overall survival (OS) were assessed., Results: Patients who received combination therapy exhibited significantly longer median PFS and OS than who just received IRE (PFS 15.1 vs. 10.6 months, P < 0.05, OS 17.9 vs. 23.2 months, P < 0.05). The combination therapy of IRE and NK cell immunotherapy significantly reduced CTCs and increased immune function and Karnofsky performance status., Conclusion: Our data suggest a novel, promising combination therapy using IRE and allogenic NK cell immunotherapy. Larger clinical trials are required to confirm these conclusions.

Purpose: Research has shown that exposure to anesthesia might increase the risks of cognitive impairments and learning difficulties. MiR-125b-5p contributed to anesthesia-induced hippocampal apoptosis. However, the role of miR-125b-5p in sevoflurane-induced cognitive impairments remains unclear., Methods: Firstly, sevoflurane was used to establish a rat model and cognitive impairment was detected by the Morris water maze (MWM) test. The hippocampus was observed by HE staining. The lentivirus-miR-125b-5p antagomiR was transfected into rats to decrease miR-125b-5p. The interaction between miR-125b-5p and LIM domain kinase 1 (LIMK1) was confirmed by the luciferase reporter assay. The mRNA and expression levels of related genes and mRNA were examined by the Quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and western blot., Results: Sevoflurane induced the cognitive dysfunction presenting with longer latency time and few platform crossings in rats. Moreover, miR-125b-5p was observed to be up-regulated in both sevoflurane-anesthesia rats and sevoflurane-treated SH-SY5Y cells. More importantly, a decrease in miR-125b-5p could prevent sevoflurane-induced hippocampal apoptosis and inflammation in rats. Moreover, LIMK1 was the target gene of miR-125b-5p. Interestingly, si-LIMK1 could restore the sevoflurane-induced cell apoptosis in SH-SY5Y cells, which was alleviated by miR-125b-5p inhibitor. Finally, the miR-125b-5p inhibitor shortened the time to find the platform and increased the number of platform crossings compared to sevoflurane-anesthesia rats in the Morris water maze test. At the same time, the expression of LIMK1 was dramatically increased., Conclusion: Altogether, these findings suggested that miR-125b-5p inhibitor could protect against the sevoflurane-induced cognitive impairments by targeting LIMK1., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis, and alterations in its function are associated with various pathological processes related to metabolic syndrome. Recently, we found that the chicken PPARγ gene is regulated by three alternative promoters (P1, P2 and P3), producing five different transcript isoforms and two protein isoforms. In this study, the P1 promoter structure was characterized. Bioinformatics identified six putative nuclear respiratory factor 1 (NRF1) binding sites in the P1 promoter, and a reporter assay showed that NRF1 inhibited the activity of the P1 promoter. Of the six putative NRF1 binding sites, individual mutations of three of them abolished the inhibitory effect of NRF1 on P1 promoter activity. Furthermore, a ChIP assay indicated that NRF1 directly bound to the P1 promoter, and real-time quantitative RT-PCR analysis showed that NRF1 mRNA expression was negatively correlated with PPARγ1 expression (Pearson's r = -0.148, p = 0.033). Further study showed that NRF1 overexpression inhibited the differentiation of the immortalized chicken preadipocyte cell line (ICP1), which was accompanied by reduced PPARγ1 mRNA expression. Taken together, our findings indicated that NRF1 directly negatively regulates the P1 promoter of the chicken PPARγ gene and inhibits adipogenesis.

