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Invasion and metastasis of breast cancer cells is an important cause of death in breast cancer patients. In the tumor microenvironment, M2 polarization of macrophages can promote the invasion and metastasis of tumor cells. OVOL2 is an evolutionarily conserved transcription regulator, but its effect in macrophages has not been described previously. The aim of this study was to investigate the effects of OVOL2 on macrophage polarity and the role of these effects in the tumor metastasis. We found that overexpression of OVOL2 in macrophages significantly inhibited M2 polarization and thus inhibits breast cancer metastasis. We propose a novel mechanism in which OVOL2 inhibits M2 polarization of macrophages and thus reduces their ability to induce invasion and metastasis of breast cancer. By shedding new light on the regulation of metastasis in cancers, our study provides a new strategy for the targeted therapy of cancer.

BACKGROUND AND PURPOSE Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored. EXPERIMENTAL APPROACH We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H-151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H-151 on imiquimod-induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed. KEY RESULTS Gene expressions of STING and its downstream target were up-regulated in lesional skin samples from psoriasis patients. Topical administration of H-151 attenuated the skin lesions in imiquimod-induced psoriatic mouse model, while the secretion of pro-inflammatory cytokines (IL-17, IL-23 and IL-6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H-151 treatment. Mechanistically, H-151 inhibited STING/NF-κB signalling in both keratinocytes and immune cells. CONCLUSION AND IMPLICATIONS H-151 displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications.

In this paper, the stiffness of carbon nanotube bundle (CNTB) reinforced composite is predicted by means of the Mori-Tanaka method and Eshelby method. The curvature of one CNTB on uniaxial aligned ...

Proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as a reliable therapeutic target for hypercholesterolemia and coronary artery heart diseases since the monoclonal antibodies of PCSK9 have launched. Disrupting the protein-protein interaction (PPI) between PCSK9 and the low-density lipoprotein receptor (LDLR) has been considered as a promising approach for developing PCSK9 inhibitors. However, PPIs have been traditionally considered difficult to target by small molecules since the PPI surface is usually large, flat, featureless, and without a "pocket" or "groove" for ligand binding. The PCSK9-LDLR PPI interface is such a typical case. In this study, a potential binding pocket was generated on the PCSK9-LDLR PPI surface of PCSK9 through induced-fit docking. On the basis of this induced binding pocket, virtual screening, molecular dynamics (MD) simulation, and biological evaluations have been applied for the identification of novel small molecule inhibitors of PCSK9-LDLR PPI. Among the selected compounds, compound 13 exhibited certain PCSK9-LDLR PPI inhibitory activity (IC50: 7.57 ± 1.40 μM). The direct binding affinity between 13 and PCSK9 was determined with a KD value of 2.50 ± 0.73 μM. The LDLR uptake function could be also restored to a certain extent by 13 in HepG2 cells. This well-characterized hit compound will facilitate the further development of novel small molecule inhibitors of PCSK9-LDLR PPI.

Background: Buyang Huanwu Tang (BYHWT) and relevant Traditional Chinese medicine (TCM) has its unique advantages in the treatment of cerebral ischemia. However, its pharmacological mechanism has not been fully explained. Objective: Base on the multi-component, also the entire disease network targets, the present study sets out to identify major bioactive ingredients, key disease targets, and pathways of BYHWT against cerebral ischemia disease by systematic pharmacological methodology. Methods: Both the bioactive compounds from the BYHWT and the positive drugs against cerebral ischemia were fully investigated. The binding targets of the positive drugs were then obtained. A virtual screening protocol was then used to highlight the compound-target interaction and network was constructed to visualize the compound-target binding effect after docking analysis. Moreover, the targets enrichment analysis for biological processes and pathways were performed to further explore the function of bio-targets protein gene and its role in the signal pathway. Results: A total of 382 active ingredients of the BYHWT and 23 candidate disease targets were identified. Virtual screening results indicated that multiple bioactive compounds targeted multiple proteins. Each compound acts on one or more targets. The mechanisms were linked to 20 signaling pathways, and the key mechanism was related to serotonergic synapse, calcium signaling pathway and camp signaling pathways. Conclusion: The present study explored the bioactive ingredients and mechanisms of BYHWT against cerebral ischemia by systematic pharmacological methodology. The novel methodology would provide a reference for the lead discovery of precursors, disease mechanism and material base for TCM.

Background Surgery is an important component in the treatment of esophageal cancer. For patients not eligible for R0 resection, defined as locally advanced unresectable esophageal cancer, a new approach is to transform the cancer into a resectable state by preoperative treatment. However, preoperative chemo/radiation is unsatisfactory. Therefore, the aim of this study was to assess the safety and efficacy of chemo/radiotherapy combined with a programmed cell death protein 1 (PD‐1) inhibitor in the preoperative transformation of unresectable esophageal cancer. Methods Patients were evaluated as having unresectable, locally advanced esophageal cancer at baseline and were re‐evaluated as possible R0 resection candidates after PD‐1 inhibitor treatment. Patient data were derived from the prospective database of Peking University Cancer Hospital Thoracic Surgery I. Preoperative chemotherapy plus PD‐1 inhibitor treatment was defined as “transformation treatment.” The objective response rate, operation rate (proportion of patients who underwent surgery), R0 rate, and treatment safety were analyzed retrospectively. Results A total of 36 patients were enrolled into the study, and 94.4% (34/36) completed the planned transformation treatment. The objective response rate was 71.4% (25/35), and 75% (27/36) of the patients who completed transformation treatment underwent surgery. For these surgical patients, 81.5% (22/27) obtained R0 resection, and 22.2% (6/22) had pathological complete response (pCR). During transformation treatment, 22.2% (8/36) patients had ≥ grade 3 complications. There were no reoperations or perioperative deaths. After surgery, 29.6% (8/27) had ≥ grade 3 complications. Conclusions Esophagectomy after immunotherapy is safe with acceptable complications. Compared with chemotherapy alone, chemotherapy combined with immunotherapy had a more favorable transformation effect for patients with unresectable esophageal cancer., Thirty‐six patients were enrolled. All patients received preoperative immunotherapy and 94.4% (34/36) completed the planned transformation treatment. The objective response rate was 71.4% (25/35), and 75% (27/36) of the patients who completed transformation treatment underwent surgery. For these surgical patients, 81.5% (22/27) obtained R0 resection, and 22.2% (6/22) had pathological complete response (pCR) as confirmed by postoperative pathological report.

Metastatic prostate cancer (mPCa) is responsible for most prostate cancer (PCa) deaths worldwide. The present study aims to explore the molecular differences between mPCa and PCa. The authors downloaded GSE6752, GSE6919, and GSE32269 from the Gene Expression Omnibus and employed integrated analysis to identify differentially expressed genes (DEGs) between mPCa and PCa. Functional and pathway-enrichment analyses were performed, and a protein–protein interaction (PPI) network and modules were constructed. Clinical mPCa specimens were collected to verify the results by performing RT-qPCR. The Cancer Genome Atlas database was used to conduct a survival analysis, and an immunohistochemical assay was performed. The invasion ability of PCa cells was verified by Transwell assay. One-hundred six consistently DEGs were found in mPCa compared with PCa. DEGs significantly enriched the positive regulation of cell proliferation, cell division, and cell adhesion in small cell lung cancer and PCa. Cell division, nucleoplasm, and cell cycle were selected from the PPI network, and the top 10 hub genes were selected. CDC20 and PTTG1 with genetic alterations were significantly associated with poorer disease-free survival. Immunohistochemical assay results showed that the expression levels of CDC20 and PTTG1 in mPCa were higher than those in PCa. The results of the migration assay indicated that CDC20 and PTTG1 could enhance the migration ability of PCa cells. The present study revealed that CDC20 and PTTG1 contribute more to migration, progression, and poorer prognoses in mPCa compared with PCa. CDC20 and PTTG1 could represent therapeutic targets in mPCa medical research and clinical studies.

Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor (α2AR) agonist, has an anti-inflammatory property and can alleviate pulmonary edema in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the mechanism is still unclear. In this study, we attempted to investigate the effect of Dex on alveolar epithelial sodium channel (ENaC) in the modulation of alveolar fluid clearance (AFC) and the underlying mechanism. Lipopolysaccharide (LPS) was used to induce acute lung injury (ALI) in rats and alveolar epithelial cell injury in A549 cells. In vivo, Dex markedly reduced pulmonary edema induced by LPS through promoting AFC, prevented LPS-induced downregulation of α-, β-, and γ-ENaC expression, attenuated inflammatory cell infiltration in lung tissue, reduced the concentrations of TNF-α, IL-1β, and IL-6, and increased concentrations of IL-10 in bronchoalveolar lavage fluid (BALF). In A549 cells stimulated with LPS, Dex attenuated LPS-mediated cell injury and the downregulation of α-, β-, and γ-ENaC expression. However, all of these effects were blocked by the PI3K inhibitor LY294002, suggesting that the protective role of Dex is PI3K-dependent. Additionally, Dex increased the expression of phosphorylated Akt and reduced the expression of Nedd4-2, while LY294002 reversed the effect of Dex in vivo and in vitro. Furthermore, insulin-like growth factor (IGF)-1, a PI3K agonists, promoted the expression of phosphorylated Akt and reduced the expression of Nedd4-2 in LPS-stimulated A549 cells, indicating that Dex worked through PI3K, and Akt and Nedd4-2 are downstream of PI3K. In conclusion, Dex alleviates pulmonary edema by suppressing inflammatory response in LPS-induced ALI, and the mechanism is partly related to the upregulation of ENaC expression via the PI3K/Akt/Nedd4-2 signaling pathway.

BACKGROUND The ideal depth of general anesthesia should achieve the required levels of hypnosis, analgesia, and muscle relaxation while minimizing physiologic responses to awareness. The choice of anesthetic strategy in patients with coronary heart disease (CHD) undergoing major noncardiac surgery is becoming an increasingly important issue as the population ages. This is because general anesthesia is associated with a risk of perioperative cardiac complications and death, and this risk is much higher in people with CHD. AIM To compare hemodynamic function and cardiovascular event rate between etomidate- and propofol-based anesthesia in patients with CHD. METHODS This prospective study enrolled consecutive patients (American Society of Anesthesiologists grade II/III) with stable CHD (New York Heart Association class I/II) undergoing major noncardiac surgery. The patients were randomly allocated to receive either etomidate/remifentanil-based or propofol/remifentanil-based general anesthesia. Randomization was performed using a computer-generated random number table and sequentially numbered, opaque, sealed envelopes. Concealment was maintained until the patient had arrived in the operating theater, at which point the consulting anesthetist opened the envelope. All patients, data collectors, and data analyzers were blinded to the type of anesthesia used. The primary endpoints were the occurrence of cardiovascular events (bradycardia, tachycardia, hypotension, ST-T segment changes, and ventricular premature beats) during anesthesia and cardiac troponin I level at 24 h. The secondary endpoints were hemodynamic parameters, bispectral index, and use of vasopressors during anesthesia. RESULTS The final analysis included 40 patients in each of the propofol and etomidate groups. The incidences of bradycardia, hypotension, ST-T segment changes, and ventricular premature beats during anesthesia were significantly higher in the propofol group than in the etomidate group (P < 0.05 for all). The incidence of tachycardia was similar between the two groups. Cardiac troponin I levels were comparable between the two groups both before the induction of anesthesia and at 24 h after surgery. When compared with the etomidate group, the propofol group had significantly lower heart rates at 3 min after the anesthetic was injected (T1) and immediately after tracheal intubation (T2), lower systolic blood pressure at T1, and lower diastolic blood pressure and mean arterial pressure at T1, T2, 3 min after tracheal intubation, and 5 min after tracheal intubation (P < 0.05 for all). Vasopressor use was significantly more in the propofol group than in the etomidate group during the induction and maintenance periods (P < 0.001). CONCLUSION In patients with CHD undergoing noncardiac major surgery, etomidate-based anesthesia is associated with fewer cardiovascular events and smaller hemodynamic changes than propofol-based anesthesia.

BACKGROUND Nonalcoholic fatty liver disease (NAFLD) affects more than one-quarter of the global population. Due to the lack of approved chemical agents, many patients seek treatment from traditional Chinese medicine (TCM) formulas. A variety of systematic reviews have been published regarding the effectiveness and safety of TCM formulas for NAFLD. AIM To critically appraise available systematic reviews and sort out the high-quality evidence on TCM formulas for the management of NAFLD. METHODS Seven databases were systematically searched from their inception to 28 February 2020. The search terms included “non-alcoholic fatty liver disease,” “Chinese medicines,” “systematic review,” and their synonyms. Systematic reviews involving TCM formulas alone or in combination with conventional medications were included. The methodological quality and risk of bias of eligible systematic reviews were evaluated by using A Measure Tool to Assess Systematic Reviews 2 (AMSTAR 2) and Risk of Bias in Systematic Review (ROBIS). The quality of outcomes was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS Seven systematic reviews were ultimately included. All systematic reviews were conducted based on randomized controlled trials and published in the last decade. According to the AMSTAR 2 tool, one systematic review was judged as having a moderate confidence level, whereas the other studies were rated as having a low or extremely low level of confidence. The ROBIS tool showed that the included systematic reviews all had a high risk of bias due to insufficient consideration of identified concerns. According to the GRADE system, only two outcomes were determined as high quality; namely, TCM formulas with the HuoXueHuaYu principle were better than conventional medications in ultrasound improvement, and TCM formulas were superior to antioxidants in alanine aminotransferase normalization. Other outcomes were downgraded to lower levels, mainly because of heterogeneity among studies, not meeting optimal information sample size, and inclusion of excessive numbers of small sample studies. Nevertheless, the evidence quality of extracted outcomes should be further downgraded when applying to clinical practice due to indirectness. CONCLUSION The quality of available systematic reviews was not satisfactory. Researchers should avoid repeatedly conducting systematic reviews in this area and focus on designing rigorous randomized controlled trials to support TCM formula applications.

Few large-sample research data sets exist on long-term survival and prognostic factors among patients with primary malignant melanoma of the esophagus (PMME), a rare malignancy associated with poor outcomes. We sought to investigate postoperative survival and prognostic factors in patients with PMME.We retrospectively analyzed long-term follow-up results for patients with PMME who underwent surgery at 10 Chinese centers between January 1998 and January 2018. We performed uni- and multivariate analyses to investigate clinicopathologic factors associated with survival.Median overall survival for the entire group (N = 70 patients) was 13.5 months. Female sex (hazard ratio [HR], 0.352; 95% confidence interval [CI], 0.138-0.900; P = .029), ≥12 lymph nodes dissected (HR, 0.274; 95% CI, 0.133-0.563; P .001), absence of lymph node metastasis (HR, 0.195; 95% CI, 0.084-0.451; P .001), and postoperative adjuvant therapy (HR, 0.474; 95% CI, 0.249-0.901; P = .023) were factors of favorable prognosis. Preoperative pathologic diagnosis of PMME was as low as 47.1%. A high proportion of patients had lymph node metastasis, including those with early-stage tumors. Rates of lymph node metastasis were 54.2% (13/24) for pT1, 44.4% (12/27) for pT2, 57.1% (8/14) for pT3, and 100% (5/5) for pT4. Regional lymph node recurrence (N = 43 [61.4%]) was the predominant postoperative pattern of recurrence or metastasis.Female sex, pN0, increased number of lymph nodes dissected, and postoperative adjuvant therapy were associated with better outcomes among patients with PMME. Preoperative pathologic diagnosis of PMME was low, patients had lymph node metastasis (even those with early-stage tumors), and regional lymph node recurrence was common.

