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Influenza virus infection is widely believed to cause mild symptoms, but can lead to high mortality and severe disease complicated by secondary bacterial pneumonia. Traditional Chinese medicine (TCM) has been proposed as a promising agent to treat respiratory viral infections. A herbal formula Lianhuaqingwen capsule (LHQW) comprising two prescriptions: Maxing Shigan decoction and Yinqiao San, has been used clinically to treat respiratory infection with immune regulatory effects. However, little is known about the capacity of LHQW against influenza-induced secondary bacterial pneumonia.This study aimed to evaluate the efficacy and underlying mechanism of LHQW on influenza A virus A/PR/8/34 (PR8) secondary methicillin-resistant Staphy-lococcus aureus (MRSA) infection.The anti-adhesion activity of LHQW against PR8-induced MRSA infection was assessed in human lung epithelial (A549) cells and the effect of LHQW on the expression of intracellular adhesion molecule 1 (ICAM-1) was detected. Also, the mRNA expression levels of inflammatory cytokines upon lipopolysaccharide (LPS) stimulation in PR8-infected A549 cells were determined. The body weight change, survivals, viral titers, colonies and the pathological parameters after LHQW treatment in severe pneumonia model have all been systematically determined.LHQW significantly reduced the adhesion of MRSA to PR8-infected A549 cells in a dose-dependent manner by suppressing the up-regulation of bacterial receptors. LHQW also markedly declined the overexpression of IL-6, IL-8, and TNF-α induced by LPS stimulated-A549 cells following influenza virus infection. Furthermore, the abnormal changes of lung index in dual-infection mice were relieved after administered with LHQW in preventive and therapeutic mode, but with no significantly difference (P 0.05). LHQW could not effectively improve survival rate or prolong the survival time of mice (P 0.05). LHQW (1000 mg/kg/d) administered prophylactically significantly decreased the lung viral titers (P 0.05), slightly downregulated IL-6 but TNF-α, IL-1β levels and improved lung pathological inflammation including neutrophil infiltration, necrosis, which is consistent with the expression of inflammatory factors.LHQW inhibited influenza-induced bacterial adhesion by down-regulating the adhesion molecules with the improvement trend on severe pneumonia, indicating that it can be used as an adjuvant medication in severe viral-bacterial pneumonia therapy rather than as a single medication.

Purpose: The aim of this study was to explore the efficacy and dose effect of intradiscal injection of simvastatin sustained release hydrogel in the treatment of discogenic low back pain in rabbits.Methods: 36 female rabbits were randomly divided into G1 and G2 groups. In group G1, L1/2 was disc degeneration (group DDD), L2/3 was normal group (control group), L3/4 was medium dose treatment group (1mg/ml, DDD+ medium group), L4/5 was normal group, L5/6 was intervertebral disc degeneration + hydrogel segment (medium group). In group G2, L1 / 2 was degenerative segment, L2 / 3 was normal group, L3 / 4 was low-dose treatment segment (0.3mg/ml, DDD + low-dose group), L4 / 5 was normal group, L5 / 6 was high-dose treatment segment (3mg / ml, DDD + high-dose group). The intervertebral disc was evaluated by X-ray, MRI, water content, and hematoxylin-eosin.Result: At 12 and 24 weeks after treatment, the% DHI of control group and DDD + high were higher than those of DDD group and DDD + gel group (P

Ethnopharmacological relevance Liu Shen Wan (LSW) is a traditional Chinese medicine (TCM) with detoxification and antiphlogistic activity; it is composed of bezoar, toad venom, musk, pearl powder, borneol and realgar. In recent years, LSW has been widely used in traditional medicine for the treatment of influenza, tonsillitis, pharyngitis, mumps, cancer and leukaemia. Aim of study The anti-influenza virus properties of LSW and its inhibition of the inflammatory response was demonstrated in our previous research; however, the effect and potential mechanism of LSW against influenza induced secondary bacteria have remained obscure. Therefore, in the present study, a model of influenza virus PR8 with secondary infection by Staphylococcus aureus (S. aureus) in vitro and in mice was established to examine the effect and potential mechanism by which LSW inhibits bacterial adhesion and subsequent severe pneumonia after viral infection. Materials and methods We investigated the effect of LSW on the PR8-induced adhesion of live S. aureus in A549 cells. RT-qPCR was used to detect the expression of adhesion molecules. Western blotting was used to determine the expression of CEACAM1, RIG-1, MDA5, p–NF–κB, and NF-κB in A549 cells. Inflammatory cytokines were detected using a Bio-Plex Pro Human Cytokine Screening Panel (R&D) in A549 cells and Mouse Magnetic Luminex Assays (R&D) in mice infected with PR8 virus and secondarily with S. aureus, respectively. Moreover, the survival rate, lung index, viral titre, bacterial loads and pathological changes in the lung tissue of mice infected with PR8 and S. aureus were investigated to estimate the effect of LSW in inhibiting severe pneumonia. Results LSW significantly decreased S. aureus adhesion following influenza virus infection in A549 cells, which may have occurred by suppressing expression of the adhesion molecule CEACAM1. In addition, treatment with LSW dramatically suppressed the induction of proinflammatory cytokines (CCL2/MCP-1 and CXCL-9/MIG) and chemokines (IL-6 and TNF-α) by PR8 infection following secondary LPS stimulation in A549 cells. Upregulation of related signalling proteins (RIG-I, MDA5 and NF-κB) induced by viruses and bacteria was suppressed by LSW in A549 cells. LSW significantly decreased the viral titres and bacterial load, prolonged survival time, and ameliorated lung inflammation and injury in mice with S. aureus infection secondary to PR8 infection. Conclusions We demonstrated that LSW prevents S. aureus adherence to influenza virus-infected A549 cells, perhaps by inhibiting the expression of the adhesion molecule CEACAM1. The upregulation of proinflammatory cytokines and related signalling proteins induced by viruses and bacteria was suppressed by LSW in A549 cells. LSW significantly ameliorated lung injury caused by viral and secondary bacterial infection. These findings provide a further evaluation of LSW and suggest a beneficial effect of LSW for the prevention of secondary bacterial infection and related complications.

Background To develop a sensitive and clinically applicable risk assessment tool identifying coronavirus disease 2019 (COVID-19) patients with a high risk of mortality at hospital admission. This model would assist frontline clinicians in optimizing medical treatment with limited resources. Methods 6415 patients from seven hospitals in Wuhan city were assigned to the training and testing cohorts. A total of 6351 patients from another three hospitals in Wuhan, 2169 patients from outside of Wuhan, and 553 patients from Milan, Italy were assigned to three independent validation cohorts. A total of 64 candidate clinical variables at hospital admission were analyzed by random forest and least absolute shrinkage and selection operator (LASSO) analyses. Results Eight factors, namely, Oxygen saturation, blood Urea nitrogen, Respiratory rate, admission before the date the national Maximum number of daily new cases was reached, Age, Procalcitonin, C-reactive protein (CRP), and absolute Neutrophil counts, were identified as having significant associations with mortality in COVID-19 patients. A composite score based on these eight risk factors, termed the OURMAPCN-score, predicted the risk of mortality among the COVID-19 patients, with a C-statistic of 0.92 (95% confidence interval [CI] 0.90–0.93). The hazard ratio for all-cause mortality between patients with OURMAPCN-score >11 compared with those with scores ≤ 11 was 18.18 (95% CI 13.93–23.71; p