Terminalia chebula (TC), a kind of Combretaceae, is a widely used herb in India and East Asia to treat cerebrovascular diseases. However, the potential mechanism of the neuroprotective effects of TC at the metabonomics level is still not clear. The present study focused on the effects of TC on metabonomics in a stroke model. Rats were divided randomly into sham, model, and TC groups. Rats in the TC group were intragastrically administered with TC for 7 days after a middle cerebral artery occlusion (MCAO) operation. The sham and the model groups received vehicle for the same length of time. Subsequently, the neuroprotective effects of TC were examined by evaluation of neurological defects, assessment of infarct volume, and identification of biochemical indicators for antioxidant and anti-inflammatory activities. Further, metabonomics technology was employed to evaluate the endogenous metabolites profiling systematically. Consist with the results of biochemical and histopathological assays, pattern recognition analysis showed a clear separation of the model group and the sham group, indicating the recovery impact of TC on the MCAO rats. Moreover, 12 potential biomarkers were identified in the MCAO model group, involving energy (lactic acid, succinic acid, and fumarate), amino acids (leucine, alanine, and phenylalanine), and glycerophospholipid (PC [16:0/20:4], PC [20:4/20:4], LysoPC [18:0], and LysoPC [16:0]) metabolism, as well as other types of metabolism (arachidonic acid and palmitoylcarnitine). Notably, it was found that metabolite levels of TC group were partially reversed to normal. In conclusion, TC could ameliorate MCAO in rats by affecting energy metabolism (glycolysis and the TCA cycle), amino acid metabolism, glycerophospholipid metabolism, and other types of metabolism.

Although surgery and high‑dose radiotherapy have been the standard treatments for glioblastoma multiforme (GBM), these therapies are palliative, due to the high risk of local relapse. Emerging evidence has demonstrated that DNA double‑strand break (DSB) repair serves a critical role in resistance to radiotherapy. Previous studies have revealed that mangiferin possesses anti‑neoplastic effects on human lung adenocarcinoma and ovarian cancer. The present study aimed to investigate the role of mangiferin in radio‑sensitivity inhuman GBM. Through in vitro experiments, decreased proliferation and increased DNA damage were observed in cells pretreated with mangiferin following radiation. Further study of the repair pathway indicated that mangiferin inhibits the non‑homologous end‑joining (NHEJ) DSB repair pathway. Furthermore, studies on key proteins in the NHEJ DSB repair pathway revealed that mangiferin inhibited the phosphorylation of serine‑protein kinase ATM, TP53‑binding protein 1 and γ‑histone H2AX (γ‑H2AX). In addition, observations on the average percentages of γ‑H2AX‑positive cells and the average number of γ‑H2AX foci per cell suggested that treatment with mangiferin decreased the number of γ‑H2AX foci in GBM cells following radiation. However, mangiferin selectively inhibited DSB repair in GBM cells, and was not able to trigger DSB repair inhibition in normal neuronal Schwann cells. Through in vivo tumor‑bearing mouse experiments, a smaller tumor volume, decreased tumor weight and prolonged life span were observed in mice treated with mangiferin following radiation. Therefore, xenograft GBM models clearly demonstrated that treatment with mangiferin treatment may increase tumor sensitivity to radiotherapy. Taken together, as demonstrated by in vivo and in vitro data, mangiferin may be a potential novel therapeutic drug for improving the radiation sensitivity of glioblastoma.

Inflammatory damage plays a pivotal role in ischemic stroke pathogenesis and may represent one of the therapeutic targets. Z-Guggulsterone (Z-GS), an active component derived from myrrh, has been used to treat various diseases. The traditional uses suggest that myrrh is a good candidate for anti-inflammatory damage. This study was to investigate the anti-inflammatory and neuroprotective effects of Z-GS following cerebral ischemic injury, as well as the exact mechanisms behind them. Rat middle cerebral artery occlusion (MCAO) model and in vitro astrocytes oxygen-glucose deprivation (OGD) model were adopted to simulate ischemic stroke. Z-GS (30 or 60 mg/kg) was administered intraperitoneally immediately after reperfusion, while astrocytes were maintained in 30 or 60 μM Z-GS before OGD treatment. The results indicated that Z-GS significantly alleviated neurological deficits, infarct volume and histopathological damage in vivo, and increased the astrocytes viability in vitro. Moreover, the treatment of Z-GS inhibited the astrocytes activation and down-regulated the mRNA levels of pro-inflammatory cytokines. Furthermore, the activated TLR4-NF-κB signaling pathways induced by MCAO or OGD were significantly suppressed by Z-GS treatment, which was achieved via inhibiting the phosphorylation of JNK. Our results demonstrated that Z-GS exerted neuroprotective and anti-inflammatory properties through preventing activation of TLR4-mediated pathway in the activated astrocytes after ischemia injury. Therefore, Z-GS could be considered as a promising candidate for the treatment of ischemic stroke., (© 2018 International Society for Neurochemistry.)

