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Abstract Background Subarachnoid hemorrhage (SAH) is a subtype of hemorrhagic stroke characterized by high mortality and low rates of full recovery. This study aimed to investigate the epidemiological characteristics of SAH between 1990 and 2021. Methods Data on SAH incidence, mortality, and disability-adjusted life-years (DALYs) from 1990 to 2021 were obtained from the Global Burden of Disease Study (GBD) 2021. Estimated annual percentage changes (EAPCs) were calculated to evaluate changes in the age-standardized rate (ASR) of incidence and mortality, as well as trends in SAH burden. The relationship between disease burden and sociodemographic index (SDI) was also analyzed. Results In 2021, the incidence of SAH was found to be 37.09% higher than that in 1990; however, the age-standardized incidence rates (ASIRs) showed a decreased [EAPC: -1.52; 95% uncertainty interval (UI) -1.66 to -1.37]. Furthermore, both the number and rates of deaths and DALYs decreased over time. It was observed that females had lower rates compared to males. Among all regions, the high-income Asia Pacific region exhibited the highest ASIR (14.09/100,000; 95% UI 12.30/100,000 − 16.39/100,000) in 2021, with an EPAC for ASIR

Abstract Background This study aimed to assess the public knowledge regarding Alzheimer’s Disease (AD) in Zhuhai, China, focusing on identifying knowledge gaps and the influence of demographic and health factors. Methods A cross-sectional study was conducted in Zhuhai, China, from October to November 2022. A total of 1986 residents from 18 communities were selected employing stratified multi-stage equi-proportional sampling. Questionnaires covering general information and the Alzheimer’s Disease Knowledge Scale (ADKS) were investigated face-to-face. Ordinal multiclass logistic regression was applied to assess the relationship between AD awareness and demographic and health characteristics. Results The average ADKS score was 18.5 (SD = 3.36) in Zhuhai. The lowest awareness rates were observed in the “Symptoms” and “Caregiving” subdomains of ADKS, with rates of 51.01% and 43.78%, respectively. The correct rates for the 30 ADKS questions ranged from 16.62 to 92.6%, showing a bimodal pattern with clusters around 80% and 20%. Women (OR = 1.203, 95% CI: 1.009–1.435), individuals aged 60 years or older (OR = 2.073, 95% CI: 1.467–2.932), those living in urban areas (OR = 1.361, 95% CI: 1.117–1.662), higher average monthly household income per capita (OR = 1.641, 95% CI: 1.297–2.082), and without any neurological or mental disorders (OR = 1.810, 95% CI: 1.323–2.478) were more likely to have higher levels of awareness about Alzheimer’s disease. Conclusions Adults in Zhuhai show a limited knowledge of AD, particularly in the ‘Symptoms’ and ‘Caregiving’ subdomains. Upcoming health campaigns must focus on bridging the knowledge gaps in different subdomains of AD, especially among subgroups with lower awareness, as identified in our study.

Abstract Gas hydrates provide alternative solutions for gas storage & transportation and gas separation. However, slow formation rate of clathrate hydrate has hindered their commercial development. Here we report a form of porous ice containing an unfrozen solution layer of sodium dodecyl sulfate, here named active ice, which can significantly accelerate gas hydrate formation while generating little heat. It can be readily produced via forming gas hydrates with water containing very low dosage (0.06 wt% or 600 ppm) of surfactant like sodium dodecyl sulfate and dissociating it below the ice point, or by simply mixing ice powder or natural snow with the surfactant. We prove that the active ice can rapidly store gas with high storage capacity up to 185 V g V w −1 with heat release of ~18 kJ mol−1 CH4 and the active ice can be easily regenerated by depressurization below the ice point. The active ice undergoes cyclic ice−hydrate−ice phase changes during gas uptake/release, thus removing most critical drawbacks of hydrate-based technologies. Our work provides a green and economic approach to gas storage and gas separation and paves the way to industrial application of hydrate-based technologies.

In the face of the unprecedented public health crisis caused by the novel coronavirus pneumonia epidemic, front-line health workers are under enormous mental pressure. This paper aims to explore the mental health challenges faced by front-line health workers in the early stages of a public health emergency, such as stress, anxiety, and depression. At the same time, the factors that increase their mental stress are analyzed, and practical measures are put forward to prevent and manage mental health problems, aiming at improving the quality of medical treatment during public health emergencies. This paper has some reference value for people engaged in mental health prevention.