Zhibai Dihuang pill (ZBDH), a Chinese herbal formula, has been widely used as an adjunctive therapy to help reduce the patient's steroid dose and maintain low disease activity in systemic lupus erythematosus (SLE).This systematic review evaluates the therapeutic effect of modified ZBDH in reducing steroid use in patients with SLE.A systematic literature search was carried out using seven databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, Chinese VIP Information and Wanfang Database, from their inception to June 1st, 2019. The search terms included "systemic lupus erythematosus," "Chinese medicine" and "clinical trial," and their synonyms. Subject headings matching the above terms were also used.This meta-analysis included randomized controlled trials that evaluated the reduction of steroid dose in patients with SLE. Traditional Chinese medicine (TCM) formulas in experimental group should be prescribed based on ZBDH and used as adjunctive therapy and the comparator should contain steroids.Two authors independently conducted database search, study selection, data extraction and quality assessment. The extracted information contained study design, sample size, recruitment mode, diagnostic criteria, inclusion and exclusion criteria, participant characteristics, TCM patterns, TCM formulas and treatment outcomes. The primary outcome was the change of steroid dose. Secondary outcomes included SLE Disease Activity Index (SLEDAI), biomarkers of disease activity and clinical response rate. STATA 15.0 was used to analyze the pooled effects reported as weighted mean difference (WMD) or odds ratio, with a 95% confidence interval (CI).In total, 20 trials involving 1470 SLE patients were included. The pooled result showed that modified ZBDH taken in combination with standard care led to a larger reduction in steroid dose, compared to standard care alone (WMD: 3.79; 95% CI: 2.58-5.01; P 0.001). Favorable outcomes were also seen in secondary outcome criteria, such as SLEDAI and complement 3. The modified ZBDH treatments were well tolerated without increasing adverse effects.The systematic review provided preliminary evidence supporting the use of ZBDH as a co-therapy to aid steroid dose reduction in patients with SLE. However, more rigorous studies should be conducted to validate these findings, and explore the mechanisms of ZBDH's relevant bioactive constituents.

Nonalcoholic steatohepatitis (NASH) is one of the important causes of cirrhosis and hepatocellular carcinoma worldwide. PPARα is highly expressed in the liver and plays a critical role in hepatic lipid metabolism. Our analysis of the gene expression profiles in the liver of humanized mice treated with a PPARα agonist and NASH patients suggested that PPARα might be a potential target for NASH therapy. This promoted us to find novel PPARα agonists. The results of virtual screening and biological evaluation identified compound A-4 as a selective PPARα agonist. It significantly regulated the target genes of PPARα involved in fatty acid metabolism and inflammation, exhibiting cellular anti-inflammatory activity. The key residues involved in the binding between PPARα ligand-binding domain (LBD) and compound A-4 were revealed by molecular dynamics (MD) simulation and further experimentally validated by the mutation study. Together, compound A-4 was well characterized as a novel lead compound for developing potent and selective PPARα agonists.

Background Hysterosalpingography (HSG) is an accepted radiologic diagnostic modality for initial infertility workup, and is generally considered uncomfortable and painful. However, the management of pain related to HSG remains inefficient. As an emerging nonpharmacologic and noninvasive pain control strategy, virtual reality (VR) distraction has been successfully used in areas such as burns, blunt force trauma, hospital-based needle procedures, dental/periodontal procedures, and urological endoscopy patients. This study aims to evaluate the analgesic effect of VR during HSG. Methods/design A single-center, parallel-group, randomized controlled trial will be carried out in the Radiology Department of Yinchuan Women and Children Healthcare Hospital, Yinchuan. A total of 200 participants who are scheduled for HSG will be enrolled in this study. The participants will be randomized (1:1) into two groups: a VR group and a blank control group. The VR group will receive routine care plus immersive VR intervention and the blank control group will receive routine care. Outcomes will be monitored at baseline, immediately after HSG and 15 min after HSG for each group. The primary outcome is the worst pain score during HSG by a visual analog scale (VAS). The secondary outcomes include: affective pain, cognitive pain, and anxiety during the HSG procedure; worst pain within 15 min after HSG; patient satisfaction and acceptance with pain management; physiological parameters; adverse effects; HSG results; and immersion perception score of the VR system (for the VR condition only). Discussion This study will focus on exploring a simply operated, noninvasive and low-cost analgesia during the HSG procedure. The results of this trial will provide data on the feasibility and safety of VR distraction therapy during HSG. Trial registration Chinese Clinical Trial Register, ChiCTR1900021342. Registered on 16 February 2019.

Objective Whether cervical disc arthroplasty (CDA) is superior to anterior cervical discectomy and fusion (ACDF) remains controversial, especially in relation to long‐term results. The present study aimed to evaluate the long‐term safety and efficiency of CDA and ACDF for cervical disc disease. Methods We performed this study according to the Cochrane methodology. An extensive search was undertaken in PubMed, Embase, and Cochrane databases up to 1 June 2019 using the following key words: “anterior cervical fusion,” “arthroplasty,” “replacement” and “artificial disc”. RevMan 5.3 (Cochrane, London, UK) was used to analyze data. Safety and efficiency outcome measures included the success rate, functional outcome measures, adverse events (AE), adjacent segment degeneration (ASD), secondary surgery, and patients’ satisfaction and recommendation rates. The OR and MD with 95% confidence interval (CI) were used to evaluate discontinuous and continuous variables, respectively. The statistically significant level was set at P

BACKGROUND Irritable bowel syndrome (IBS) and functional constipation (FC) are two commonly encountered functional gastrointestinal disorders in clinical practice and are usually managed with Western medicines in cooperation with traditional Chinese medicine (TCM) interventions. Although clinical practice guidelines (CPGs) have been developed to assist clinicians with their decisions, there are still gaps in management with regard to integrative medicine (IM) recommendations. AIM To comprehensively review the currently available CPGs and to provide a reference for addressing the gaps in IBS and FC management. METHODS We searched mainstream English and Chinese databases and collected data from January 1990 to January 2019. The search was additionally enriched by manual searches and the use of publicly available resources. Based on the development method, the guidelines were classified into evidence-based (EB) guidelines, consensus-based (CB) guidelines, and consensus-based guidelines with no comprehensive consideration of the EB (CB-EB) guidelines. With regard to the recommendations, the strength of the interventions was uniformly converted to a 4-point grading scale. RESULTS Thirty CPGs met the inclusion criteria and were captured as data extraction sources. Most Western medicine (WM) CPGs were developed as EB guidelines. All TCM CPGs and most IM CPGs were identified as CB guidelines. Only the 2011 IBS and IM CPG was a CB-EB set of guidelines. Antispasmodics and peppermint oil for pain, loperamide for diarrhea, and linaclotide for constipation were relatively common in the treatment of IBS. Psyllium bulking agents, polyethylene glycol and lactulose as osmotic laxatives, bisacodyl and sodium picosulfate as stimulant laxatives, lubiprostone and linaclotide as prosecretory agents, and prucalopride were strongly recommended or recommended in FC. TCM interventions were suggested based on pattern differentiation, while the recommendation level was considered to be weak or insufficient. CONCLUSION WM CPGs generally provide a comprehensive management algorithm, although there are still some gaps that could be addressed with TCM. Specific high-quality trials are needed to enrich the evidence.

Objectives It is imperative to develop efficient strategies on the treatment of prostate cancer. Here, we constructed multifunctional nanoparticles, namely AS1411@MPDA‐DTX (AMD) for targeted and synergistic chemotherapy/photothermal therapy of prostate cancer. Materials and Methods Mesoporous polydopamine (MPDA) nanoparticles were prepared by a one‐pot synthesis method, DTX was loaded through incubation, and AS1411 aptamer was modified onto MPDA by the covalent reaction. The prepared nanoparticles were characterized by ultra‐micro spectrophotometer, Fourier transform infrared spectra, transmission electron microscope, and so on. The targeting ability was detected by selective uptake and cell killing. The mechanism of AMD‐mediated synergistic therapy was detected by Western blot and immunofluorescence. Results The prepared nanoparticles can be easily synthesized and possessed excellent water solubility, stability, and controlled drug release ability, preferentially in acidic context. Based on in vitro and in vivo results, the nanoparticles can efficiently target prostate cancer cells, promote DTX internalization, and enhance the antitumor effects of chemo‐photothermal therapy strategies under the NIR laser irradiation. Conclusions As a multifunctional nanoplatform, AS1411@MPDA‐DTX could efficiently target prostate cancer cells, promote DTX internalization, and synergistically enhance the antiprostate cancer efficiency by combining with NIR irradiation., Schematic diagram of AS1411@MPDA‐DTX‐mediated synergistic therapy for prostate cancer and the underlying mechanism.