Background Delayed wound healing is one of the major complications of diabetes mellitus and is characterized by prolonged inflammation, delayed re-epithelialization and consistent oxidative stress, although the detailed mechanism remains unknown. In this study, we aimed to investigate the potential role and effect of pterostilbene (PTE) and hematopoietic stem cells (HSCs) on diabetic wound healing. Methods Diabetic rats were used to measure the epigenetic changes in both HSCs and peripheral blood mononuclear cells (PBMCs). A cutaneous burn injury was induced in the rats and PTE-treated diabetic HSCs were transplanted for evaluation of wound healing. In addition, several biomedical parameters, including gene expression, oxidative stress, mitochondrial function and inflammation in macrophages, were also measured. Results Our data showed that PTE had a much stronger effect than resveratrol on accelerating diabetic wound healing, likely because PTE can ameliorate diabetes-induced epigenetic changes to estrogen receptor β promoter in HSCs, while resveratrol cannot. Further investigation showed that bone marrow transplantation of PTE-treated diabetic HSCs restores diabetes-induced suppression of estrogen receptor β and its target genes, including nuclear respiratory factor-1 and superoxide dismutase 2, and protects against diabetes-induced oxidative stress, mitochondrial dysfunction and elevated pro-inflammatory cytokines in both PBMCs and macrophages, subsequently accelerating cutaneous wound healing. Conclusions HSC may play an important role in wound healing through transferring epigenetic modifications to subsequent PBMCs and macrophages by differentiation, while PTE accelerates diabetic wound healing by modulating diabetes-induced epigenetic changes in HSCs. Thus, PTE may be a novel therapeutic strategy for diabetic wound healing.

Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with poor prognosis. In this study, we aimed to investigate the potential mechanism of latent membrane protein 1 (LMP1)-mediated tumorigenesis and provide a novel therapeutic strategy for targeting the EBV DNA genome. We found that LMP1 upregulated the expression of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1β (PGC1β) through activation of nuclear factor-κB (NF-κB). Furthermore, the activated PGC1β upregulated the expression of 8-oxoguanine DNA glycosylase (OGG1) through the coactivation of nuclear respiratory factor 1 (NRF1) and GA-binding protein α (GABPα), preventing reactive oxygen species (ROS)-mediated base incision in the EBV genome and favoring its survival. Interruption of hexokinase domain component 1 (HKDC1) by either shRNA or Tf-D-HKC8 peptide suppressed the interaction of HKDC1 with voltage-dependent anion channel 1 (VDAC1), triggering mitochondrial dysfunction and excessive generation of ROS, thus resulting in EBV suppression through ROS-mediated DNA damage. Suppression of the EBV genome inhibited the expression of the LMP1/PGC1β/HKDC1/OGG1 signaling pathway, forming a positive feed forward loop for the generation of ROS, hence inhibiting the EBV genome and subsequent EBV-associated tumor development. We concluded that LMP1 triggers EBV-associated tumorigenesis through activation of the PGC1β pathway. This study provided a novel therapeutic strategy for the treatment of EBV-associated tumors by targeting HKDC1.

A new drug discovery strategy by inducing the degradation of oncoproteins through ubiquitin-proteasome system (UPS) has gained a lot of traction in the last decade (Verma et al. Mol Cell 77(3):446-460, 2020; Huang, Dixit. Cell Res 26:484, 2016). Multiple degrader platforms, such as IMiDs (Kronke et al. Science 343:301-305, 2014; Lu et al. Science 343:305-309; 2014), PROTAC (proteolysis targeting chimera) (Winter et al. Science 348:1376-1381, 2015), and molecular glues (Tan et al. Nature 446:640-645, 2007), have been approved or currently being developed in clinical trials. Compared to conventional drug inhibitors, degraders have a lot of advantages, such as catalytic mechanisms of action (MOA), no requirement of high-affinity ligands with targets, and potentially more sustained efficacy (Verma et al. Mol Cell 77(3):446-460, 2020; Huang, Dixit. Cell Res 26:484, 2016; Bondeson et al. Nat Chem Biol 11:611-617). Here, we describe protocols that measure intrinsic protein ubiquitination, degrader-induced target protein degradation, and cancer cell proliferation evaluation, as these protocols can help evaluate the potential of a drug target using a degrader platform.

Background The coronavirus disease 2019 (COVID-19) is an emerged respiratory infectious disease with kidney injury as a part of the clinical complications. However, the dynamic change of kidney function and its association with COVID-19 prognosis are largely unknown. Methods In this multicenter retrospective cohort study, we analyzed clinical characteristics, medical history, laboratory tests, and treatment data of 12,413 COVID-19 patients. The patient cohort was stratified according to the severity of the outcome into three groups: non-severe, severe, and death. Findings. The prevalence of elevated blood urea nitrogen (BUN), elevated serum creatinine (Scr), and decreased blood uric acid (BUA) at admission was 6.29%, 5.22%, 11.66%, respectively. The trajectories showed elevation of BUN level and Scr level, as well as a reduction of BUA level during 28 days after admission in death cases. Increased all-cause mortality risk was associated with elevated baseline levels of BUN and Scr, and decreased level of BUA. Conclusion The dynamic changes of the three kidney function markers were associated with different severity and poor prognosis of COVID-19 patients. BUN showed close association and high potential for predicting adverse outcomes in COVID-19 patients for severity stratification and triage., Graphical Abstract, Highlights ● A cohort of 12,413 COVID-19 patients was retrospectively investigated ● Elevated baseline levels of BUN and Scr correlated with high risk of COVID-19 mortality ● Decreased BUA level on admission was associated with high risk of COVID-19 mortality, Liu et al. show that among 12,413 cases of COVID-19, an elevation of baseline BUN level and Scr level, and a decrease of baseline BUA level were associated with adverse outcomes in patients. These findings may help the risk stratification and triage of COVID-19 patients according to kidney function indicators.

// Junlin Yi 1 , Xiaodong Huang 1 , Zhengang Xu 2 , Shaoyan Liu 2 , Xiaolei Wang 2 , Xiaohui He 3 , Dehong Luo 4 , Jingwei Luo 1 , Jianping Xiao 1 , Shiping Zhang 1 , Kai Wang 1 , Yuan Qu 1 , Yuan Tang 1 , Weixin Liu 1 , Guozhen Xu 1 , Li Gao 1 and Dian Wang 5 1 Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China 2 Department of Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China 3 Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China 4 Department of Diagnostic Radiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China 5 Department of Radiation Oncology, Rush University Medical Center, Chicago, USA Correspondence to: Li Gao, email: // Keywords : head and neck squamous cell carcinoma; preoperative radiotherapy; concurrent chemoradiotherapy; multimodality treatment; organ function preservation Received : November 22, 2016 Accepted : January 11, 2017 Published : February 05, 2017 Abstract Purpose: To determine the role of preoperative concurrent chemoradiotherapy in the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC). Methods: A total of 222 patients with stage III/IVA-B HNSCC were randomly assigned to receive preoperative concurrent chemoradiotherapy (Pre-S CRT, weekly cisplatin 30mg/m 2 ) or preoperative radiotherapy alone (Pre-S RT). Survival analysis was estimated by the Kaplan-Meier method and compared by the log-rank test. Results: With a medial follow-up of 59 month, the 5-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) of Pre-S CRT v Pre-S RT group were 53.8% v 39.0% (hazard ratio [HR], 0.74, 95% CI, 0.50 to 1.10, P = 0.13), 53.2% v 38.7%, (HR, 0.69, 95% CI, 0.47 to 1.01, P =0.06), and 80.4% v 68.1% (HR, 0.53, 95% CI, 0.28 to 0.98, P = 0.04), respectively. In patients with larynx-hypopharynx primaries, the 5-year OS, PFS and DMFS of Pre-S CRT v Pre-S RT were 62.7% v 38.8% (HR, 0.59, 95% CI 0.35 to 1.02, P = 0.054), 63.1% v 39.9% (HR, 0.52; 95% CI 0.30 to 0.89, P = 0.03) and 86.2% v 63.3% (HR, 0.35, 95% CI 0.15 to 0.82, P = 0.01), respectively. Conclusion: The addition of weekly cisplatin concurrent to preoperative RT does not improve OS, but improve DMFS in locally advanced HNSCC. However, in a subset of patients with the larynx-hypopharynx primaries, preoperative chemoradiotherapy has significantly improved PFS and DMFS, and has also provided a borderline benefit in OS in comparison with preoperative radiotherapy alone.