As one of the concrete admixtures, water reducing admixtures and superplasticizers are usually used to reduce the mixing water volume and improve the performance of the harden concrete while maintaining better workability of the fresh concrete. However, the concrete strength and durability properties are affected differently by different types and dosages of the water reducing admixtures and superplasticizers. Based on the published literatures, this paper comprehensively reviews and analyzes this problem. Different types of the concretes, including ordinary Portland cement concrete, ordinary Portland cement concrete containing pozzolan, fly ash and ground granulated blast furnace slag, calcium sulfoaluminate cement concrete, ferrite aluminate cement concrete, recycled aggregates concrete, lightweight aggregate concrete, self-compacting concrete and ultra-high performance concrete, are considered to discuss the influence of types and dosages of the water reducing admixtures and superplasticizers on their strengths. Water absorption, frost resistance and permeability resistance of the concrete are mainly reviewed to discuss this influence on the durability properties of the concrete. Then, some suggestions on the application of the water reducing admixtures and superplasticizers in reinforced concrete structures and projects are proposed.

Inversion tillage with straw amendment is widely applied in northeastern China, and it can substantially increase the storage of carbon and improve multiple subsoil functions. Soil microorganisms are believed to be the key to this process, but research into their role in subsoil amelioration is limited. Therefore, a field experiment was conducted in 2018 in a region in northeastern China with Hapli-Udic Cambisol using four treatments: conventional tillage (CT, tillage to a depth of 15 cm with no straw incorporation), straw incorporation with conventional tillage (SCT, tillage to a depth of 15 cm), inversion tillage (IT, tillage to a depth of 35 cm) and straw incorporation with inversion tillage (SIT, tillage to a depth of 35 cm). The soils were managed by inversion to a depth of 15 or 35 cm every year after harvest. The results indicated that SIT improved soil multi-nutrient cycling variables and increased the availability of key nutrients such as soil organic carbon, total nitrogen, available nitrogen, available phosphorus and available potassium in both the topsoil and subsoil. In contrast to CT and SCT, SIT created a looser microbial network structure but with highly centralized clusters by reducing the topological properties of average connectivity and node number, and by increasing the average path length and the modularity. A Random Forest analysis found that the average path length and the clustering coefficient were the main determinants of soil multi-nutrient cycling. These findings suggested that SIT can be an effective option for improving soil multi-nutrient cycling and the structure of microbial networks, and they provide crucial information about the microbial strategies that drive the decomposition of straw in Hapli-Udic Cambisol.

Abstract This study focuses on the prevalence and characteristics of anxiety in patients with pulmonary nodules that was assessed by Hamilton Anxiety Scale (HAMA) scores. A total of 890 patients were enrolled in this study, including incidence of absence of anxiety n = 343 (38.54%), mild or probable anxiety n = 459 (51.57%) and moderate or definite anxiety n = 79 (8.88%) and obvious anxiety n = 9 (1.01%), respectively. According to the definition of anxiety, 88 (9.89%) patients were enrolled in anxiety group. The incidence of anxiety in females was significantly higher than male (11.98% vs. 7.20%, p = 0.018), patients with respiratory symptoms were significantly higher than without respiratory symptoms (13.33% vs. 8.50%, p = 0.029) and diameter of pulmonary nodules >8 mm is significantly higher than ≤8 mm (13.35% vs. 7.10%, p = 0.002). Regression analysis showed that female (OR = 0.548, 95% CI: 0.340–0.884), family history of malignant tumour (OR = 1.691, 95% CI: 1.067–2.678), respiratory symptoms (OR = 1.713, 95% CI: 1.073–2.733) and diameter >8 mm (OR = 2.135, 95% CI: 1.350–3.375) were independent risk factors of anxiety. Further analysis of 88 patients with anxiety showed the sum of psychic anxiety was significantly higher than somatic anxiety (16.66 ± 2.46 vs. 0.97 ± 1.10, p