Traditional Chinese medicines, including Radix Salvia miltiorrhiza (SM) and Lignum Dalbergia odorifera (DO) extracts, have historically been used to treat myocardial ischemia and other cardiovascular diseases. The volatile oil of DO (DOO) is one of the main components of DO. The aim of the present study was to assess the cardioprotective effects and possible underlying mechanisms of SM‑DOO in pigs with ameroid constriction‑induced chronic myocardial ischemia. An ameroid constrictor was placed around the left anterior descending coronary artery of pigs to induce chronic myocardial ischemia. At weeks 2, 6 and 8, myocardial injury markers and blood gas levels were detected. At week 8, coronary angiography, echocardiography and hemodynamics analysis were performed to evaluate myocardial function. Following sacrifice, myocardial tissue was collected and subjected to morphological, histopathological and apoptosis assays. Western blotting was used to detect the protein expression of Bcl‑2 associated X (Bax), Bcl‑2, Akt, phosphorylated (p)‑Akt, glycogen synthase kinase (GSK)‑3β and p‑GSK‑3β. It was revealed that SM‑DOO treatment following chronic myocardial ischemia significantly downregulated the expression of myocardial injury markers, ameliorated myocardial oxygen consumption, increased collateralization, reduced regional cardiac dysfunction and limited the extent of myocardial damage. Furthermore, the results of an apoptosis assay revealed that the apoptosis rate was decreased, the expression of Bax decreased and Bcl‑2 increased, and the ratio of Bcl‑2/Bax was increased. Further experiments indicated that treatment with SM‑DOO increased the phosphorylation of Akt and GSK‑3β. These findings suggest that SM‑DOO treatment ameliorates myocardial injury in a chronic myocardial ischemia model, and that the underlying mechanisms responsible may be associated with the activation of the Akt/GSK‑3β signal pathway. Thus, experimental evidence that SM‑DOO may be an effective drug for the prevention and treatment of chronic myocardial ischemia in clinical applications has been provided.

Background: Data are limited on the benefits and risks of dose reduction in managing side effects associated with antipsychotic treatment. As an example, antipsychotic dose reduction has been recommended in the management of tardive dyskinesia (TD), yet the benefits of lowering doses are not well studied. However, stable maintenance treatment is essential to prevent deterioration and relapse in schizophrenia., Methods: A retrospective cohort study was conducted to analyze the healthcare burden of antipsychotic dose reduction in patients with schizophrenia. Medical claims from six US states spanning a six-year period were analyzed for ≥10% or ≥ 30% antipsychotic dose reductions compared with those from patients receiving a stable dose. Outcomes measured were inpatient admissions and emergency room (ER) visits for schizophrenia, all psychiatric disorders, and all causes, and TD claims., Results: A total of 19,556 patients were identified with ≥10% dose reduction and 15,239 patients with ≥30% dose reduction. Following a ≥ 10% dose reduction, the risk of an all-cause inpatient admission increased (hazard ratio [HR] 1.17; 95% confidence interval [CI] 1.11, 1.23; P < 0.001), and the risk of an all-cause ER visit increased (HR 1.09; 95% CI 1.05, 1.14; P < 0.001) compared with controls. Patients with a ≥ 10% dose reduction had an increased risk of admission or ER visit for schizophrenia (HR 1.27; 95% CI 1.19, 1.36; P < 0.001) and for all psychiatric disorders (HR 1.16; 95% CI 1.10, 1.23; P < 0.001) compared with controls. A dose reduction of ≥30% also led to an increased risk of admission for all causes (HR 1.23; 95% CI 1.17, 1.31; P < 0.001), and for admission or ER visit for schizophrenia (HR 1.31; 95% CI 1.21, 1.41; P < 0.001) or for all psychiatric disorders (HR 1.21; 95% CI 1.14, 1.29; P < 0.001) compared with controls. Dose reductions had no significant effect on claims for TD., Conclusion: Patients with antipsychotic dose reductions showed significant increases in both all-cause and mental health-related hospitalizations, suggesting that antipsychotic dose reductions may lead to increased overall healthcare burden in some schizophrenia patients. This highlights the need for alternative strategies for the management of side effects, including TD, in schizophrenia patients that allow for maintaining effective antipsychotic treatment.