The variations of the aortic arch and its branches are rare. The surgical treatment of esophageal cancer would be challenged for combination with this anomaly. This study intends to review significant group cases to analyze the influence of this variation on esophagectomy. Methods From 2013 to 2019, 19 patients with aortic arch and brachiocephalic vessels variations underwent esophagectomy, accounting for 0.3% during the same period. The abnormalities were distributed as follows: left-sided aortic arch combined with aberrant right subclavian artery (LAA + ARSA) occurred 13 cases, right-sided aortic arch anomalies with mirror image arch branches (RAA + MIAB) in 1 case, and right-sided aortic arch combined with aberrant left subclavian artery (RAA + ALSA) in 5 case. Of the patients with LAA + ARSA, 11 patients underwent the McKeown esophagectomy, and 2 patients via transhiatal. All patients with RAA underwent left thoracotomy approach.Perioperative outcomes and long-term survival were analyzed. Results The tumors were mostly located in the upper and middle thorax (47.4% and 42.1%). The R0 resection rate was 89.5% (17/19). Recurrent laryngeal nerve injury occurred in 2 patients, anastomotic fistula in 1 patient. Two patients died within 30 days postoperatively. The yield of lymph nodes was 21.8 ± 9.4. The sampling rate of lymph nodes along the recurrent laryngeal nerve was 61.5% in LAA + ARSA group, while 16.7% in RAA group. Recurrence happened in 5 cases (29.4%), including 2 regional relapse. Four patients died after recurrence, with a median time to death of 20 months (range: 10–48 months). Conclusion For aortic arch and brachiocephalic artery variations in esophageal cancer, aberrant right subclavian artery and right-sided aortic arch are the most common types. The surgical strategy is closely related to the aortic arch position. Due to the combined variation of the recurrent laryngeal nerve, the upper mediastinal lymph nodes dissection would be conservative, but with acceptable oncologic results.

Background: Perioperative neurocognitive disorders (PND) are the most common postoperative complications with few therapeutic options. Salidroside, a plant-derived compound, has gained increased attention as treatment for various neurological diseases and particularly modifier of microglia-mediated neuroinflammation. However, the effect of salidroside on orthopedic surgery-induced cognitive dysfunction and the underlying mechanisms are largely unknown.Methods: The Morris water maze test was used to investigate potential effects of salidroside in the animal model of tibia fracturing with intramedullary fixation. Therapeutic mechanism and related signaling pathways of salidroside in PND were further investigated with animal tissues and microglial cultures in vitro by molecular biology tests.Results: Here we found that salidroside greatly attenuated cognitive impairment in mice after orthopedic surgery. Neuroinflammation in mouse hippocampus were also attenuated by salidroside. Meanwhile, salidroside treatment induced a switch in microglia polarization to the anti-inflammatory phenotype. In vitro, salidroside suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype to the anti-inflammatory phenotype. Mechanically, molecular docking studies revealed potential AMPK activation activity of salidroside. And salidroside did up-regulated the AMPK pathway proteins. Moreover, AMPK antagonist abolished the effects of salidroside in vivo and in vitro.Conclusions: Taken together, our results demonstrated that salidroside effectively suppressed PND by suppressing microglia-mediated neuroinflammation through activating AMPK pathway, and it might be a novel therapeutic approach for PND.

Copy number variations (CNVs), including deletions and duplications on the Y chromosome, are known genetic factors in azoospermia. Therefore, it is important to identify novel pathogenic CNVs related to azoospermia. In this study, we compared CNVs detected by STS-PCR and NGS in 107 individuals with nonobstructive azoospermia (NOA). STS-PCR analysis revealed that 8.14% (9/107) of patients had AZF deletions. The highest percentage of deletions was located in the AZFc region, followed by AZFa and AZFb+c. Positive CNVs, including four duplications, six deletions and three complex CNVs, were detected using NGS methods in 12.15% (13/107) of NOA patients. Both the duplications and deletions detected in q11.223 were confirmed to increase the genetic risk for NOA. A comparison between the STS-PCR results and NGS methods revealed concordant CNV-positive results in 4 of 107 cases (3.74%). The discrepancies included 6 cases with CNVs identified by NGS but not detected by STS-PCR, and two cases were detected by STS-PCR but not by NGS. Notably, four duplications were not identified and three complex CNVs were detected as simple deletions using STS-PCR analysis. The NGS method provides comprehensive results in detecting Y chromosome-linked CNVs, including deletions and duplications, which might broaden our understanding of NOA.

Background Colorectal carcinoma (CRC) is the third most common cancer and the second most common cause of cancer-related death worldwide. RNA N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play an important role in cancer. However, the roles of m6A and METTL3 in CRC progression are still elusive. Methods Adenoma and CRC samples were applied to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate their associations with survival of CRC patients. The biological functions of METTL3 were investigated by CCK8, wound healing and transwell assays. M6A epitranscriptomic microarray, RNA stability and luciferase reporter assays were performed to explore the mechanism of METTL3 in CRC. Results m6A and METTL3 levels were significantly upregulated in both adenoma and CRC tissues, and the CRC patients with high m6A or METTL3 level had both shorter overall survival. METTL3 knockdown markedly inhibited the proliferation, migration and invasion of CRC cells. M6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown markedly inhibited the degradation of CRB3 mRNA to increase the CRB3 expression. In addition, CRB3 level was also markedly reduced in both adenoma and CRC tissues, and the CRC patients with high CRB3 level had higher overall survival and disease free survival. CRB3 knockdown significantly promoted the proliferation, migration and invasion of CRC cells. Finally, CRB3 knockdown inhibited Hippo pathway, and increased nuclear localization of YAP. Conclusions The m6A and METTL3 levels were significantly increased in both adenoma and CRC tissues. The CRC patients with high m6A or METTL3 levels had shorter overall survival. Mechanistically, METTL3 regulated the initiation and progression of CRC via regulating m6A-CRB3-Hippo pathway.

Acute pain is the most common complaint in Emergency Department (ED) admissions, and options for analgesia are limited. Nitrous oxide/oxygen possesses many properties showing it may be an ideal analgesic in the ED.The aim of this study is to evaluate the safety and analgesic effect of the fixed nitrous oxide/oxygen mixture for trauma patients in the ED.We enrolled 60 patients in this double-blind, randomized study. The treatment group received conventional pain treatment plus a mixture of 65% nitrous oxide/oxygen. The control group received the conventional pain treatment plus oxygen. Primary outcome was the reduction in pain intensity at 5 and 15 min after the start of intervention. Secondary outcomes include adverse events, physiological parameters, and satisfaction from both patients and health care professionals.Initial pain scores for the nitrous oxide/oxygen group (6.0 [5.0-8.0]) and the oxygen group (6.75 [5.0-9.0]) were comparable (p = 0.57). The mean numerical rating scale scores at 5 min were 3.4 ± 1.8 and 7.0 ± 1.8 for nitrous oxide/oxygen and oxygen, respectively (p 0.01). The mean pain intensity at 15 min in the treatment group was 3.0 ± 1.9, compared with 6.3 ± 2.2 in the control group (p 0.01). Both patients' (8.0 [7.0-9.0] vs. 4.0 [2.0-6.0], p 0.01) and physicians' (8.5 [8.0-9.0] vs. 4.0 [3.0-6.0], p 0.01) satisfaction scores in the treatment group were significantly higher than the oxygen group. No serious adverse events were observed.This study gives supporting evidence for the safety and effectiveness of using self-administered nitrous oxide/oxygen mixture in the ED for moderate-to-severe traumatic pain.