BackgroundWith the improvement of immunosuppressive regimens, the success rate and availability of ABO-incompatible (ABO-i) kidney transplantation (KT) have gradually increased. However, the management of immunosuppression protocols and complications associated with ABO-i KT is complex. Here, we report a clinical case of ABO-i living donor KT with allograft dysfunction caused by acute blood group antibody-dependent rejection triggered by human parvovirus B19 (B19V).Case reportThe ABO blood group of the recipient was O, and that of the donor was B. The recipient had high baseline anti-B antibody titers (IgM, 1:1024; IgG, 1:64). Before transplantation, he completed a desensitization protocol comprising plasma exchange, double-filtration plasmapheresis, and rituximab, which maintained a low blood group antibody level and resulted in successful transplantation. Two weeks after surgery, the recipient developed a B19V infection combined with acute T-cell-mediated rejection. After the anti-rejection regimen, acute rejection (AR) was successfully reversed, but B19V persisted. One week after AR stabilization, the patient experienced acute antibody-mediated rejection that was more severe and refractory, resulting in the loss of the transplanted kidney.ConclusionDesensitization combined with immunosuppressants can lead to overimmunosuppression and cause various infections. Infections could break the accommodation state of the patient, thereby inducing AR and resulting in the loss of the transplanted kidney.

Abstract Background Awake craniotomy (AC) has become gold standard in surgical resection of gliomas located in eloquent areas. The conscious sedation techniques in AC include both monitored anesthesia care (MAC) and asleep-awake-asleep (AAA). The choice of optimal anesthetic method depends on the preferences of the surgical team (mainly anesthesiologist and neurosurgeon). The aim of this study was to compare the difference in physiological and blood gas data, dosage of different drugs, the probability of switching to endotracheal intubation, and extent of tumor resection and dysfunction after operation between AAA and MAC anesthetic management for resection of gliomas in eloquent brain areas. Methods Two-hundred and twenty-five patients with super-tentorial tumor located in eloquent areas underwent AC from 2009 to 2021 in Xijing Hospital. Forty-one patients underwent AAA technique, and the rest one-hundred eighty-four patients underwent MAC technique. Anesthetic management, dosage of different drugs, intraoperative complications, postoperative outcomes, adverse events, extent of resection and motor, and sensory and language dysfunction after operation were compared between MAC and AAA. Result There was no significant difference in gender, KPS score, MMSE score, glioma grade, type, and growth site between the patients in the two groups, except the older age of patients in MAC group than that in AAA group. During the whole process of operation, there were greater pulse pressure difference (P = 0.046), shorter operation time (P = 0.039), less dosage of remifentanil (P = 0.000), more dosage of dexmedetomidine (P = 0.013), more use of antiemetics (81%, P = 0.0067), lower use of vasoactive agent (45.1%, P = 0.010), and lower probability of conversion to general anesthesia (GA, P = 0.027) in MAC group than that in AAA group. Blood gas analysis showed that PetCO2 (P = 0.000), Glu concentration (P = 0.000), and PaCO2 (P = 0.000) were higher, but SPO2 (P = 0.002) and PaO2 (P = 0.000) were lower in MAC group than that in AAA group. In the postoperative recovery stage, compared with that of AAA group, the probability of dysfunction in MAC group at 1, 3, 5, and 7 days after operation was lower, which were 27.8% vs 53.6% (P = 0.003), 31% vs 68.3% (P = 0.000), 28.8% vs 63.4% (P = 0.000), and 25.6% vs 58.5% (P = 0.000), respectively. Conclusion Compared with AAA, it seems that MAC has more advantages in the management for resection of gliomas in eloquent brain areas, and MAC combined with multiple monitoring such as cerebral cortical mapping, neuronavigation, and ultrasonic detection is worthy of popularization for the resection of gliomas in eloquent brain areas.

Objectives: To explore the utilization, barriers, and factors associated with the targeted treatment of Chinese metastatic colorectal cancer (mCRC) patients.Methods: A total of 1,688 mCRC patients from 19 hospitals in 14 cities were enrolled from March 2020 to March 2021 using stratified, multistage cluster sampling. The use of targeted therapy and any barriers patients experienced were collected. Logistic regression analyses were conducted to identify the factors associated with initiating targeted treatment.Results: About 51.6% of the patients initiated targeted therapy, of whom 44.5%, 20.2%, and 35.2% started first-, second-, and third-line treatment, respectively. The most reported barriers were high medical costs and a lack of belief in the efficacy of targeted therapy. Patients treated in the general hospital, diagnosed at an older age, less educated, and who had a lower family income, no medical insurance, poor health-related quality of life, metastasis outside the liver/lung or systemic metastasis, a shorter duration of mCRC were less likely to initiate targeted therapy.Conclusion: Reduced medical costs and interventional education to improve public awareness could facilitate the use of targeted treatment for mCRC.