The preparation of folic acid-dextran-coenzyme Q 10 (FA-DEX-CoQ 10 ) nanopreparation was optimized by high-pressure homogenization to improve the dissolution and oral bioavailability of CoQ 10 . The preparation conditions of FA-DEX-CoQ 10 nanopreparation were optimized by single-factor and orthogonal experimental design. The properties of CoQ 10 raw materials, CoQ 10 physical mixtures, and FA-DEX-CoQ 10 nanopreparation were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The concentration of CoQ 10 in rat plasma was determined by high-performance liquid chromatography, and the corresponding pharmacokinetic parameters were calculated. The optimal preparation method is as follows: mass ratio of CoQ 10 /FA-DEX of 1:18, mass ratio of stabilizer/CoQ 10 of 0.4:1, 6 homogenization cycles, and homogenization pressure of 800 bar. These conditions resulted in a mean particle size of 87.6 nm. SEM showed that the particles was spherical. DSC and XRD analyses showed that the crystallinity of FA-DEX-CoQ 10 nanopreparation decreased. FA-DEX-CoQ 10 possesses long-term stability. By single-factor and orthogonal experiments, the dissolution rate, C max , and area under the curve (AUC) of the optimized FA-DEX-CoQ 10 nanopreparation were 3.95, 2.7, and 2.4 times as much as those of the raw materials. The results showed that FA-DEX-CoQ 10 nanopreparation had better oral bioavailability.

DNA detection with high sensitivity and specificity has tremendous potential as molecular diagnostic agents. Graphene and graphene-based nanomaterials, such as graphene nanopore, graphene nanoribbon, graphene oxide, and reduced graphene oxide, graphene-nanoparticle composites, were demonstrated to have unique properties, which have attracted increasing interest towards the application of DNA detection with improved performance. This article comprehensively reviews the most recent trends in DNA detection based on graphene and graphene-related nanomaterials. Based on the current understanding, this review attempts to identify the future directions in which the field is likely to thrive, and stimulate more significant research in this subject.

Changes of interleukin (IL)-1β, IL-6, IL-17 and tumor necrosis factor-α (TNF-α) in gingival crevicular fluid in patients with fixed orthodontic gingivitis after treatment with Kangfuxin solution were analyzed to explore the clinical effect of Kangfuxin solution in patients with orthodontic gingivitis. A total of 78 patients diagnosed with fixed orthodontic gingivitis in Weifang People's Hospital from January 2015 to March 2017 were selected. Thirty-nine patients were treated with gingival cleansing as control group, and the other 39 patients were treated with gingival cleansing plus spraying and sublingual administration with Kangfuxin solution as treatment group. The general data of patients were collected, and the changes of IL-1β, IL-6, IL-17 and TNF-α in gingival crevicular fluid were measured, the bleeding index (BI), probing depth (PD), swelling and pain grades were recorded, and the clinical curative effects were compared between the two groups. The curative effect in treatment group was better than that in control group (p<0.05). After treatment, gingival BI and PD in both groups were lower than those before treatment. The curative effect in treatment group was better than that in control group (p<0.05). The levels of gingival pain and swelling after treatment in treatment group were mainly in grade I. The levels of gingival pain and swelling after treatment in control group were mainly in grade II and III (p<0.05). After treatment, the effective rate of control group was 76.92% and that of treatment group was 97.44% (p<0.05). It was found that the levels of IL-6 and TNF-α in gingival crevicular fluid were positively correlated with PD. The use of Kangfuxin solution in the treatment of patients with orthodontic gingivitis can effectively reduce the levels of IL-1β, IL-6, IL-17 and TNF-α in gingival crevicular fluid, and improve the periodontal conditions and the effective rate of treatment.