Xia Tian,* Meng Liu,* Xiaodong Huang, Qingxi Zhu, Weijie Liu, Wei Chen, Yanli Zou, Yishan Cai, Shasha Huang, Aifang Chen, Ting Zhan, Min Huang, Xiaoli Chen, Zheng Han, Jie Tan Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zheng Han; Jie Tan Email 422435466@qq.com; 549774892@qq.comBackground: Noscapine is an opium alkaloid that has recently been shown to potentiate anti-cancer therapeutic effects by inducing apoptosis in various malignant cells without any detectable toxicity. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear.Materials and Methods: In this study, we explored the anti-cancer activity of noscapine in 5-fluorouracil (5-FU)-resistant human colon cancer cell lines HT29/5-FU and LoVo/5-FU and investigated the possible underlying mechanism. The apoptosis and mitochondrial morphology of cells were detected by TUNEL assay and transmission electron microscopy (TEM). The mitochondrial membrane potential (MMP) was determined using JC-1. The mitochondrial permeability transition pore (mPTP) opening was detected by the calcein-AM/cobalt assay. The levels of glucose, lactic, and ATP in cells were evaluated by ELISA kits. Relative protein expression levels were detected by Western blot.Results: We verified that PTEN was involved in noscapine-induced apoptosis in HT29/5-FU and LoVo/5-FU cells. Noscapine greatly increased mitochondrial damage by altering mitochondrial morphology, inducing mitochondrial membrane potential depolarization, and enabling mitochondrial permeability transition pore opening in HT29/5-FU and LoVo/5-FU cells. In addition, noscapine inhibited the Warburg effect by decreasing the levels of glucose, lactic acid, and ATP and inhibiting the protein expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in HT29/5-FU and LoVo/5-FU cells. However, PTEN interference counteracted the effect of noscapine on mitochondrial damage and the Warburg effect in HT29/5-FU and LoVo/5-FU cells by decreasing the activation of PI3K/mTOR signaling.Conclusion: These results indicated that noscapine induced the apoptosis of HT29/5-FU and LoVo/5-FU human colon cancer cells by regulating mitochondria damage and the Warburg effect via PTEN, and the process is closely related to the PI3K/mTOR signaling pathway.Keywords: colon cancer, noscapine, mitochondrial damage, PTEN, PI3K/mTOR

Object With the gradual advancement of laparoscopic technology, surgeries can be successfully performed with the help of laparoscopy increasingly. This study initially explored the difference between laparoscopic right posterior sectionectomy (LRPS) and open right posterior sectionectomy (ORPS)of liver in our center, discussed the effectiveness, benefits and safety of LRPS and introduce some surgical techniques in our center. Materials and methods We retrospectively analyze 96 cases of liver tumor located in the right posterior lobe of liver in our institution from January 2015 to January 2018. There were 46 cases performed the LRPS surgery and 50 cases performed the ORPS surgery. Through analysis of the perioperative outcomes of these two groups by a case control study, we compare the differences between these two groups. Results There was no significant difference between the LRPS and ORPS group in demographic and baseline characteristics before surgery. Patients in the LRPS group were significantly superior to ORPS in terms of postoperative liver function recovery, postoperative inflammatory factor level, pain sensation (3.03 ± 0.79 vs 4.58 ± 1.25), abdominal incision length (6.25 ± 2.34 vs 32.15 ± 3.21), carrying abdominal drainage tube time (3.26 ± 0.77 vs 4.83 ± 0.76), recovery of bowel function time (1.6 ± 0.61 VS 3.05 ± 0.85)and postoperative hospital stay (5.73 ± 0.99 vs 7.16 ± 0.95) (P Conclusion Compared with the traditional ORPS, LRPS has the advantages of minor injury, faster recovery and mild inflammatory reaction. The LRPS is safe and feasible, and it should be gradually promoted in clinical practice.

Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder, which causes a range of physical, cognitive, and medical challenges. To retrospectively analyze the clinical characteristics and genetic variations of Chinese patients, and to provide experience for further diagnosis and treatment of CdLS in Chinese children, we identified 15 unrelated Chinese children who presented with unusual facial features, short stature, developmental delay, limb abnormalities, and a wide range of health conditions. In this study, targeted-next generation sequencing was used to screen for causal variants and the clinically relevant variants were subsequently verified using Sanger sequencing. DNA sequencing identified 15 genetic variations, including 11 NIPBL gene variants, two SMC1A gene variants, one RAD21 gene variant, and one HDAC8 variant. The phenotype of these patients was summarized and differences between this cohort and another four groups were compared. The clinical manifestations of the patients in this cohort were mostly consistent with other ethnicities, but several clinical features in our cohort had different frequencies compared with other groups. We identified 15 deleterious variants of which 11 were novel. Variants in the NIPBL gene were the most common cause in our cohort. Our study not only expands upon the spectrum of genetic variations in CdLS, but also broadens our understanding of the clinical features of CdLS.

Gastric cancer (GC) is a complex and heterogeneous disease, making it difficult to ascertain the optimal therapeutic approach for individual GC patients. Stromal and immune cell infiltration in GC has a strong correlation with clinical outcomes; however, the underlying mechanisms that drive immunosuppression remain vastly undiscovered. Recent studies validated that anthrax toxin receptor 1 (ANTXR1) is aberrantly expressed in several cancers and holds promise as a new therapeutic target for cancer. However, its immunological roles in GC are still unclear. Here, we show that we identify the distinct stromal and immune cell infiltration in GC between the high and low ANTXR1 expression group by analyzing genomic data. Clinically, ANTXR1 is highly expressed in GC and correlates with adverse clinicopathological characteristics. Additionally, high ANTXR1 expression is linked to markedly poor clinical outcomes and resistance to chemotherapy, whereas the low ANTXR1 expression group is correlated with better outcomes and response to chemotherapy in GC patients. We further revealed the differential landscape of somatic tumor mutation burden (TMB) between the two groups and observed that patients with high ANTXR1 expression suffered from a lower TMB, potentially leading to less sensitivity to checkpoint therapy. Molecularly, results displayed that ANTXR1 is an immunosuppressive element, which may perform its function via promoting the secretion of immunosuppressive factors that play a significant role in modulating tumor-associated fibroblast transformation, M2 macrophage polarization, and T cell exhaustion. Gene set enrichment analysis revealed that cancer-related pathways including epithelial-to-mesenchymal transition, focal adhesion, and transforming growth factor-β (TGF-β) signaling pathways were enriched in high ANTXR1 expression tumors. Our work suggests that ANTXR1 could not only serve as a valuable prognostic biomarker in GC but also be deemed as a potential immunotherapeutic target and useful biomarker of sensitivity to chemotherapy.

The genus Acinetobacter has recently emerged as bacterial pathogens associated with mass mortalities in aquaculture. Yet scarce information is available on Acinetobacter venetianus as a potential pathogen of whiteleg shrimp Penaeus vannamei. In the present study, an A. venetianus pathogen (SHF1) was confirmed as a causative agent of red leg disease in freshwater-cultured whiteleg shrimp. It showed a mean lethal dose (LD50) value of 3.8 × 105 CFU mL−1 and developed multiple resistances to phenicols, quinolones and tetracycline drugs used in aquaculture. In addition, the pathogenic A. venetianus could be effectively controlled by Bdellovibrio powder at 0.8 mg L−1, which exhibited significant antibacterial effect and displayed good protection against A. venetianus challenge in P. vannamei for six days. As far as we know, this is the first study to identify A. venetianus as a potential bacterial pathogen of red leg disease in freshwater-farmed whiteleg shrimp.