Background DNA damage repair is an important mechanism of platinum resistance. HOXB7 is one member of HOX family genes, which are essential developmental regulators and frequently dysregulated in cancer. Recently, its relevance in chemotherapy resistance and DNA damage repair has also been addressed. However, little is known regarding the association between HOXB7 and chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Methods The association between HOXB7 expression detected by immunohistochemisty and tumor regression grade (TRG) and long-term survival was analyzed in 143 ESCC patients who underwent neoadjuvant chemotherapy. CCK8 assay was used to examine the effect of cisplatin in a panel of four ESCC cell lines. A stable cell strain with HOXB7 knockdown of KYSE150 and KYSE450 was established to explore the effect on cisplatin sensitivity. The interaction of HOXB7 with Ku70, Ku80 and DNA-PKcs was determined by GST-pull down, coimmunoprecipitation and immunofluorescent colocalization. Finally, we investigated whether disrupting HOXB7 function by a synthetic peptide HXR9 blocking the formation of HOXB7/PBX could enhance cisplatin sensitivity in vitro and in vivo. Results High expression of HOXB7 was associated with cisplatin resistance and worse chemotherapy efficacy. HOXB7 knockdown reinforced cisplatin sensitivity. It was identified that HOXB7 interacts with Ku70, Ku80 and DNA-PKcs. HOXB7 knockdown was related to the downregulation of Ku70, Ku80 and DNA-PKcs as well as arrested cell cycle in S phase. HOXB7 inhibition by HXR9 had a synergistic effect to improve cisplatin sensitivity. Conclusion HOXB7 may be a biomarker for the prediction of chemoresistance of ESCC and serves as a promising therapeutic target.

Background The morbidity of knee arthritis is increasing among aged people and total knee arthroplasty has been its mainstream treatment to date. Postoperative rehabilitation is an important part of the procedure. However, the intense pain during the functional exercise involved has always been a challenge for both patients and health care professionals. The aim of this study is to test the analgesic effect of a mixture of nitrous oxide/oxygeb (1:1) inhalation for patients who are doing functional exercise 1 month after total knee arthroplasty. Methods/design This double-blind, randomized, placebo-controlled study will be implemented in the Rehabilitation Department in the General Hospital of Ningxia Medical University. Patients aged between 50 and 75 years who underwent a primary unilateral total knee arthroplasty are eligible for inclusion. The key exclusion criteria include: epilepsy, pulmonary embolism, intestinal obstruction, aerothorax. The treatment group (A) will receive a pre-prepared nitrous oxide/oxygen mixture plus conventional treatment (no analgesics), and the control group (B) will receive oxygen plus conventional treatment (no analgesics). Patients, physicians, therapists, and data collectors are all blind to the experiment. Assessments will be taken immediately after functional exercise begins (T0), 5 min (T1) after functional exercise begins, and 5 min after functional exercise has finished (T2). Patients will be randomly allocated between a treatment group (A) and a control group (B) in a ratio of 1:1. Primary outcome, including pain severity in the procedure, will be taken for each group. Secondary outcomes include blood pressure, heart rate, oxygen saturation, side effects, knee joint range of motion, Knee Society Score (KSS), rescue analgesia need, and satisfaction from both therapists and patients. Discussion This study will focus on exploring a fast and efficient analgesic for patients who are doing functional exercise after total knee arthroplasty. Our previous studies suggested that the prefixed nitrous oxide/oxygen mixture was an efficacious analgesic for the management of burn-dressing pain and breakthrough cancer pain. The results of this study should provide a more in-depth insight into the effects of this analgesic method. If this treatment proves successful, it could be implemented widely for patients doing functional exercise in the rehabilitation department. Trial registration ChiCTR-INR-17012891. Registered on 6 October 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3472-7) contains supplementary material, which is available to authorized users.

Purpose To investigate the relationship of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in male population having spouses with early spontaneous abortion. Methods A total of 345 males whose spouses had at least one early spontaneous abortion were included in the study group, and 145 males who planned to have a second child were included in the control group. Semen was collected in a sterile cup by masturbation. After liquefaction, the sperm concentration and forward motility sperm rate (PR) were obtained. The genomic DNA was extracted from peripheral vein, followed by MTHFR C677T polymorphism detection through PCR-gold magnetic nanoparticle chromatography. Results The numbers of alleles and genotypes of MTHFR in the case group were 303 (C), 387 (T), 64 (CC), 175 (CT), and 106 (TT) cases, respectively. The numbers of allele and genotype of MTHFR in the control group were 167 (C), 123 (T), 145 (CC), 65 (CT), and 29 (TT) cases. There were significant differences in the distribution frequency of genotypes (χ2 = 17.005, P = 0.000) and alleles (χ2 = 15.295, P = 0.000) between the two groups. For cases with more spontaneous abortion, more cases had CT and TT phenotypes. Participants with genotype CT had the highest sperm concentration and PR in both groups (P

Pellino1 is an E3 ubiquitin ligase that plays a key role in positive regulation of innate immunity signaling, specifically required for the production of interferon when induced by viral double-stranded RNA. We report the identification of the tumor suppressor protein, p53, as a binding partner of Pellino1. Their interaction has a K𝘥 of 42 ± 2 μM and requires phosphorylation of Thr18 within p53 and association with the forkhead-associated (FHA) domain of Pellino1. We employed laser micro-irradiation and live cell microscopy to show that Pellino1 is recruited to newly occurring DNA damage sites, via its FHA domain. Mutation of a hitherto unidentified nuclear localization signal within the N-terminus of Pellino1 led to its exclusion from the nucleus. This study provides evidence that Pellino1 translocates to damaged DNA in the nucleus and has a functional role in p53 signaling and the DNA damage response. Agency for Science, Technology and Research (A*STAR) This research was supported by Academic Research Fund Tier 1 (Singapore) grant 2014-T1-001-274 (RG53/14) to PCFC and BMRC (Singapore) grant 0912219/599 to JL.

Phenology is an important indicator of global climate change. Revealing the spatiotemporal characteristics of crop phenology is vital for ameliorating the adverse effects of climate change and guiding regional agricultural production. This study evaluated the spatiotemporal variability of soybean’s phenological stages and key growth periods, and assessed their sensitivity to key climatic factors, utilizing a long-term dataset (1992–2018) of soybean phenology and associated meteorological data collected at 51 stations across China. The results showed that (1) during the soybean growing seasons from 1992 to 2018, the average temperature (0.34 ± 0.09 ℃ decade−1) and cumulative precipitation (6.66 ± 0.93 mm decade−1) increased, but cumulative sunshine hours (− 33.98 ± 1.05 h decade−1) decreased. (2) On a national scale, dates of sowing, emergence, trifoliate, anthesis, and podding of soybean were delayed, while the maturity date showed an advancing trend. The vegetative growth period (− 0.52 ± 0.24 days decade−1) and whole growth period (− 1.32 ± 0.30 days decade−1) of soybean were shortened, but the reproductive growth period (0.05 ± 0.26 days decade−1) was slightly extended. Trends in soybean phenological stages and key growth periods diverged in regions. Soybean phenological stages were delayed in Huang-Huai-Hai soybean zone, whereas advanced in southern soybean zone. Moreover, the key growth periods were greatly shortened in northern soybean zone. (3) In general, the sensitivity of soybean key growth periods to temperature was negative, whereas those to precipitation and sunshine hours differed among regions. In particular, most phenological stages were negatively sensitive to sunshine hours. Our results will provide scientific support for decision-making in agricultural production practices.

Background: Acupuncture is a classical complementary therapy, but benefits in palliative cancer pain are still unclear due to lack of consistent evidence. Objectives: To comprehensively evaluate th...

Mesalamine has been well used in the improvement of ulcerative colitis (UC) in clinics, however, the underlying mechanisms were not well illustrated. To explore its efficacy from the perspective of gut microbiota and related metabolites, we employed 16S rRNA sequencing and metabolomics approaches in stool samples across 14 normal healthy controls (NC group), 10 treatment-naïve UC patients (UC group) and 14 UC patients responded to mesalamine treatment (mesalamine group). We noted that the gut microbiota diversity and community composition were remarkably perturbed in UC group and partially restored by mesalamine treatment. The relative abundance of 192 taxa in genus level were significantly changed in UC group, and 168 genera were significantly altered after mesalamine intervention. Meanwhile, a total of 127 metabolites were significantly changed in UC group and 129 metabolites were significantly altered after mesalamine treatment. Importantly, we observed that many candidates including 49 genera (such as Escherichia-shigella, Enterococcus and Butyricicoccus) and 102 metatoblites (such as isoleucine, cholic acid and deoxycholic acid) were reversed by mesalamine. Spearman correlation analysis revealed that most of the candidates were significantly correlated with Mayo score of UC, and the relative abundance of specific genera were significant correlated with the perturbation of metabolites. Pathway analysis demonstrated that genera and metabolites candidates were enriched in many similar molecular pathways such as amino acid metabolism and secondary metabolites biosynthesis. Importantly, ROC curve analysis identified a gut microbiota signature composed of five genera including Escherichia-Shigella, Streptococcus, Megamonas, Prevotella_9 and [Eubacterium] _coprostanoligenes _group which might be used to distinguish UC group from both NC and mesalamine group. In all, our results suggested that mesalamine might exert a beneficial role in UC by modulating gut microbiota signature with correlated metabolites in different pathways, which may provide a basis for developing novel candidate biomarkers and therapeutic targets of UC.