Objective: The retrospective study aimed to estimate prevalence of hyperkalemia using a large US commercial claims database., Methods: Adults with serum potassium lab data (2010 to 2014) and ≥1 calendar year of data were included from a large US commercial claims database. Hyperkalemia was defined as ≥2 serum potassium measurements >5.0 mEq/L or one hyperkalemia diagnosis code (ICD-9-CM, 276.7) or one sodium polystyrene sulfonate fill. Hyperkalemia prevalence was estimated for the overall population and subgroups with hyperkalemia-related comorbidities by calendar year. Hyperkalemia prevalence was also standardized to the US population to estimate the number of US adults with hyperkalemia., Results: The analysis included 2,270,635 patients (2010-2014). The annual prevalence of hyperkalemia in the overall population was 1.57% in 2014, with higher rates observed in patients with chronic kidney disease (CKD), heart failure, diabetes and hypertension. Among patients with CKD and/or heart failure, the 2014 annual prevalence was 6.35%. Among patients with hyperkalemia, 48.43% had CKD and/or heart failure in 2014. The prevalence of hyperkalemia was higher in patients with more severe CKD, as well as older patients and men. Extrapolating those results to the US population supports that 1.55% or 3.7 million US adults had hyperkalemia in 2014., Conclusions: An estimated 3.7 million US adults had hyperkalemia in 2014, and this prevalence rate has increased since 2010. In patients with CKD and/or heart failure, the annual prevalence of hyperkalemia was 6.35% in 2014, and about half of all patients with hyperkalemia have either CKD and/or heart failure.

Much evidence suggests a role for inflammation in the pathogenesis of endometriosis. Although investigators in numerous case-control studies have found elevation of inflammatory markers in patients with endometriosis, results were not consistent, and no prior prospective study is known to exist. We conducted a case-control study nested within the Nurses' Health Study II in which we examined associations between levels of plasma inflammatory markers (interleukin-1 beta, interleukin-6, soluble tumor necrosis factor α receptors 1 and 2, and high-sensitivity C-reactive protein) and the risk of laparoscopically confirmed endometriosis. From blood collections in 1996-1999 and 2007, we ascertained 350 cases patients with incident endometriosis and 694 matched controls. Women with interleukin-1 beta levels in quintiles 2-4 had a higher risk of endometriosis (for the second quintile, relative risk (RR) = 3.30, 95% confidence interval (CI): 1.06, 10.3; for the third quintile, RR = 3.36, 95% CI: 1.09, 10.4; and for the fourth quintile, RR = 4.64, 95% CI: 1.58, 13.6; P for trend = 0.62), which suggested an association beginning at 0.47 pg/mL or greater. A significant nonlinear association with levels of soluble tumor necrosis factor α receptor 2 was observed, with elevated risk of endometriosis at concentrations greater than 3,400 pg/mL. Plasma interleukin-6, soluble tumor necrosis factor α receptor 1, and high-sensitivity C-reactive protein levels were not associated with endometriosis risk. Further research in larger studies with younger age at blood collection and longer time from blood to surgical diagnosis are required to confirm these associations.