Background The mosquitoes Aedes aegypti and Ae. albopictus are the primary vectors of dengue virus, and their geographic distributions are predicted to expand further with economic development, and in response to climate change. We aimed to estimate the impact of future climate change on dengue transmission through the development of a Suitable Conditions Index (SCI), based on climatic variables known to support vectorial capacity. We calculated the SCI based on various climate change scenarios for six countries in the Asia-Pacific region (Australia, China, Indonesia, The Philippines, Thailand and Vietnam). Methods Monthly raster climate data (temperature and precipitation) were collected for the period January 2005 to December 2018 along with projected climate estimates for the years 2030, 2050 and 2070 using Representative Concentration Pathway (RCP) 4·5, 6·0 and 8·5 emissions scenarios. We defined suitable temperature ranges for dengue transmission of between 17·05–34·61 °C for Ae. aegypti and 15·84–31·51 °C for Ae. albopictus and then developed a historical and predicted SCI based on weather variability to measure the expected geographic limits of dengue vectorial capacity. Historical and projected SCI values were compared through difference maps for the six countries. Findings Comparing different emission scenarios across all countries, we found that most South East Asian countries showed either a stable pattern of high suitability, or a potential decline in suitability for both vectors from 2030 to 2070, with a declining pattern particularly evident for Ae. albopictus. Temperate areas of both China and Australia showed a less stable pattern, with both moderate increases and decreases in suitability for each vector in different regions between 2030 and 2070. Interpretation The SCI will be a useful index for forecasting potential dengue risk distributions in response to climate change, and independently of the effects of human activity. When considered alongside additional correlates of infection such as human population density and socioeconomic development indicators, the SCI could be used to develop an early warning system for dengue transmission.

Background: A methodical comparison of confirmed and suspected COVID-19 patients has not been previously reported. Therefore, we thoroughly analyzed the demographic and clinical characteristics between these groups to identify mortality risk factors.Methods: A retrospective cohort of 1,276 hospitalized COVID-19 pneumonia patients at Tongren Hospital (Wuhan, China; January 27 to March 3, 2020) was studied. Cox regression analyses were performed to evaluate multiple mortality risk factors. Results: Both cohorts of confirmed (n=797) and suspected (n=479) patients exhibited typical demographic, clinical, and radiological characteristics. Treatment methods were consistent and both groups shared similarities in many demographic and clinical characteristics: age (≥65, 45.9% vs 41.8%, P=0.378) and lung disease (12.5% vs 14.6%, P=0.293). However, confirmed patients exhibited more severe disease manifestations than those in suspected patients: a higher incidence of fever (65.4% vs 58.0%, P9/L vs 1.22×109/L, P=0.022), higher C-reactive protein (CRP) (11.60 mg/L vs 7.61mg/L, P=0.021), and more severe radiographic manifestations (lung infection incidence, 3.8% vs 3.0%, P=0.014; ground-glass opacity lesion incidence, 2.3% vs 2.0%, P=0.033). The dynamic profiles of lymphocytes, monocytes, D-dimer, and CRP, clearly delineated confirmed patients from suspected patients exhibiting critical illness. Cox regression analysis demonstrated that lung disease (adjusted hazard ratio 8.972, 95% CI: 3.782-21.283), cardiovascular disease (3.083, 1.347-7.059), neutrophil count (1.189, 1.081-1.307), age (1.068, 1.027-1.110), and ground-glass opacity lesions (1.039, 95% 1.013-1.065), were the main risk factors for mortality in confirmed patients; lung disease (14.725, 2.187-99.147), age (1.076, 1.004-1.153), and CRP level (1.012, 95% CI 1.004-1.020) were the primary factors in suspected patients.Conclusions: Suspected patients with serious illness should seek medical attention to reduce mortality. Multiple factors must be assessed to determine the mortality risk and the appropriate treatment.

Dengue, chikungunya and Zika viruses share similar disease features, rendering them difficult to distinguish clinically. Incapacitating arthralgia/arthritis is a specific manifestation associated with chikungunya virus infection. However, the profile of arthralgia/arthritis in Zika virus (ZIKV) cases has not been well characterized. Articles were extracted from PubMed and Scopus databases reporting original data from patients with arthralgia/arthritis, according to the Cochrane Collaboration. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 137 articles reporting ZIKV-associated joint symptoms were reviewed. Arthralgia was more frequently reported (n = 124 from case studies, n = 1779 from population-based studies) than arthritis (n = 7 and n = 121, respectively). Arthralgia was resolved in &lt, 1 week in 54%, and within 1&ndash, 2 weeks in 40% of cases. The meta-analysis of cases in population-based studies identified a pooled prevalence of 53.55% for arthralgia. The pooled prevalence of arthralgia/arthritis during outbreaks depended on the geographic location, with a higher joint symptom burden observed in the Americas compared to South East Asia (Brazil: 60.79%, Puerto Rico: 68.89% and South East Asia: 26.46%). We conclude that non-specific constitutional arthralgia is the most common joint manifestation during ZIKV infection, being present in nearly half of cases but resolving by two weeks in &gt, 90% of these. We found no evidence of chronic rheumatic manifestations following ZIKV infection.

BACKGROUND Esthesioneuroblastoma (ENB) is a rare malignant neoplasm. Currently, no consistent and universal staging system for ENB exists. The aim of this study is to propose a TNM-based classification. SUBJECTS AND METHODS Hundred and forty-two patients from our institution, with ENB pathologically confirmed between July 1978 and December 2018, were reviewed. All patients were restaged according to the Kadish stage, Morita stage and American Joint Committee on Cancer (AJCC) T classification from clinical and radiological data. Multivariate Cox proportional hazard regression analyses were performed to determine the impact of various factors. The goodness-of-fit and predictive accuracy of the different staging systems were calculated using R software. RESULTS The median follow-up time was 57 months (range: 4-229 months). According to the Kadish system, the 5-year overall survival (OS) for patients with stage A, B and C was 100%, 83.6% and 64.2%, respectively (P = .055). With respect to the Morita classification, 5-year OS for stages A, B, C and D was 100%, 83.6%, 70.7% and 50.0%, respectively (P = .004). Analysis based on the proposed staging model demonstrated 5-year OS for stage I, II, III and IV disease was 100%, 88.9%, 75.9% and 49.0%, respectively (P

Supplemental Digital Content is available in the text., The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019, to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for high-sensitivity cardiac troponin I was 7.12 ([95% CI, 4.60–11.03] P

Background The aim of this study is to evaluate the efficacy of different treatment strategies and the potential prognostic factors of esthesioneuroblastoma (ENB). Materials and methods Between April 1984 and December 2018, 138 patients with non-metastatic ENB were retrospectively analyzed. The treatment modalities mainly included surgery alone (n = 7), radiotherapy alone (n = 33), concurrent chemoradiotherapy (n = 17), surgery combined with current chemoradiotherapy (n = 32), and surgery plus radiotherapy (n = 49). Results The median follow-up time for the entire cohort was 61 months (range, 4–231 months). The 5-year overall survival (OS), locoregional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS) rate were 69.6, 78.0 and 73.9%, respectively. Surgery combined with radiotherapy elicited superior survival results, and the combination of surgery and current chemoradiotherapy achieved the best prognoses for all patients, patients with advanced Kadish disease, patients receiving intensity modulated radiation therapy and those with positive surgical margin. Univariate analysis identified orbital invasion and treatment modalities were predictors for OS, LRFFS and DMFS. Lymph node metastasis was associated with OS and DMFS, but not LRFFS. Intracranial invasion, advanced Kadish stage and not receiving concurrent chemotherapy were also predictive of lower OS. Multivariate analyses indicated that lymph node metastasis was an independent prognostic factor affecting DMFS, whereas treatment modalities was independent prognostic factors for OS and LRFFS. Conclusion Orbital invasion, intracranial invasion, lymph node metastasis and advanced Kadish disease at initial diagnosis were significantly associated with inferior prognosis. Regarding the treatment modality, the optimal strategy remined surgery with radiotherapy-based multimodality treatment. The concurrent chemoradiotherapy may play a more beneficial role.