IntroductionThis cross-sectional study evaluated the involvement of patients with advanced colorectal cancer (CRC) in treatment decision-making, assessed the treatment efficacy according to their self-reports, and investigated the influencing factors.MethodsPatients with advanced CRC were recruited from 19 hospitals from March 2020 to March 2021 by a multi-stage multi-level sampling method. A self-designed questionnaire was used to collect demographic and clinical characteristics, involvement of CRC patients in treatment decision-making, treatment methods, and self-reported efficacy. Univariate and unordered multinomial logistic regression analyses were used to evaluate the factors affecting the involvement in treatment decision-making and self-reported efficacy.ResultsWe enrolled 4533 patients with advanced CRC. The average age at diagnosis was 58.7 ± 11.8 years. For the treatment method, 32.4% of patients received surgery combined with chemotherapy, 13.1% of patients underwent surgery combined with chemotherapy and targeted therapy, and 9.7% of patients were treated with surgery alone. For treatment decision-making, 7.0% of patients were solely responsible for decision-making, 47.0% of patients shared treatment decision-making with family members, 19.0% of patients had family members solely responsible for treatment decision-making, and 27.0% of patients had their physicians solely responsible for treatment decision-making. Gender, age, education level, family income, marital status, treatment cost, hospital type, and treatment method were significantly associated with the involvement of patients in treatment decision-making. A total of 3824 patients submitted self-reported efficacy evaluations during treatment. The percentage of patients with good self-reported efficacy was 76.5% (for patients treated for the first time), 61.7% (for patients treated for the second time), and 43.2% (for patients treated after recurrence and metastasis), respectively. Occupation, education level, average annual family income, place of residence, time since cancer diagnosis, hospital type, clinical stage, targeted therapy, and involvement in treatment decision-making were the main influencing factors of self-reported efficacy of treatment.DiscussionConclusively, CRC patients are not highly dominant in treatment decision-making and more likely to make treatment decisions with their family and doctors. Timely and effective communication between doctors and patients can bolster patient involvement in treatment decision-making.

ObjectiveThe aim of our study was to evaluate the prognostic value of gated SPECT MPI in non-obstructed coronary arteries (INOCA) patients, sought to stratify patients more accurately and thus derive more reliable prognostic information.Materials and methodsIn total, 167 patients with INOCA were enrolled. The patients were divided into two groups according to their SSS. Patients were followed-up regularly in terms of major adverse cardiovascular event (MACE), including cardiac death, nonfatal myocardial infarction, stroke, re-hospitalization with angina pectoris, and recurrent angina pectoris. Kaplan-Meier curves and Cox's proportional hazards models were used to analyze survival and identify predictive factors.ResultsAdverse cardiac events occurred in 33 cases (19.8%). The rate of MACE was higher in the summed stress score (SSS) ≥4 group than in the SSS 0–3 group (30.1% vs. 9.5%, respectively, P = 0.001) and MACE-free survival was lower (annual MACE-free rates of 87.5% vs. 96.2%, respectively, P = 0.003). Event-free survival was consistently higher in patients with normal arteries than in those with non-obstructive coronary artery disease (annual MACE-free rates of 96.1% and 88.4%, P = 0.035). When the SSS and the CAG results were combined, patients with normal coronary arteries (SSS 0–3) had the best prognosis and those with non-obstructive coronary artery stenosis (SSS ≥ 4) had the worst. However, the early prognosis of patients with non-obstructive coronary artery disease and SSS of 0–3 was comparable to that of patients with normal coronary arteries and SSS ≥ 4 (annual MACE-free rates of 100%, 94.6%, 93.1%, and 78.2%, respectively). Multivariate Cox's regression indicated that the SSS [hazard ratio (HR) = 1.126, 95% confidence interval (CI) 1.042–1.217, P = 0.003] and non-obstructive coronary artery disease (HR = 2.559, 95% CI 1.249–5.246, P = 0.01) were predictors of adverse cardiac events.ConclusionSPECT MPI data were prognostic for INOCA patients, thus identifying groups at high risk. The long-term predictive efficacy of such data exceeded that of CAG data. A combination of the two measures more accurately stratified INOCA patients in terms of risk.