Sclerotinia sclerotiorum is a devastating plant pathogen that attacks numerous economically important broad acre and vegetable crops worldwide. Mycoviruses are widespread viruses that infect fungi, including S. sclerotiorum . As there were no previous reports of the presence of mycoviruses in this pathogen in Australia, studies were undertaken using RNA&#95;Seq analysis to determine the diversity of mycoviruses in 84 Australian S. sclerotiorum isolates collected from various hosts. After RNA sequences were subjected to BLASTp analysis using NCBI database, 285 contigs representing partial or complete genomes of 57 mycoviruses were obtained, and 34 of these (59.6%) were novel viruses. These 57 viruses were grouped into 10 distinct lineages, namely Endornaviridae (four novel mycoviruses), Genomoviridae (isolate of SsHADV-1), Hypoviridae (two novel mycoviruses), Mononegavirales (four novel mycovirusess), Narnaviridae (10 novel mycoviruses), Partitiviridae (two novel mycoviruses), Ourmiavirus (two novel mycovirus), Tombusviridae (two novel mycoviruses), Totiviridae (one novel mycovirus), Tymovirales (five novel mycoviruses), and two non-classified mycoviruses lineages (one Botrytis porri RNA virus 1, one distantly related to Aspergillus fumigatus tetramycovirus-1). Twenty-five mitoviruses were determined and mitoviruses were dominant in the isolates tested. This is not only the first study to show existence of mycoviruses in S. sclerotiorum in Australia, but highlights how they are widespread and that many novel mycoviruses occur there. Further characterization of these mycoviruses is warranted, both in terms of exploring these novel mycoviruses for innovative biocontrol of Sclerotinia diseases and in enhancing our overall knowledge on viral diversity, taxonomy, ecology, and evolution.

Technological innovation and increased affordability have contributed to the widespread adoption of genome sequencing technologies in biomedical research. In particular large cancer research consortia have embraced next generation sequencing, and have used the technology to define the somatic mutation landscape of multiple cancer types. These studies have primarily utilised the Illumina HiSeq platforms. In this study we performed whole genome sequencing of three malignant pleural mesothelioma and matched normal samples using a new platform, the BGISEQ-500, and compared the results obtained with Illumina HiSeq X Ten. Germline and somatic, single nucleotide variants and small insertions or deletions were independently identified from data aligned human genome reference. The BGISEQ-500 and HiSeq X Ten platforms showed high concordance for germline calls with genotypes from SNP arrays (>99%). The germline and somatic single nucleotide variants identified in both sequencing platforms were highly concordant (86% and 72% respectively). These results indicate the potential applicability of the BGISEQ-500 platform for the identification of somatic and germline single nucleotide variants by whole genome sequencing. The BGISEQ-500 datasets described here represent the first publicly-available cancer genome sequencing performed using this platform.

Previous studies have shown that ocean acidification has little effect on adult Tigriopus japonicus copepods, and mainly impairs the early development and reproduction of females. This study investigated the possible interactive effect between CO 2 -induced seawater acidification and food availability on larval development and reproductive output in T. japonicus. Copepods were exposed to either pH8.1 or pH7.3 under different food concentrations (0.5×10 4 -80.0×10 4 cells/mL). Both the development of nauplii and copepodites was delayed at pH7.3 with a greater effect at lower food concentrations. The reproductive output followed a bell-shaped curve with the highest reproductive output at food concentrations between 30×10 4 and 40×10 4 cells/mL. As an indicator of oxidative stress, the activity of superoxide dismutase increased at lower pH, with a greater increase at lower food concentrations. Therefore, the effect of elevated pCO 2 on T. japonicus was food dependent., (Copyright © 2017. Published by Elsevier Ltd.)