Pentacyclic triterpenes (PTs) are the active ingredients of many medicinal herbs and pharmaceutical formulations, and are well-known for their anti-inflammatory activity. On the other hand, anti-inflammatory effects of AMP-activated protein kinase (AMPK) have recently drawn much attention. In this study, we found that a variety of naturally occurring PTs sapogenins and saponins could stimulate the phosphorylation of AMPK, and identified δ-oleanolic acid (10) as a potent AMPK activator. Based on these findings, 23 saponin derivatives of δ-oleanolic acid were synthesized in order to find more potent anti-inflammatory agents with improved pharmacokinetic properties. The results of cellular assays showed that saponin 29 significantly inhibited LPS-induced secretion of pro-inflammatory factors TNF-α and IL-6 in THP1-derived macrophages. Preliminary mechanistic studies showed that 29 stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). The bioavailability of 29 was significantly improved in comparison with its aglycon. More importantly, 29 showed significant anti-inflammatory and liver-protective effects in LPS/D-GalN-induced fulminant hepatic failure mice. Taken together, PTs saponins hold promise as therapeutic agents for inflammatory diseases.

While emerging studies have demonstrated the benefit of exercise in Substance Use Disorder (SUD) recovery outcomes, lack of motivation to engage in exercise has been indicated as one of many perceived barriers that contribute to low recruitment and adherence rates in SUD treatment. The current study aimed to explore participants’ perceptions of attending a supervised exercise program (boot camp workouts, walking/running practice, and a race event) while in treatment for SUD. A total of 109 participants were recruited to a 14-week exercise training program and 61 chose to participate in, and completed, a race at the close of the program. Interviews were conducted during weeks 6 through 14 and data were examined using Thematic Analysis. Three main themes were identified: (1) pushing forward recovery through running, (2) gaining a sense of achievement by crossing the finish line, and (3) building a sense of belonging in the program. Implications for SUD recovery programs are discussed.

Sirtuin 3 (SIRT3) is a potential therapeutic target for cardiovascular, metabolic, and other aging-related diseases. In this study, we investigated the role of SIRT3 in diabetic cardiomyopathy (DCM). Mice were injected with streptozotocin (STZ, 60 mg/kg, ip) to induce diabetes mellitus. Our proteomics analysis revealed that SIRT3 expression in the myocardium of diabetic mice was lower than that of control mice, as subsequently confirmed by real-time PCR and Western blotting. To explore the role of SIRT3 in DCM, SIRT3-knockout mice and 129S1/SvImJ wild-type mice were injected with STZ. We found that diabetic mice with SIRT3 deficiency exhibited aggravated cardiac dysfunction, increased lactate dehydrogenase (LDH) level in the serum, decreased adenosine triphosphate (ATP) level in the myocardium, exacerbated myocardial injury, and promoted myocardial reactive oxygen species (ROS) accumulation. Neonatal rat cardiomyocytes were transfected with SIRT3 siRNA, then exposed to high glucose (HG, 25.5 mM). We found that downregulation of SIRT3 further increased LDH release, decreased ATP level, suppressed the mitochondrial membrane potential, and elevated oxidative stress in HG-treated cardiomyocytes. SIRT3 deficiency further raised expression of necroptosis-related proteins including receptor-interacting protein kinase 1 (RIPK1), RIPK3, and cleaved caspase 3, and upregulated the expression of inflammation-related proteins including NLR family pyrin domain-containing protein 3 (NLRP3), caspase 1 p20, and interleukin-1β both in vitro and in vivo. Collectively, SIRT3 deficiency aggravated hyperglycemia-induced mitochondrial damage, increased ROS accumulation, promoted necroptosis, possibly activated the NLRP3 inflammasome, and ultimately exacerbated DCM in the mice. These results suggest that SIRT3 can be a molecular intervention target for the prevention and treatment of DCM.

Sperm quality is important for in vitro fertilisation and embryo transfer and intracytoplasmic sperm injection in the treatment of human infertility. The purpose of this study was to screen for biomarkers that could evaluate sperm quality. We analysed semen samples in 172 fertile males; multivariate logistic regression analysis showed that the levels of COX1 (17.5 ng/ml) in seminal plasma may represent a useful biomarker for sperm quality (area under the curve: 0.745; sensitivity: 0.808; specificity: 0.722). Analysis indicated that the values of parameters related to sperm quality changed significantly (p < .05) between COX1 level ≥ 17.5 ng/ml group and COX1 level < 17.5 ng/ml group. Further analysis of two consecutive semen samples (1-hr interval) from 48 subjects revealed that the first semen samples (COX1 levels ≥ 17.5 ng/ml) had a higher sperm concentration and a larger proportion of spermatozoa showing progressive motility, a lower rate of sperm DNA fragmentation and a lower proportion of spermatozoa undergoing the acrosome reaction spontaneously (p < .05); identical results were observed for the second semen samples. These data indicated that COX1 could be used as an indicator for sperm status and may be helpful for identifying better quality spermatozoa for artificial insemination.

Supplemental Digital Content is available in the text, Background: Non-alcoholic fatty liver disease (NAFLD) with abnormal transaminase were main targeted disorder in clinical intervention. Acupuncture embedding has been used as a modified acupuncture therapy in current management, while no comprehensive summarization has been established. Hence, we conducted a systematic review and meta-analysis to evaluate the effectiveness and safety of acupoint embedding alone or in combination for NAFLD with abnormal transaminase, and to provide potential regimen for further verification. Methods: Seven English and Chinese databases were systematically researched from inception to February 28, 2019, including PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese biomedical literature database (SinoMed), Chinese National Knowledge Infrastructure (CNKI), Chinese VIP information (VIP), and WanFang database. Academic dissertations were also searched as supplement. The searching terms included “nonalcoholic fatty liver disease,” “acupoint embedding,” “clinical trial,” with their corresponding synonyms. Randomized controlled trials (RCTs) and quasi-RCTs involving acupoint embedding alone or in combination for adult patients with NAFLD with abnormal transaminase were included. The diagnosis of NAFLD should be confirmed by radiologic evidence. Two researchers independently completed predefined data sets extraction and quality assessment. STATA 15.0 was applied to estimate the combined effect presented as odds ratio or mean difference (MD) with a 95% confidence interval (CI). The primary outcome was the change of serum alanine aminotransferase (ALT). Results: A total of fifteen studies with 1349 patients were included. Meta-analysis reported that acupoint embedding alone or in combination was superior to conventional medications on ALT change (MD: 16.58, 95%CI: [10.42, 22.74], P < .001). The benefits were also demonstrated in other outcomes, including aspartate aminotransferase, triglyceride, and total cholesterol, total efficacy rate and radiological efficacy rate. The safety profile of acupoint embedding was satisfactory. BL18 (Ganshu) was the most frequently utilized acupoint. Conclusion: To some extent, the systematic review supported the application of acupoint embedding in management of NAFLD, while further high-quality studies should be designed to evaluate the practical effect of acupoint embedding.