Abstract Objective To analyze the clinicopathological characteristics of patients with papillary thyroid carcinoma (PTC) and its influence on the distribution of lymph node metastasis at each lateral level of the neck to guide precise treatment of the lateral area. Methods The clinicopathological data of patients with PTC initially diagnosed and treated at our hospital from February 2014 to September 2021 were collected; the metastatic status of each lateral level was recorded, and correlations were analyzed. Results A total of 203 patients were enrolled in this study. There were 67 males and 136 females, with an average age of 41.1 years. In the lateral cervical area, lymph node metastasis was found at level IIa in 81 patients (39.9%); level III, 171 patients (84.2%); level IV, 122 patients (60%); and level Vb, 18 patients (8.9%). Correlation analysis showed that age (r = 0.198, P

Abstract Mutations in the GJB2 gene (encoding Connexin26(Cx26)) are the most common cause of hereditary deafness, accounting for about a quarter of all cases. Sensory epithelial damage is considered to be one of the main causes of deafness caused by GJB2 gene mutation. Dexamethasone (DEX) is widely used in the treatment of a variety of inner ear diseases including sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), and deafness caused by ototoxic drugs. Whether DEX has a direct therapeutic effect on hereditary deafness, especially GJB2-related deafness, remains unclear. In this study, we revealed that DEX can effectively prevent hair cell death caused by oxidative stress in cochlear explants. Additionally, two distinct Cx26-null mouse models were established to investigate whether systemic administration of DEX alleviate the cochlear sensory epithelial injury or deafness in these models. In a specific longitudinally Cx26-null model that does not cause deafness, systemic administration of DEX prevents the degeneration of outer hair cells (OHCs) induced by Cx26 knockout. Similarly, in a targeted-Deiter’s cells (DCs) Cx26-null mouse model that causes deafness, treatment with DEX can almost completely prevent OHCs loss and alleviates auditory threshold shifts at some frequencies. Additionally, we observed that DEX inhibited the recruitment of CD45-positive cells in the targeted-DCs Cx26-null mice. Taken together, our results suggest that the protective effect of dexamethasone on cochlear sensory epithelial damage and partially rescue auditory function may be related to the regulation of inner ear immune response in Cx26 deficiency mouse models.

Abstract Background Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor‐1 (PD‐1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD‐1 inhibitor on the advanced HCC beyond oligometastasis. Methods In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD‐1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD‐1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression‐free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM). Results The 6‐, 12‐ and 24‐month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30–0.66; p < .001). The 6‐, 12‐ and 18‐month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33–0.63; p < .001) between the two collections. Conclusions Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD‐1 inhibitor led to significant improvements in survival.

Kai-Xin-San (KXS) is a Chinese medicine formulation that is commonly used to treat depression caused by dual deficiencies in the heart and spleen. Recent studies indicated that miRNAs were involved in the pathophysiology of depression. However, there have been few studies on the mechanism underlying the miRNAs directly mediating antidepressant at clinical level, especially in nature drugs and TCM compound. In this study, we identified circulating miRNAs defferentially expressed among the depression patients (DPs), DPs who underwent 8weeks of KXS treatment and health controls (HCs). A total of 45 miRNAs (17 were up-regulated and 28 were down-regulated) were significantly differentially expressed among three groups. Subsequently, qRT-PCR was used to verify 10 differentially expressed candidate miRNAs in more serum samples, and the results showed that 6 miRNAs (miR-1281, miR-365a-3p, miR-2861, miR-16-5p, miR-1202 and miR-451a) were consistent with the results of microarray. Among them, miR-1281, was the novel dynamically altered and appeared to be specifically related to depression and antidepressant effects of KXS. MicroRNA-gene-pathway-net analysis showed that miR-1281-regulated genes are mostly key nodes in the classical signaling pathway related to depression. Additionally, our data suggest that ADCY1 and DVL1 were the targets of miR-1281. Thus, based on the discovery of miRNA expression profiles in vivo, our findings suggest a new role for miR-1281 related to depression and demonstrated in vitro that KXS may activate cAMP/PKA/ERK/CREB and Wnt/β-catenin signal transduction pathways by down-regulating miR-1281 that targets ADCY1 and DVL1 to achieve its role in neuronal cell protection.