Dickkopf-1 (DKK1) is an inhibitor of canonical Wnt signaling pathway and regulates hair follicle morphogenesis and cycling. To investigate the potential involvement of DKK1 in wool production and quality traits, we characterized the genomic structure of ovine DKK1 , performed polymorphism detection and association analysis of ovine DKK1 with wool production and quality traits in Chinese Merino. Our results showed that ovine DKK1 consists of four exons and three introns, which encodes a protein of 262 amino acids. The coding sequence of ovine DKK1 and its deduced amino acid sequence were highly conserved in mammals. Eleven single nucleotide polymorphisms (SNPs) were identified within the ovine DKK1 genomic region. Gene-wide association analysis showed that SNP5 was significantly associated with mean fiber diameter (MFD) in the B (selected for long wool fiber and high-quality wool), PW (selected for high reproductive capacity, high clean wool yield and high-quality wool) and U (selected for long wool fiber with good uniformity, high wool yield and lower fiber diameter) strains ( p < 4.55 × 10 -3 = 0.05/11). Single Nucleotide Polymorphisms wide association analysis showed that SNP8 was significantly associated with MFD in A strain and fleece weight in A (selected for large body size), PM (selected for large body size, high reproductive capacity and high meat yield) and SF (selected for mean fiber diameter less than 18 μm and wool fiber length between 5 and 9 cm) strains ( p < 0.05), SNP9 was significantly associated with curvature in B and U strains ( p < 0.05) and SNP10 was significantly associated with coefficient of variation of fiber diameter in A, PW and PM strains and standard deviation of fiber diameter in A and PM strains ( p < 0.05). The haplotypes derived from these 11 identified SNPs were significantly associated with MFD ( p < 0.05). In conclusion, our results suggest that DKK1 may be a major gene controlling wool production and quality traits, also the identified SNPs (SNPs5, 8, 9 and 10) might be used as potential molecular markers for improving sheep wool production and quality in sheep breeding., Competing Interests: The authors declare no conflict of interest.

Purpose: Menstrual cycle characteristics are markers of endocrine milieu. However, associations between age at menarche and adulthood sex steroid hormone levels have been inconsistent, and data on menstrual characteristics and non-sex steroid hormones are sparse., Methods: We assessed the relations of menstrual characteristics with premenopausal plasma sex steroid hormones, sex hormone binding globulin (SHBG), prolactin, and growth factors among 2,745 premenopausal women (age 32-52) from the Nurses' Health Study II. Geometric means and tests for trend were calculated using multivariable general linear models., Results: Early age at menarche was associated with higher premenopausal early-follicular free estradiol (percent difference < 12 vs. > 13 years = 11%), early-follicular estrone (7%), luteal estrone (7%), and free testosterone (8%) (all p trend  < 0.05). Short menstrual cycle length at age 18-22 was associated with higher early-follicular total (< 26 vs. > 39 days = 18%) and free estradiol (16%), early-follicular estrone (9%), SHBG (7%), lower luteal free estradiol (- 14%), total (- 6%), and free testosterone (- 15%) (all p trend  < 0.05). Short adult menstrual length was associated with higher early-follicular total estradiol (< 26 vs. > 31 days = 14%), SHBG (10%), lower luteal estrone (- 8%), progesterone (- 9%), total (- 11%) and free testosterone (- 25%), and androstenedione (- 14%) (all p trend  < 0.05). Irregularity of menses at 18-22 was associated with lower early-follicular total (irregular vs. very regular = - 14%) and free estradiol (- 14%), and early-follicular estrone (- 8%) (All p trend  < 0.05). Irregularity of adult menstrual cycle was associated with lower luteal total estradiol (irregular vs. very regular = - 8%), SHBG (- 3%), higher total (8%), and free testosterone (11%) (all p trend  < 0.05)., Conclusions: Early-life and adulthood menstrual characteristics are moderately associated with mid-to-late reproductive year's hormone concentrations. These relations of menstrual characteristics with endogenous hormone levels could partially account for associations between menstrual characteristics and reproductive cancers or other chronic diseases.

Introduction: There are limited data on the cost of hyperkalemia., Methods: This retrospective analysis of the Truven MarketScan claims database assessed the economic burden of hyperkalemia among selected adult patients with hyperkalemia and matched controls., Results: A total of 39,626 cases (patients with hyperkalemia) were matched to 39,626 controls (patients without hyperkalemia) based on age, dialysis, chronic kidney disease (CKD) stage, heart failure, and renin-angiotensin aldosterone system inhibitor use. Compared with controls, cases incurred $4128 (95% confidence interval [CI] $3893-$4363) higher 30-day total health care costs ($5994 vs. $1865) and $15,983 (95% CI $15,026-$16,940) higher 1-year costs ($31,844 vs. $15,861). Among 11,221 matched pairs of patients with CKD and/or heart failure, cases incurred $5553 (95% CI $5059-$6047) higher 30-day total health care costs ($8165 vs. $2612) and $24,133 (95% CI $21,748-$26,518) higher 1-year costs ($48,994 vs. $24,861) than controls. The multivariable adjusted 1-year total health care cost difference was $15,606 (95% CI $14,648-$16,576) among all patients and $25,156 (95% CI $23,529-$26,757) among patients with CKD and/or heart failure. Cases had higher resource utilization rates including inpatient admissions (30-day: 0.14 vs. 0.03; 1-year: 0.44 vs. 0.19), outpatient visits (30-day: 3.33 vs. 2.28; 1-year: 26.58 vs. 18.53), and emergency department visits (30-day: 0.16 vs. 0.06; 1-year: 0.86 vs. 0.50) (all P  < 0.001). When hospitalized, cases stayed 1.51 days (95% CI 1.22-1.80) longer and were 40% more likely to be readmitted., Conclusion: These data indicate that hyperkalemia is associated with a significant economic burden on afflicted patients and the health care system.