Activation of AMPK emerges as a potential therapeutic approach to metabolic diseases. AdipoRon is claimed to be an adiponectin receptor agonist that activates AMPK through adiponectin receptor 1 (AdipoR1). However, AdipoRon also exhibits moderate inhibition of mitochondrial complex I, leading to increased risk of lactic acidosis. In order to find novel AdipoRon analogues that activate AMPK without inhibition of complex I, 27 analogues of AdipoRon were designed, synthesized and biologically evaluated. As results, benzyloxy arylamide B10 was identified as a potent AMPK activator without inhibition of complex I. B10 dose-dependently improved glucose tolerance in normal mice, and significantly lowered fasting blood glucose level and ameliorated insulin resistance in db/db diabetic mice. More importantly, unlike the pan-AMPK activator MK-8722, B10 did not cause cardiac hypertrophy, probably owing to its selective activation of AMPK in the muscle tissue but not in the heart tissue. Together, B10 represents a novel class of AMPK activators with promising therapeutic potential against metabolic disease.

This study aims to evaluate the safety and analgesic efficacy of pre-mixed nitrous oxide/oxygen mixture treatment of pain induced by dressing change for perianal abscess.This protocol is a randomized, double-blind, placebo-controlled trial.This study will be implemented in the Hospital of Traditional Chinese Medicine. Subjects enrolled in this study are hospitalized patients who suffered from moderate to severe pain due to dressing change after incision and drainage. Two hundred patients will be selected and randomly assigned to either an intervention or a control group. The intervention group will get routine pain treatment plus pre-mixed nitrous oxide/oxygen mixture treatment and the control group will be treated with routine pain management plus medical air treatment. All these patients, medical staff and investigators are blind to the nature of the gas in each cylinder, which is randomized. Data will be collected at baseline (T0), 5 min (T1) after the starting of intervention and 5 min post intervention (T2) for each group. The primary outcome is the level of pain relief at T1 and T2. The secondary outcomes cover physiological parameters, adverse events, satisfaction of patients and health professionals and the acceptance from patients.Results of this study will be discussed and the safety and effect of nitrous oxide/oxygen treatment of pain induced by dressing change will be proven.When the finding of this study has an active effect on the treatment of pain caused by dressing change, it may provide more options for nursing staff to choose nurse-led analgesia techniques and then improving the level and quality of pain care as well as patients' overall satisfaction with the Anorectal Department in China.目的: 本研究旨在评估肛周脓肿术后换药引起疼痛时的预混合一氧化二氮/氧气混合物治疗的安全性和镇痛效果。 设计: 该方案是一项随机、双盲、安慰剂对照试验。 方法: 本研究将在中医医院实施。本研究的受试者是因切开引流后换药而引起中度至重度疼痛的住院患者。共计200名患者,这些患者将被随机分配到干预组或对照组。干预组接受常规疼痛治疗加上预混合一氧化二氮/氧气混合物治疗,而对照组主要接受常规疼痛治疗和医用气体治疗。所有患者、医务人员和调查人员都不清楚气瓶中气体的性质,并且,这些气瓶都是随机分配。应分别在基线(T0)、干预开始后5分钟(T1)和干预结束后5分钟(T2)收集数据。主要疼痛缓解结果见T1和T2。次要结果包括生理参数、不良事件、患者和卫生专业人员的满意度以及患者的接受程度等。 讨论: 将讨论这项研究的结果,并对一氧化二氮/氧气治疗换药引起的疼痛的安全性和效果进行证明。 影响: 如果本研究的调查结果显示,治疗过程中,换药引起的疼痛可带来积极影响,则可为护理人员选择镇痛技术,并且所选择的阵痛技术将由护士主导,从而提高我国肛肠科疼痛护理的水平和质量,提高患者的整体满意度,并可为患者提供更多选择。.

Background The current study aimed to determine the oncological efficacy and surgical safety of multiple pulmonary resections (MPRs) after prior curative surgery for local regional recurrent or second primary lung cancers. Methods All cases of lung cancer included in our prospective database between January 2000 and July 2015 were retrospectively reviewed. The oncological efficacy endpoints for synchronous and metachronous MPR were five-year overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) rates after the second surgery. The surgical safety endpoints were postoperative mortality and complications (Clavien-Dindo classification) within 30 days. Results In total, 67 MPR cases were identified. There were no significant differences in the five-year OS and DFS between the synchronous MPR group (n = 50) and the propensity score-matched solitary major pulmonary resection group (n = 250) (5-year OS 84.5% vs. 69.0%, log rank P = 0.112; DFS 64.4% vs. 58.0%, log rank P = 0.278). The five-year OS and PFS of the metachronous MPR group (n = 17) were significantly better than those in the non-surgical control group (n = 19) (5-year OS 94.1% vs. 50.7%, log rank P = 0.005; 5-year PFS 53.9% vs. 10.5%, log rank P = 0.020). No postoperative mortality or severe complications occurred in the MPR group. Conclusion The oncological efficacy of MPR is superior to the non-surgical approach for the management of local regional recurrent or second primary lung cancer, with comparable postoperative mortality and complications.

The essential medicine——insulin cannot be easily accessed and afforded in many countries. To help address this issue, we evaluated the availability, affordability and price of insulin products in Nanjing, eastern China. Two cross-sectional studies were conducted in 2016 and 2018. A total of 56 hospital pharmacies were sampled, using a simplified and adapted World Health Organization/Health Action International (WHO/HAI) methodology. Prices were expressed as Median Price Ratios (MPRs) to Australian Pharmaceutical Benefit Scheme (PBS) prices. In addition, we investigated the price components of seven selected insulin products as a case study before and after the Online Centralized Procurement Policy for Hospital Drugs in May, 2018. Affordability was presented as the number of daily wages of the lowest paid unskilled government worker (LPGW) required to purchase 1000IU of insulin based on the average courses of treatment, approximately 30 days’ treatment. The availability of insulin products was very high in secondary hospitals and tertiary hospitals both in 2016 and 2018, but in community hospitals was very low. In 2018, the availability of prandial insulin products showed fluctuation compared to 2016. The availability of pre-mixed human insulin products was over 95% overall, and also very high (80%) in community hospitals in 2018. The prices of insulin products were much lower than PBS prices of Australian in this study, with the MPRs less than 1 (0.32 to 0.71 in 2016 vs. 0.30 to 0.68 in 2018) for all insulin types. But insulin products in Nanjing in 2016 and 2018 were considered unaffordable, because the number of daily wages of the LPGW needed to purchase for the 30 days treatment of insulin products ranged from 2.26 to 8.49 in 2016 and 1.88 to 7.09 in 2018. The manufacturers’ selling price contributed the main part (74.15% to 77.70% before and 74.86% to 91.51% after the implementation of the bidding policy) of the price components of target insulin brands. The availability of insulin products was high in secondary hospitals and tertiary hospitals, but lower in community hospitals. However, the affordability in community hospitals was better than other hospitals, but the insulin products were still unaffordable for patients on low incomes. Further improvements of the availability accessibility and affordability of medicines in advancing health insurance policies and lowering drug prices should be put forward.

Globally, breast cancer is the most common malignancy affecting women. The incidence of breast cancer has been growing among Asian American women. Mammography is a screening procedure that provides early diagnosis for the timely treatment to reduce premature mortality due to breast cancer. However, there are no national data available that summarize the rates of mammography screening among Asian American women. Some small-scale studies have reported low rates of mammography uptake among Asian American women. This cross-sectional study utilized the fourth-generation, multi-theory model (MTM) of health behavior change to explain the correlates of mammography screening among Asian American women between the ages of 45–54 years. A 44-item instrument was evaluated for face, content, and construct validity (using structural equation modeling) and reliability (Cronbach’s alpha) and administered electronically to a nationally representative sample of Asian American women (n = 374). The study found that Asian American women who have had received mammograms in the past 12 months as per recommendations, all three constructs of MTM, namely, participatory dialogue (β = 0.156, p &lt, 0.05), behavioral confidence (β = 0.236, p &lt, 0.001), and changes in the physical environment (β = 0.426, p &lt, 0.001) were statistically significant and crucial in their decision to initiate getting a mammogram, accounting for a substantial 49.9% of the variance in the decision to seek mammography. The study also found that the MTM constructs of emotional transformation (β = 0.437, p &lt, 0.001) and practice for change (β = 0.303, p &lt, 0.001) were significant for maintaining the repeated behavior of getting annual mammograms and were responsible for 53.9% of the variance. This evidence-based study validates the use of MTM in designing and evaluating mammography screening promotion programs among Asian American women aged 45–54 years.