Summary: Background: The evidence of radiofrequency ablation (RFA) following transarterial chemoembolisation (TACE) combined with sorafenib for intermediate-stage recurrent hepatocellular carcinoma (RHCC) is limited. Patient responses to this treatment vary because of the heterogeneous nature of RHCC, making it important to identify patients who are most likely to benefit from this combination therapy. The aim of this study was to evaluate the efficacy of RFA following TACE and sorafenib for the intermediate-stage RHCC. Methods: This retrospective, multicentre, cohort study included 363 patients with intermediate-stage RHCC underwent TACE combined with sorafenib (TACE-sorafenib group) or RFA following TACE and sorafenib (TACE-sorafenib + RFA group) between January 01, 2009 to December 31, 2015 from four institutions in China. Overall survival (OS), progression-free survival (PFS) and efficacy of patients were compared between the two groups by propensity score–matching (PSM). Findings: The 1-, 3-, and 5-year OS rates were 97.7%, 83.7%, 54.7% in TACE-sorafenib + RFA group, and 93.3%, 57.0%, 32.7% in TACE-sorafenib group. The 1-, 2-, and 3-year PFS rates were 85.3%, 58.0%, 26.9% in TACE-sorafenib + RFA group, and 55.3%, 30.7%, 15.3% in TACE-sorafenib group. Compared with the TACE-sorafenib group, the TACE-sorafenib + RFA group had significantly longer OS (HR, 0.54; 95%CI, 0.40–0.73; P

Objective. To study the effect of congenital dyskeratosis 1 (DKC1) on neuroblastoma and its regulation mechanism. Methods. The expression of DKC1 in neuroblastoma was analyzed by TCGA database and molecular assay. NB cells were transfected with siDKC1 to observe the effects of DKC1 on proliferation, cloning, metastasis, and invasion, and apoptosis and apoptosis-related proteins. The tumor-bearing mouse model was constructed, shDKC1 was transfected to observe the tumor growth and tumor tissue changes, and the expression of DKC1 and Ki-67 was detected. Screening and identification of miRNA326-5p targeting DKC1. NB cells were treated with miRNA326-5p mimic or inhibitors to detect the expression of DKC1. NB cells were transfected with miRNA326-5p and DKC1 mimics to detect cell proliferation, apoptosis, and apoptotic protein expression. Results. DKC1 was highly expressed in NB cells and tissues. The activity, proliferation, invasion, and migration of NB cells were significantly decreased by DKC1 gene knockout, while apoptosis was significantly increased. The expression level of B-cell lymphoma-2 in shDKC1 group was significantly lower than that of the control group, while the expression level of BAK, BAX, and caspase-3 was significantly higher than that of the control group. The results of experiments on tumor-bearing mice were consistent with the above results. The results of miRNA assay showed that miRNA326-5p could bind DKC1 mRNA to inhibit the protein expression, thereby inhibiting the proliferation of NB cells, promoting their apoptosis, and regulating the expression of apoptotic proteins. Conclusion. miRNA326-5p targeting DKC1 mRNA regulates apoptosis-related proteins to inhibit neuroblastoma proliferation and promote the apoptotic process.

2-(2-Phenylethyl)chromones (PECs) contribute to the distinctive fragrance of agarwood. Here the authors identify a diarylpentanoid-producing polyketide synthase from Aquilaria sinensis and show how it catalyzes PEC formation.

Background: Several meta-analyses have analyzed the association of GSTM1 present/null, GSTT1 present/null, and GSTP1 IIe105Val polymorphisms with leukemia risk. However, the results of these meta-analyses have been conflicting. Moreover, they did not evaluate the combined effects of the three aforementioned gene polymorphisms. Furthermore, they did not appraise the credibility of the positive results. Finally, many new studies have been published. Therefore, an updated meta-analysis was conducted.Objectives: To further explore the relationship of the three aforementioned gene polymorphisms with leukemia risk.Methods: The crude odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the association of the individual and combined effects of the three aforementioned genes. Moreover, the false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP) were applied to verify the credibility of these statistically significant associations.Results: Overall, the individual GSTM1, GSTT1, and GSTP1 IIe105Val polymorphisms added leukemia risk. On combining GSTM1 and GSTT1, GSTM1 and GSTP1, and GSTT1 and GSTP1 polymorphisms, positive results were also observed. However, no significant association was observed between the combined effects of these three polymorphisms with leukemia risk in the overall analysis. Moreover, when only selecting Hardy–Weinberg equilibrium (HWE) and medium- and high-quality studies, we came to similar results. However, when the FPRP and BFDP values were applied to evaluate the credibility of positive results, the significant association was only observed for the GSTT1 null genotype with leukemia risk in Asians (BFDP = 0.367, FPRP = 0.009).Conclusion: This study strongly suggests a significant increase in the risk of leukemia in Asians for the GSTT1 null genotype.