Background:Pancreatic cancer is an aggressive type of cancer with poor prognosis, short survival rate, and high mortality. Drug resistance is a major cause of treatment failure in the disease. MiR-331-3p has been reported to play an important role in several cancers. We previously showed that miR-331-3p is upregulated in pancreatic cancer and promotes pancreatic cancer cell proliferation and epithelial-to-mesenchymal transition–mediated metastasis by targeting ST7L. However, it is uncertain whether miR-331-3p is involved in drug resistance.Methods:We investigated the relationship between miR-331-3p and pancreatic cancer drug resistance. As part of this, microRNA mimics or inhibitors were transfected into pancreatic cancer cells. Quantitative polymerase chain reaction was used to detect miR-331-3p expression, and flow cytometry was used to detect cell apoptosis. The Cell Counting Kit-8 assay was used to measure the IC50 values of gemcitabine in pancreatic cancer cells. The expression of multidrug resistance protein 1, multidrug resistance-related protein 1, breast cancer resistance protein, β-Catenin, c-Myc, Cyclin D1, Bcl-2, and Caspase-3 was evaluated by Western blotting.Results:We confirmed that miR-331-3p is upregulated in gemcitabine-treated pancreatic cancer cells and plasma from chemotherapy patients. We also confirmed that miR-331-3p inhibition decreased drug resistance by regulating cell apoptosis and multidrug resistance protein 1, multidrug resistance-related protein 1, and breast cancer resistance protein expression in pancreatic cancer cells, whereas miR-331-3p overexpression had the opposite effect. We further demonstrated that miR-331-3p effects in drug resistance were partially reversed by ST7L overexpression. In addition, overexpression of miR-331-3p activated Wnt/β-catenin signaling in pancreatic cancer cells, and ST7L overexpression restored activation of Wnt/β-catenin signaling.Conclusions:Taken together, our data demonstrate that miR-331-3p contributes to drug resistance by activating Wnt/β-catenin signaling via ST7L in pancreatic cancer cells. These data provide a theoretical basis for new targeted therapies in the future.

Background and aims Coronavirus disease 2019 (COVID-19) is a new infectious disease. To reveal the hepatic injury related to this disease and its clinical significance, we conducted a multicenter retrospective cohort study that included 5,771 adult patients with COVID-19 pneumonia in Hubei Province. Approach and results We reported the distributional and temporal patterns of liver injury indicators in these patients and determined their associated factors and death risk. Longitudinal liver function tests were retrospectively analyzed and correlated with the risk factors and death. Liver injury dynamic patterns differed in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL). AST elevated first, followed by ALT, in severe patients. ALP modestly increased during hospitalization and largely remained in the normal range. The fluctuation in TBIL levels was mild in the non-severe and the severe groups. AST abnormality was associated with the highest mortality risk compared with the other indicators of liver injury during hospitalization. Common factors associated with elevated liver injury indicators were lymphocyte count decrease, neutrophil count increase, and male gender. Conclusion The dynamic patterns of liver injury indicators and their potential risk factors may provide an important explanation for the COVID-19-associated liver injury. Because elevated liver injury indicators, particularly AST, are strongly associated with the mortality risk, our study indicates that these parameters should be monitored during hospitalization.

Background The mechanism of eucalyptus volatile oil application on the prevention and treatment of burn infections caused by Pseudomonas aeruginosa (PA) was need to examined.Methods The effect of eucalyptus volatile oil on bacterial biofilm was investigated using a PA biofilm model. The expression of LasI mRNA in PA was detected by RT-PCR. Results The minimum inhibitory concentration test showed that the volatile oil of Eucalyptus urophylla in 20% concentration or more could exert an antibacterial effect. However, neither high nor low concentration of the eucalyptus volatile oil had a zone of inhibition. In scanning electron microscopy, the volatile oil group exhibited a significant delay compared with the control group. The volatile oil group also had a significantly lower LasI mRNA expression than the control group. Conclusion As a Chinese medicine, the volatile oil of E. urophylla can affect PA proliferation and biofilm formation by interfering with the expression of LasI, thereby successfully preventing and treating burn infection caused by PA.

Background: Wingless and Int-related protein (Wnt) ligands were aberrantly expressed in human diseases. However, the aberrant level of Wnt ligands have not been explored in serum. Here, we aimed to identify the WNT4 level in serum and explore its oncogenic role in colorectal cancer (CRC). Methods: Serum samples from 40 CRC patients and 28 healthy donors were collected to measure the levels of WNT4. CRC tissue samples from patients were collected to explore the resource of WNT4. Further, we used CRC cells and xenograft mouse model to explore the oncogenic role of WNT4. Findings: WNT4 was significantly upregulated in serum of colorectal cancer (CRC) patients, and CRC tissues were identified as an important source of elevated WNT4 levels in CRC patients. Interestingly, the elevated WNT4 in serum was downregulated after tumor resection. Next, we found that WNT4 could contributed to epithelial-to-mesenchymal transition and activated fibroblasts by activating WNT4/β-catenin pathway in vitro and in vivo; besides, angiogenesis was also induced via WNT4/β-catenin/Ang2 pathway. Those effects could be reversed by ICG-001, a β-catenin/TCF inhibitor. Interpretation: These data indicated that WNT4 may be a potential biomarker for CRC and provided evidence to support a critical role of WNT4 in promoting CRC cell metastasis by inducing epithelial-to-mesenchymal transition, activating fibroblasts and promoting angiogenesis in the colorectal tumor microenvironment. Funding Statement: This work was supported by the National Natural Science Foundation of China (grant number 81672387 and 81770899). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: Informed consents were signed by those patients and healthy donors before sample collection. All works were approved by the ethics review board of Renmin Hospital of Wuhan University and carried out in compliance with the Declaration of Helsinki of the World Medical Association.

Background Wingless and Int-related protein (Wnt) ligands are aberrantly expressed in patients with colorectal cancer (CRC). However, the aberrant level of Wnt ligands in serum have not been explored. Here, we aimed to identify the levels of WNT4 in serum and explored its oncogenic role in CRC. Methods The Oncomine database was used to analyze the relationship between WNT4 and the prognosis of CRC. ELISA was performed to measure WNT4 levels in serum and conditioned medium from fresh CRC tissues and adjacent normal tissues. Western blot and immunohistochemistry were carried out to measure the expression of WNT4 in human CRC tissues and adjacent normal tissues. The migration and invasion of CRC cells were determined by trans-well assay, and the effects of WNT4 on CRC invasion and metastasis in vivo were verified by tumor xenograft in nude mice. Cancer-associated fibroblasts (CAFs) and angiogenesis in subcutaneous nodules were detected by immunofluorescence (IF). In addition, the suspended spheres formation and tube formation assay were performed to explore the effects of WNT4 on CAFs and angiogenesis respectively. Results WNT4 was significantly upregulated in serum of CRC patients, and CRC tissues were identified as an important source of elevated WNT4 levels in CRC patients. Interestingly, elevated levels of WNT4 in serum were downregulated after tumor resection. Furthermore, we found that WNT4 contributed to epithelial-to-mesenchymal transition (EMT) and activated fibroblasts by activating the WNT4/β-catenin pathway in vitro and in vivo. Moreover, angiogenesis was induced via the WNT4/β-catenin/Ang2 pathway. Those effects could be reversed by ICG-001, a β-catenin/TCF inhibitor. Conclusion Our findings indicated that serum levels of WNT4 may be a potential biomarker for CRC. WNT4 secreted by colorectal cancer tissues promote the progression of CRC by inducing EMT, activate fibroblasts and promote angiogenesis through the canonical Wnt/β-catenin signalling pathway.