Triple-negative breast cancer (TNBC) shares the molecular features facilitating epithelial-to-mesenchymal transition (EMT), which contributed to tumor invasion and metastasis. A platinum(IV) conjugate ketoplatin deriving from FDA-approved drugs cisplatin and ketoprofen was designed and prepared to enhance antitumor activity and suppress EMT in TNBC via positive impact on inflammatory microenvironment by modulating COX-2 signal. As a prodrug, ketoplatin afforded 50.26-fold higher cytotoxicity than cisplatin against TNBC mesenchymal-stem cell-like MDA-MB-231 cells, partly attributing to its dramatic increase of cellular uptake and DNA damage. More importantly, EMT progress in MDA-MB-231 was markedly restrained by ketoplatin, resulting from the suppression of vimentin and N-cadherin mediated by down-regulated COX-2. Further in vivo investigation exhibited that ketoplatin effectively inhibited tumor growth and reduced systemic toxicity compared to cisplatin. Overall, ketoplatin possessed high antitumor activity and low toxicity against TNBC MDA-MB-231 in vitro and in vivo.

Importance Safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) vs neoadjuvant chemotherapy (nCT) for treatment of locally advanced esophageal squamous cell carcinoma (ESCC) remain uncertain given lack of high-level clinical evidence. Objective To compare safety and long-term survival of nCRT followed by minimally invasive esophagectomy (MIE) with that of nCT followed by MIE for patients with locally advanced ESCC. Design, Setting, and Participants A prospective, multicenter, open-label, randomized clinical trial that compared safety and efficacy of nCRT vs nCT followed by MIE for patients with locally advanced ESCC. From January 1, 2017, to December 31, 2018, 264 patients with ESCC of clinical stages from cT3 to T4aN0 to 1M0 were enrolled. Analysis was performed on an intention-to-treat basis from January 1, 2017, to August 30, 2020. Interventions Eligible patients were randomized to the nCRT group (n = 132) or the nCT group (n = 132) by a computer-generated random system. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while 40 Gy of concurrent radiotherapy was added for the nCRT group. At about 6 weeks after neoadjuvant therapy, MIE via thoracoscopy and laparoscopy was performed for the patients in both groups. Main Outcomes and Measures The primary outcome was 3-year overall survival. Secondary outcomes included postoperative complications, mortality, postoperative pathologic outcome, recurrence-free survival time, and quality of life. Results Among 264 patients (226 men [85.6%]; mean [SD] age, 61.4 [6.8] years), postoperative morbidity was 47.4% in the nCRT group (54 of 114) and 42.6% in the nCT group (46 of 108), with no significant difference between groups (difference, 4.8%; 95% CI, −8.2% to 17.5%;P = .48). Distribution of the severity of complications was similar between the 2 groups based on Clavien-Dindo classification. The 90-day perioperative mortality rate was 3.5% for the nCRT group (4 of 114) and 2.8% for the nCT group (3 of 108) (P = .94). The R0 resection rates were similar between groups (109 of 112 [97.3%] vs 100 of 104 [96.2%];P = .92). However, patients in the nCRT group had a higher pathologic complete response (residual tumor, 0%) rate (40 of 112 [35.7%] vs 4 of 104 [3.8%];P Conclusions and Relevance Initial results of the trial showed that nCRT followed by MIE has similar safety to and better histopathologic outcome than nCT followed by MIE for treatment of locally advanced ESCC. Trial Registration ClinicalTrials.gov Identifier:NCT03001596

Adequate micro-modeling for composites is the basic and key precondition for their property prediction. This study takes fiber-reinforced composites (FRCs) as an example and focuses on the linkages among fiber content, porosity and aggregation in the microstructure of composites, as well as their effect on the overall mechanical properties. A novel two-parameter agglomeration model is developed to take both the tightly packed filler assemblies and the porosity into account, in which the fiber weight fraction is used as an independent variable to express the volumetric composition. Meanwhile, an improved two-scale approach based on Mori–Tanaka (M–T) homogenization theory is utilized to predict the effective properties of FRCs. Three typical FRCs: three-dimensional (3D) randomly distributed FRCs, two-dimensional (2D) randomly distributed ones and unidirectionally (UD) distributed ones, are investigated in detail. The proposed model and method are validated by available experimental data. A parametric study reveals that due to the synergistic influence of fiber content, porosity and local aggregation, a maximum stiffness of FRCs can be achieved by making fibers uniformly dispersed in the matrix and setting the fiber weight fraction to be a certain transition value, which is characterized as a best possible condition with high fiber content and low porosity.

Background Xuesaitong dispersible tablet (XST) product has been clinically proven to be effective for treating cardio-cerebrovascular disease. Furthermore, herb–drug interactions between the XST product and drugs that are commonly co-administered, such as aspirin (ASA), must be explored to ensure safe clinical use. Study design and methods The current study aims to investigate whether the XST product interacts with ASA when they are administered concomitantly to ensure safety and efficacy. A ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) method was developed for the simultaneous determination of ginsenoside Rg1 (Rg1), ginsenoside Rd (Rd), notoginsenoside R1 (R1) and salicylic acid (SA) in rat plasma to investigate the pharmacokinetic interaction of XST and ASA in blood stasis model rats. Results and conclusion The ASA and XST combination noticeably altered R1 and Rg1 absorption, distribution and disposition. This study indicates that co-administration of XST and ASA can cause an apparent herb–drug pharmacokinetic interaction in blood stasis model rats.

Knowledge of aerosol chemistry in densely populated regions is critical for effective reduction of air pollution, while such studies have not been conducted in Changzhou, an important manufacturing base and populated city in the Yangtze River Delta (YRD), China. This work, for the first time, performed a thorough chemical characterization on the fine particulate matter (PM2.5) samples, collected during July 2015 to April 2016 across four seasons in this city. A suite of analytical techniques was employed to measure the organic carbon (OC), elemental carbon (EC), water-soluble organic carbon (WSOC), water-soluble inorganic ions (WSIIs), trace elements, and polycyclic aromatic hydrocarbons (PAHs) in PM2.5; in particular, an Aerodyne soot particle aerosol mass spectrometer (SP-AMS) was deployed to probe the chemical properties of water-soluble organic aerosol (WSOA). The average PM2.5 concentration was found to be 108.3 µg m−3, and all identified species were able to reconstruct ∼ 80 % of the PM2.5 mass. The WSIIs occupied about half of the PM2.5 mass (∼ 52.1 %), with SO42−, NO3−, and NH4+ as the major ions. On average, nitrate concentrations dominated over sulfate (mass ratio of 1.21), indicating that traffic emissions were more important than stationary sources. OC and EC correlated well with each other and the highest OC ∕ EC ratio (5.16) occurred in winter, suggesting complex OC sources likely including both secondary and primary ones. Concentrations of eight trace elements (Mn, Zn, Al, B, Cr, Cu, Fe, Pb) can contribute up to ∼ 5.0 % of PM2.5 during winter. PAH concentrations were also high in winter (140.25 ng m−3), which were predominated by median/high molecular weight PAHs with five and six rings. The organic matter including both water-soluble and water-insoluble species occupied ∼ 21.5 % of the PM2.5 mass. SP-AMS determined that the WSOA had average atomic oxygen-to-carbon (O ∕ C), hydrogen-to-carbon (H ∕ C), nitrogen-to-carbon (N ∕ C), and organic matter-to-organic carbon (OM ∕ OC) ratios of 0.54, 1.69, 0.11, and 1.99, respectively. Source apportionment of WSOA further identified two secondary OA (SOA) factors (a less oxidized and a more oxidized oxygenated OA) and two primary OA (POA) factors (a nitrogen-enriched hydrocarbon-like traffic OA and a local primary OA likely including species from cooking, coal combustion, etc.). On average, the POA contribution outweighed SOA (55 % vs. 45 %), indicating the important role of local anthropogenic emissions in the aerosol pollution in Changzhou. Our measurement also shows the abundance of organic nitrogen species in WSOA, and the source analyses suggest these species are likely associated with traffic emissions, which warrants more investigations on PM samples from other locations.