BackgroundThe association between tumor location and breast cancer prognosis has been controversial. We sought to explore the relationship between tumors located in central and nipple portion (TCNP) and Chinese breast cancer.Patients and methodsA total of 1,427 breast cancer patients were recruited. There were 328 cases of TCNP and 1,099 cases of tumors in the breast peripheral quadrant (TBPQ). The chi-square test was used to compare different variables between TCNP and TBPQ groups. A one-to-one propensity score matching (PSM) was applied to construct a matched sample consisting of pairs of TCNP and TBPQ groups. Kaplan–Meier curves were used for survival analysis of disease-free survival (DFS), breast cancer-specific survival (BCSS) and overall survival (OS). The Cox proportional hazards regression model was applied to identify prognostic risk factors.ResultsThe median follow-up time was 58 months. Compared to TBPQ, TCNP patients had significantly larger tumor size, more frequent metastasis to lymph nodes (LN) and more proportions of TNM stage II–III. DFS, OS and BCSS rates were markedly lower in the TCNP group as compared to the TBPQ group before and after PSM (all p

Abstract Nonalcoholic fatty liver disease (NAFLD) is considered as a severe threat to human health. It has been reported that tea has abundant bioactive compounds and beneficial effects. In our study, the effects of 12 tea extracts on NAFLD were assessed and compared at the dose of 200 mg/kg body weight in mice fed with a high‐fat diet (HFD) for 15 weeks. Enshi Yulu Tea, Fenghuang Narcissus Tea, and Yihong Tea showed strong effects in suppressing the accumulation of epididymal and perirenal adipose tissue as well as the increases of body weight and liver weight. The histopathological analysis revealed that hepatic steatosis and adipocyte hypertrophy induced by a HFD could be ameliorated by tea supplementation. In addition, Enshi Yulu Tea and Qing Brick Tea exerted more remarkable functions on decreasing the level of serum triglyceride and preventing hepatic fat accumulation, respectively. Furthermore, Fenghuang Narcissus Tea, Enshi Yulu Tea, and Qing Brick Tea could reverse the abnormal change in the levels of glutathione and superoxide dismutase. Moreover, 13 phytoconstituents were detected and quantified in these teas with high‐performance liquid chromatography (HPLC) method. The correlation analysis demonstrated that gallic acid might decrease MDA level, and the reduction of liver weight might be attributed to ellagic acid. However, it should be paid attention to some teas that showed hepatotoxicity with elevated levels of aspartate transaminase and alanine aminotransferase. Several teas showed strong effects in the prevention of NAFLD, which could be developed into functional foods against NAFLD.

Abnormal placentation is associated with recurrent spontaneous abortion (RSA) risk. Here the authors report that low embryonic villous succinate level associates with risk of RSA in patients, and increasing succinate levels is sufficient to reduce the incidence rate in a mouse model of spontaneous abortion.

Objective The aim of the present study was to use a gelatin sponge impregnated with dexamethasone, combined with minimally invasive transforaminal lumbar interbody fusion (MIS‐TLIF) and no drainage tube after the operation for early postoperative recurrence of root pain caused by edema. Methods A prospective case series study was designed. From September 2015 to January 2018, eligible patients diagnosed with lumbar degenerative disease underwent MIS‐TLIF combined with a gelatin sponge impregnated with dexamethasone and no drainage tube after surgery. The short‐term clinical data were collected, such as visual analog scale (VAS) scores for low back pain and leg pain preoperatively and on postoperative days (POD) 1–10, time bedridden postoperatively, and length of hospital stay postoperatively. Long‐term indicators include the Japanese Orthopaedic Association (JOA) score, the Oswestry Disability Index (ODI) score, and the 36‐Item Short‐Form Health Survey (SF‐36) score, evaluated preoperatively and 1 week, 3 months, and more than 1 year postoperatively. Results Complete clinical data was obtained for 139 patients. All patients were followed up for more than 12 months (13.7 ± 3.3 months). The average bedridden period was 1.5 ± 0.4 days and hospital stays were 2.7 ± 0.9 days. The VAS score of leg and back pain on POD 1–10 were all decreased compared with preoperation (all P