Purpose: To explore the efficacy of concomitant chemotherapy in intensity-modulated radiotherapy (IMRT) to treat stage II nasopharyngeal carcinoma (NPC). Methods and Materials: In this randomized phase 2 study [registered with ClinicalTrials.gov (NCT01187238)], eligible patients with stage II (2010 UICC/AJCC) NPC were randomly assigned to either IMRT alone (RT group) or IMRT combined with concurrent cisplatin (40 mg/m2, weekly) (CCRT group). The primary endpoint was overall survival (OS). The second endpoints included local failure-free survival (LFFS), regional failure-free survival (RFFS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and acute toxicities. Results: Between May 2010 to July 2012, 84 patients who met the criteria were randomized to the RT group (n = 43) or the CCRT group (n = 41). The median follow-up time was 75 months. The OS, LFFS, RFFS, DFS, and DMFS for the RT group and CCRT group were 100% vs. 94.0% (p = 0.25), 93.0% vs. 89.3% (p = 0.79), 97.7% vs. 95.1% (p = 0.54), 90.4% vs. 86.6% (p = 0.72), and 95.2% vs. 94.5% (p = 0.77), respectively. A total of 14 patients experienced disease failure, 7 patients in each group. The incidence of grade 2 to 4 leukopenia was higher in the CCRT group (p = 0.022). No significant differences in liver, renal, skin, or mucosal toxicity was observed between the two groups. Conclusion: For patients with stage II NPC, concomitant chemotherapy with IMRT did not improve survival or disease control but had a detrimental effect on bone marrow function.

We read with interest the study by Lei and colleagues on the association between markers of liver injury and mortality in coronavirus disease 2019 (COVID‐19) in China. The authors have painstakingly collated data from a large number of COVID‐19 patients from multiple centers across Wuhan. They found that an increase in aspartate aminotransferase (AST) and its dynamicity correlated with COVID‐19‐related liver injury and patient outcomes. They concluded that the dynamic patterns of liver injury indicators, represented by AST, correspond with COVID‐19‐related liver injury.

To study the growth inhibition and cell cycle changes in nasopharyngeal carcinoma (CNE1) cells after transfection with p53 gene. A mixture of nano-liposomes and plasmid containing p53 was used for transfecting CNE1 cells. Cellular apoptosis was examined after transfection using the CCK-8 reagent method with flow cytometry. The results showed that a ratio of nanoliposome/p-ORF-GFP of 3.5:1 showed the highest transfection efficiency in CNE1 cells. The cells transfected with a mixture of composites in this proportion showed significant apoptosis of up to 50–70%. In addition, we observed that cell cycle changes-measured using flow cytometry-as well as cellular apoptosis were accelerated after administration of composites. The CCK-8 kit was used to determine the viability of nano-liposome-encapsulated p53 transfected cells. In vitro experiments showed that the combination significantly inhibited the growth of CNE1 cells with an inhibition rate of approximately 63.8%. Therefore, the nanocomposites have a significant effect on inhibiting the growth of CNE1 cells. Through the investigation of apoptosis and cell cycle changes in CNE1 cells we found that the nanoliposome-encapsulated p53 gene can inhibit growth in these cells, and might therefore serve as a novel treatment strategy for adjuvant treatment of nasopharyngeal carcinoma and ca also reduce incompatibility issues with radiotherapy and chemotherapy. This method can also provide technical and theoretical support for the development of novel drugs.

Several hyperbranched polysilicon (HBPS) materials with different end group modifications were designed and synthesized and the structures were characterized. The modified HBPS polymers were applied to the adsorption of benzoylurea insecticides (BUs). The binding mode and binding energy between the HBPS and BUs were quantified and the results of an adsorption kinetics study and an adsorption thermodynamics experiment were verified by calculation and mutual verification. The adsorption mechanism of BUs onto HBPS was also discussed. The theoretical results show that the most effective way to combine the adsorbent and BUs is via hydrogen bonding when the end group is an amino group. Moreover, the most effective combination when the end group is β-cyclodextrin is the interaction of the BUs with the interior of the cavity to form a host–guest coating. The theoretical results of other end group-modified HBPS materials were also obtained and verified by adsorption experiments. In this work, an experimental method for obtaining the binding mode by theoretical calculations and then verifying it according to adsorption experiments was established.

Objective This study is aimed to evaluate the long-term outcomes and management approaches in different histological subtypes of primary nasopharyngeal adenocarcinoma (NPAC). Materials and methods 71 patients with NPAC at our institution between 1984 and 2016 were reviewed, including adenoid cystic carcinoma (ACC) in 43 patients, mucoepidermoid carcinoma (MEC) in 17 patients, and primary traditional adenocarcinoma (AC) in 11 patients. 37 patients received primary radiotherapy and 34 patients underwent primary surgery. Results The median time of follow-up was 77 months. The 5-year overall survival rate (OS), locoregional failure-free survival rate (LRFFS) and distant metastasis failure-free survival rate (DFFS) were 69.9%, 67.1% and 77.9%, respectively. Patients who received combined modality therapy had better 5-year OS (73.7% vs 66.2%, p = 0.065) and LRFFS (73.1% vs 64.5%, p = 0.047) than patients receiving single modality therapy. Regarding the different histological subtypes, the survival rates of patients with ACC undergoing primary radiotherapy and primary surgery were similar (5-year OS 82.3% vs 68.8%, LRFFS 70.0% vs 70.8%, p＞0.05). As to patients with MEC and AC, those who underwent primary surgery achieved better 5-year OS (75.6% vs 45.5%, p = 0.001) and LRFFS (70.6%% vs 57.1%, p = 0.014) than those who received primary radiotherapy. Multivariate analyses indicated that histological subtypes and radiotherapy technique were independent factors for OS. Conclusions The optimal treatment policy for NPAC remained the combination of radiotherapy and surgery. For patients with ACC, radiotherapy could be considered as the primary treatment. Surgery was suggested to be the primary treatment in patients with MEC and AC.

Objective To investigate the prevalence and distribution of cervical lymph node metastasis (LNM) in locally advanced supraglottic squamous cell carcinoma (LASCC) and guide the delineation of clinical lymph node target volumes. Materials and methods We reviewed patients defined as LASCC from January 2000 to December 2017 in our hospital. The primary tumor was operated on using partial or total laryngectomy, and all patients underwent bilateral neck dissection (levels II-IV at least). Univariate and multivariate logistic regressions were used to find risk factors associated with LNM. Results A total of 206 patients were enrolled. In the whole group, the rate of ipsilateral metastasis (IM) was 60.9% (67 patients), whereas contralateral metastasis was 25.5% (28 patients). Only positive ipsilateral lymph nodes contributed to contralateral metastasis (p = 0.001). Seventy-six cases were diagnosed with clinical positive lymph nodes (cN+). IM of primary lesions mainly located within the unilateral sites (n = 49 patients) was detected in levels II, III, and IV with lymph node metastasis ratios of 73.5% (36 patients), 63.3% (31 patients), and 20.4% (10 patients), respectively, and contralateral metastasis of 36.7% (18 patients), 16.3% (8 patients), and 6.1% (3 patients), respectively. Involvement of level II or III was associated with metastasis of level IV. No one developed contralateral level IV involvement without metastasis of contralateral levels II and III. A total of 130 cases had clinically negative neck lymph nodes (cN0). The prevalence of occult metastasis (OM) was 35.4%. Among 62 patients with unilateral lesions, the rates of OM to ipsilateral neck levels II, III, and IV were 21, 11.1, and 1.6%, respectively, whereas contralateral neck levels were 6.3, 4.8, and 0%, respectively. In terms of the risk factors, histopathological differentiation was related to OM (p = 0.003). Two of 25 people were with level VIb metastasis, and both of them were with subglottic involvement. Conclusion Neck levels II to IV are most frequently involved and should be included in clinical target volume (CTV) in cN+ patients. Contralateral IV may be omitted when contralateral levels II and III are negative. In cN0 patients, ipsilateral levels II and III are suggested to be included in the CTV, whereas whether contralateral levels II and III should be included needs further research.