The present study was performed to investigate the potential role of Danshensu in therapeutic angiogenesis in ischemic myocardium and endothelial progenitor cells (EPCs) function. The rat model of myocardial infarction (MI) injury was induced by left anterior descending coronary artery ligation for 14 days. Danshensu significantly alleviated myocardial ischemia injury by ameliorating left ventricular function and reducing infarct size. Furthermore, Danshensu potentiated post-ischemia neovascularization as evidenced by increased microvessel density in infarction boundary zone, as well as the expression of marker proteins vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Moreover, Danshensu notably promoted stromal cell-derived factor-1α (SDF-1α) level in plasma and C-X-C chemokine receptor type 4 (CXCR4) expression in peri-infarction myocardium, and AMD3100 (CXCR4 antagonist) could reverse the angiogenic and cardioprotective effects of Danshensu. For in vitro study, EPCs were isolated from bone marrow of rats. On the one hand, Danshensu provided significant cytoprotection against hypoxia insult by boosting EPCs viability and inhibiting apoptosis, and upregulated Akt phosphorylation. On the other hand, Danshensu enhanced proangiogenic functions of EPCs on cell migration and tube formation, and increased SDF-1α and CXCR4 expression. Likewise, the cytoprotection and proangiogenic functions of Danshensu on EPCs were partly negated by LY294002 (PI3K antagonist) and CXCR4 siRNA, respectively. Taken together, our results suggested that the cardioprotection of Danshensu in MI rats may be related to promoting myocardial neovascularization. The possible mechanisms may involve improving EPCs survival in hypoxia condition through Akt phosphorylation, and accelerating EPCs proangiogenic functions through SDF-1α/CXCR4 axis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Lucilia sericata maggots have beneficial properties; however, their protective effects on burn wounds have yet to be fully elucidated. In the present study, a deep second‑degree burn rat model was used to investigate the burn wound healing properties of aqueous extract of maggots (MAE). The anti‑inflammatory, antioxidative and antibacterial activities were examined. In addition, the protein expression levels of Akt, vascular endothelial growth factor A (VEGFA) and nuclear factor‑κB (NF‑κB) were detected by western blotting. The findings of the present study revealed that MAE treatment increased burn wound healing and hydroxyproline content in the burn‑treated rats. A total of seven compounds (MAE‑P1‑P7) were separated from MAE and a comparative study was performed to identify the major active component. The results demonstrated that MAE‑P6 exerted greater antibacterial activity compared with the other compounds. MAE‑P6 treatment reduced tissue levels of malondialdehyde, tumor necrosis factor‑α and interleukin‑6, and increased superoxide dismutase activity. Furthermore, MAE‑P6 increased the expression levels of VEGFA and reduced NF‑κB expression through Akt, which was verified by treatment with the Akt‑specific inhibitor, LY294002. In conclusion, the present study demonstrated that the beneficial effects of MAE on burn wound healing were due to its antibacterial, antioxidative and anti‑inflammatory activities. MAE‑P6 reduced the release of inflammatory cytokines via the Akt/NF‑κB signaling pathway, and regulated angiogenesis and vasopermeability via the Akt/VEGFA pathway.