Background. In patients with gastric cancer (GC), peritoneal metastasis is an indication of the end stage and often indicates a poor outcome. The diagnosis of peritoneal metastasis, especially occult peritoneal metastasis (OPM), remains a challenge for surgeons. This study was designed to explore the relationship between OPM and clinicopathological characteristics and preoperative hematological parameters in patients with GC and to develop a nomogram to predict the probability of OPM before surgery. Methods. A total of 672 patients with GC from our center were included, including 583 OPM-negative and 89 OPM-positive patients. These patients were divided into training and validation groups based on when they received treatment. OPM was diagnosed during surgery in patients without any signs of metastasis through imaging examination. Predictive factors were screened by least absolute shrinkage and selection operator logistic regression of all 18 characteristics. The nomogram of OPM was constructed based on these filtered variables. The discriminative and calibration performance of the model were simultaneously evaluated. Results. A total of six variables, including tumor size, degree of differentiation, depth of invasion, Glasgow prognosis score, and plasma levels of CA125 and fibrinogen, were selected for integration into the final predictive nomogram. The area under curve (AUC) of the nomogram with six factors was 0.906 (95% confidence interval (CI): 0.872-0.941) and 0.889 (95% CI: 0.795-0.984) in the training and validation groups, respectively. Calibration plots of the nomogram in the two sets revealed a good consistency between predicted and actual probabilities. Decision curve analysis showed that the nomogram had a positive net benefit among all threshold probabilities between 0% and 82%. This nomogram was superior to models incorporating only clinicopathologic or hematologic features. Conclusion. Both clinicopathological and preoperative hematological parameters are significantly associated with OPM. The nomogram constructed with six factors could be used to calculate the probability of OPM and identify the high-risk population in GC. This may be helpful for early detection of OPM in patients with GC.

Background Posterior percutaneous endoscopic cervical foraminotomy and diskectomy has remarkably evolved with successful results. Although percutaneous endoscopic cervical diskectomy (PECD) has gained popularity, the risk of surgical failure may be a major obstacle to performing PECD. We analyzed unsuccessful cases requiring reoperation. The objective of this article was to find common causes of surgical failure and elucidate the limitations of the conventional PECD technique. Methods Surgery-related complications were reviewed from the initial 252 cases of a single surgeon. The patients had cervical disk herniation or radiculopathy and underwent percutaneous endoscopic surgical management. We investigated clinical outcomes and complications. A retrospective review was performed on all patients who had undergone PECD between April 2013 and April 2016. Unsuccessful PECD was defined as a case requiring reoperation within 6 weeks after primary surgery. Chart review was done, and pre-, intra-, and postoperative radiographic reviews were performed. All unsuccessful PECD cases were classified according to the type of herniated disc, location of herniation, extruded disk migration, working channel position, and intra- and postoperative findings. Results The mean operative time was 89.4 minutes (range, 60–180 minutes). The mean intraoperative blood loss was 20.3 mL (range, 10–800 mL). Cerebrospinal fluid leakage occurred in 1 patient and healed well. The follow-up period ranged from 24 to 60 months. The mean score on the visual analog scale improved from 8.67 ± 1.30 preoperatively to 7.83 ± 1.40 at 1 month postoperatively to 1.67 ± 1.30 at the final follow-up (P Conclusions Surgeons should be aware of the specific complications for the PECD approach.

Our previous work demonstrated the good biocompatibility and bactericidal activity of a plasma-sprayed Zn and Ag co-incorporated calcium silicate ceramic coating (Ag-Ca2ZnSi2O7), namely Ag-HT. In this work, we evaluated the influence of the surface roughness of Ag-HT coatings for Escherichia coli adhesion behavior, considering that surface topography is an important factor that regulates bacterial responses to biomaterials. Surface characteristics of as-sprayed and satin-finished Ag-HT coatings were investigated by scanning electron microscopy and measured using a surface roughness tester. Bacterial adhesion experiments showed that the number of viable E. coli cells on the as-sprayed or satin-finished coating surfaces was substantially lower than on the Ti-6Al-4V control surface, which can be explained by the antimicrobial effect of Ag and/or Zn. Moreover, the density of E. coli on the as-sprayed Ag-HT coating was considerably lower than on the satin-finished derivative. We attribute this difference to the fact that the as-sprayed coating surface was relatively smooth at a scale comparable to the size of an individual bacterium, while the satin-finished surface was slightly rough at this length scale and thus favored bacterial adhesion.

As one of effective technologies, tailor welded blank (TWB) has been extensively applied to improve structural performance and efficiency of material usage for lightweight automobile. The vehicle door is an important part of structure that presents many design requirements including stiffness, natural frequency, etc. However, finding an optimal layout of the multi-material TWB welding lines of a vehicle door remains fairly challenging through conventional design methods. This study proposed a multi-objective topology optimization method for this purpose. The compromise programming approach (CAP) coupled with the mean frequency method (MFM) is introduced to handle the multi-objective optimization involving stiffness and natural frequency criteria for multiple load cases. The multi-objective problems are then solved by the extended bi-directional evolutionary structural optimization (BESO) method. The design examples demonstrate that the proposed approach is suitable for the multi-objective and multi-material topology optimization (MMTO) of TWB indoor panel. The study also provides the design guidance for lightweight and multi-material structures with the TWB technology.

Multiple myeloma (MM) is an incurable hematologic malignancy due to inevitable relapse and chemoresistance development. Our preliminary data show that MM cells express high levels of PGC1β and LDHA. In this study, we investigated the mechanism behind PGC1β‐mediated LDHA expression and its contribution to tumorigenesis, to aid in the development of novel therapeutic approaches for MM. Real‐time PCR and western blotting were first used to evaluate gene expression of PGC1β and LDHA in different MM cells, and then, luciferase reporter assay, chromatin immunoprecipitation, LDHA deletion report vectors, and siRNA techniques were used to investigate the mechanism underlying PGC1β‐induced LDHA expression. Furthermore, knockdown cell lines and lines stably overexpressing PGC1β or LDHA lentivirus were established to evaluate in vitro glycolysis metabolism, mitochondrial function, reactive oxygen species (ROS) formation, and cell proliferation. In addition, in vivo xenograft tumor development studies were performed to investigate the effect of PGC1β or LDHA expression on tumor growth and mouse survival. We found that PGC1β and LDHA are highly expressed in different MM cells and LDHA is upregulated by PGC1β through the PGC1β/RXRβ axis acting on the LDHA promoter. Overexpression of PGC1β or LDHA significantly potentiated glycolysis metabolism with increased cell proliferation and tumor growth. On the other hand, knockdown of PGC1β or LDHA largely suppressed glycolysis metabolism with increased ROS formation and apoptosis rate, in addition to suppressing tumor growth and enhancing mouse survival. This is the first time the mechanism underlying PGC1β‐mediated LDHA expression in multiple myeloma has been identified. We conclude that PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism. Targeting the PGC1β/LDHA pathway may be a novel therapeutic strategy for multiple myeloma treatment.

Background The phosphoglucomutase 1 (PGM1) enzyme plays a central role in glucose homeostasis by catalyzing the inter-conversion of glucose 1-phosphate and glucose 6-phosphate. Recently, PGM1 deficiency has been recognized as a cause of the congenital disorders of glycosylation (CDGs). Methods Two Chinese Han pediatric patients with recurrent hypoglycemia, hepatopathy and growth retardation are described in this study. Targeted gene sequencing (TGS) was performed to screen for causal genetic variants in the genome of the patients and their parents to determine the genetic basis of the phenotype. Results DNA sequencing identified three variations of the PGM1 gene (NM_002633.2). Patient 1 had a novel homozygous mutation (c.119delT, p.Ile40Thrfs*28). In patient 2, we found a compound heterozygous mutation of c.1172G>T(p.Gly391Val) (novel) and c.1507C>T(p.Arg503*) (known pathogenic). Conclusions This report deepens our understanding of the clinical features of PGM1 mutation. The early molecular genetic analysis and multisystem assessment were here found to be essential to the diagnosis of PGM1-CDG and the provision of timely and proper treatment.

Spatiotemporal variations in internal solitary wave (ISW) polarity over the continental shelf of the northern South China Sea (SCS) were examined based on mooring-array observations from October 2013 to June 2014. Depression ISWs were observed at the easternmost mooring, where the water depth is 323 m. Then, they evolved into elevation ISWs at the westernmost mooring, with a depth of 149 m. At the central mooring, with a depth of 250 m, the ISWs generally appeared as depression waves in autumn and spring but were elevation waves in winter. Seasonal variations in stratification caused this seasonality in polarity. On the intraseasonal time scales, anticyclonic eddies can modulate ISW polarity at the central mooring by deepening the thermocline depth for periods of approximately 8 days. During some days in autumn and spring, depression ISWs and ISWs in the process of changing polarity from depression to elevation appeared at time intervals of 10–12 h because of the thermocline deepening caused by internal tides. Isotherm anomalies associated with eddies and internal tides have a more significant contribution to determining the polarity of ISWs than do the background currents. The observational results reported here highlight the impact of multiscale processes on the evolution of ISWs.

Spinal disk herniation can induce radicular pain through chemical irritation caused by proinflammatory and immune responses. Bone marrow mesenchymal stem cells (BMSCs) are a unique type of adult stem cell with the functions of suppressing inflammation and modulating immune responses. This study was undertaken to observe the effect of intrathecal BMSCs on the treatment of mechanical allodynia and the suppression of microglial activation in a rat noncompressive disk herniation model. The model was induced by the application of nucleus pulposus (NP) to the L5 dorsal root ganglion (DRG). The study found that the use of NP in the DRG can induce abnormal mechanical pain, increase the contents of the proinflammatory factors TNF-α and IL-1β, decrease the content of the anti-inflammatory cytokine TGF-β1 and activate microglia in the spinal dorsal horns (L5) (P

Key points T-wave alternans (TWA) and T-wave lability (TWL) are precursors of ventricular arrhythmias in long QT syndrome; however, the mechanistic link remains to be clarified. Computer simulations show that action potential duration (APD) prolongation and slowed heart rates promote APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos can exacerbate pre-existing or induce de novo APD dispersion, which combines with enhanced ICa,L to result in premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs can directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or further exacerbate the APD dispersion to cause spontaneous initiation of ventricular arrhythmias. Experiments conducted in transgenic long QT rabbits show that PVC alternans occurs at slow heart rates, preceding spontaneous intuition of ventricular arrhythmias. Abstract T-wave alternans (TWA) and irregular beat-to-beat T-wave variability or T-wave lability (TWL), the ECG manifestations of action potential duration (APD) alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization-mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre-existing APD dispersion and, in addition, APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced ICa,L , resulted in a tissue-scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate-induced PVC alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions.

The present study investigated the concentrations of residues of four groups of pesticides in the People's Republic of China: organophosphorus, carbamate, pyrethroid, and triazine pesticides. Twenty-six pesticides were examined using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry in 2,169 samples of 12 typical vegetables collected from 15 provinces in China. The results showed that 908 (41.9%) samples were positive, with 133 (6.1%) samples exceeding the limit legal in China. Leafy vegetables showed higher positive rates than fruits and root vegetables. Organophosphorus, carbamate, pyrethroid, and triazine pesticides were found in 11.8, 7.7, 13.9, and 10.9% of the samples, respectively, which provided important information on current concentrations of cumulative assessment group pesticide residues for vegetables in China. Of the positive samples, a slight violation rate of 1.9% for the organophosphorus pesticide category exceeded China's maximum residue limits. Positive rates for chlorpyrifos in celery, pak-choi, and leeks were higher, but fewer exceeded China's maximum residue limits.

Selenium (Se) is an essential trace element with strong antioxidant activity, showing a great prospect in the treatment of spinal cord injury (SCI). However, the narrow gap between the beneficial and toxic effects has limited its further clinical application. In this experiment, we used porous Se@SiO2 nanocomposites (Se@SiO2) modified by nanotechnology as a new means of release control to investigate the anti-oxidative effect in SCI. In vitro Se@SiO2 toxicity, anti-oxidative and anti-inflammatory effects on microglia were assayed. In vivo we investigated the protective effect of Se@SiO2 to SCI rats. Neurological function was evaluated by Basso, Beattie and Bresnahan (BBB). The histopathological analysis, microglia activation, oxidative stress, inflammatory factors (TNF-α, IL-1β and IL-6) and apoptosis were detected at 3 and 14 days after SCI. The favorable biocompatibility of Se@SiO2 suppressed microglia activation, which is known to be associated with oxidative stress and inflammation in vivo and in vitro. In addition, Se@SiO2 improved the rat neurological function and reduced apoptosis via caspase-3, Bax and Bcl-2 pathways in SCI. Se@SiO2 was able to treat SCI and reduce oxidative stress, inflammation and apoptosis induced by microglia activation, which may provide a novel and safe strategy for clinical application.

A pretreatment method using hyperbranched polyester (HBPE) composite as sorbent based on dispersive micro-solid-phase (d-μ-SPE) extraction preceding high-performance liquid chromatography analysis was developed for the determination of benzoylurea insecticides (BUs) in water samples. Parameters that may influence the extraction efficiency, such as the diameter and the amount of the sorbent, extraction and desorption time and the pH value of the solution, were investigated and optimized using batch and column procedures. Under optimized conditions, good linearity was obtained for all of the tested compounds, with r values of at least 0.9924. The linearity of the method was determined in the range of 1–25 000 μg L−1. The limits of detection (LODs) ranged from 0.024 to 0.068 μg L−1. The recoveries of the four benzoylurea insecticides in water samples increased from 85.50–96.12%. The results confirmed the possibility of using hyperbranched polyester in the determination of relatively hydrophobic trace pesticides residues. Finally, the proposed method was applied to the determination of BUs in water samples with satisfactory results.

Epstein-Barr virus (EBV) has widely infected more than 90% of human populations. Currently, there is no efficient way to remove the virus because the EBV carriers are usually in a latent stage that allows them to escape the immune system and common antiviral drugs. In the effort to develop an efficient strategy for the removal of the EBV virus, we have shown that betulinic acid (BA) slightly suppresses EBV replication through SOD2 suppression with subsequent reactive oxygen species (ROS) generation and DNA damage in EBV-transformed LCL (lymphoblastoid cell line) cells. Chidamide (CDM, CS055), a novel histone deacetylase inhibitor (HDACi), could significantly switch EBV from the latent stage to the lytic stage with increased gene expression of BZLF1 and BMRF1, but has a small effect on EBV replication due to the suppression effect of CDM-mediated ROS generation. Interestingly, a combination of BA and CDM synergistically inhibits EBV replication with ROS over-generation and subsequent DNA damage and apoptosis. Overexpression of SOD2 diminishes this effect, while SOD2 knockdown mimics this effect. An in vivo xenograft tumor development study with the tail vein injection of EBV-transformed LCL cells in nude mice proves that the combination of BA and CDM synergistically increases superoxide anion release in tumor tissues and suppresses EBV replication and tumor growth, and significantly prolongs mouse survival. We conclude that the combination of BA and CDM could be an efficient strategy for clinical EBV removal.