Overactivation of the PI3-K/Akt/mTOR signaling pathway and inhibition of autophagy in the brain are involved in Alzheimer’s disease. The present paper’s goal was to explore the potential mechanisms of geniposide to protect against Alzheimer’s disease. We treated the human neuroblastoma SH-SY5Y cell line with Aβ1-42 as an Alzheimer’s disease in vitro model to explore the potential mechanisms of geniposide to protect against Alzheimer’s disease. Further, SH-SY5Y cells damaged by Aβ1-42 were treated with geniposide. Akt/mTOR-related proteins and autophagy-associated proteins were measured to reveal the molecular mechanisms by which geniposide protects against Aβ1-42-induced toxicity. Results showed that Akt and mTOR’s geniposide inhibited phosphorylation induced by Aβ1-42, enhanced expression of the LC3II/LC3I ratio, and Atg7 and Beclin1 expression and inhibited expression of p62 induced by Aβ1-42. Our results lead us to hypothesize that inhibition of the Akt/mTOR signaling pathway and autophagy enhancement are fundamental molecular mechanisms for geniposide to protect against Aβ toxicity.

Background and PurposeThe proportion of patients with somatic diseases associated with anxiety is increasing each year, and pulmonary nodules have become a non-negligible cause of anxiety, the mechanism of which is unclear. The study focus on the cerebral blood flow (CBF) of anxiety in patients with pulmonary nodules to explore the cerebral perfusion pattern of anxiety associated with pulmonary nodules, blood perfusion status and mode of pulmonary nodule induced anxiety state.Materials and MethodsPatients with unconfirmed pulmonary nodules were evaluated by Hamilton Anxiety Scale (HAMA). The total score > 14 was defined as anxiety group, and the total score ≤ 14 points was defined as non-anxiety group. A total of 38 patients were enrolled, of which 19 patients were the anxiety group and 19 were the non-anxiety group. All subjects underwent arterial spin labeling imaging using a 3.0 T MRI. A two-sample t-test was performed to compare the CBF between the two groups. The CBF was extracted in brain regions with difference, and Spearman correlation was used to analyze the correlation between CBF and HAMA scores; ROC was used to analyze the performance of CBF to distinguish between the anxiety group and the non-anxiety group.ResultsThe CBF in the right insula/Heschl’s cortex of the anxiety group decreased (cluster = 109, peak t = 4.124, and P < 0.001), and the CBF in the right postcentral gyrus increased (cluster = 53, peak t = −3.912, and P < 0.001) in the anxiety group. But there was no correlation between CBF and HAMA score. The ROC analysis of the CBF of the right insula/Heschl’s cortex showed that the AUC was 0.856 (95%CI, 0.729, 0.983; P < 0.001), the optimal cutoff value of the CBF was 50.899, with the sensitivity of 0.895, and specificity of 0.789. The ROC analysis of CBF in the right postcentral gyrus showed that the AUC was 0.845 (95%CI, 0.718, 0.972; P < 0.001), the optimal cutoff value of CBF was 43.595, with the sensitivity of 0.737, and specificity of 0.842.ConclusionThe CBF of the right insula/Heschl’s cortex decreased and the CBF of the right postcentral gyrus increased in patients with pulmonary nodules under anxiety state, and the CBF of the aforementioned brain regions can accurately distinguish the anxiety group from the non-anxiety group.

Abstract Transplantation of olfactory ensheathing cells (OECs) has been demonstrated to be beneficial for spinal cord injury (SCI) by modulating neuroinflammation, supporting neuronal survival and promoting angiogenesis. Besides OECs, the conditioned medium (CM) from OECs has also been proved to have therapeutic effects for SCI, indicating that the bioactive substances secreted by OECs are essential for its protective effects. Nevertheless, there is still little information regarding the underlying mechanisms. Considering that exosomes are crucial for intercellular communication and could be secreted by different types of cells, we speculated that the therapeutic potential of OECs for SCI might be partially based on their exosomes. To examine whether OECs could secret exosomes, we isolated exosomes by polyethylene glycol‐based method, and identified them by electron microscopy study, nanoparticle tracking analysis (NTA) and western blotting. In view of phagocytic ability of microglia and its distinct roles in microenvironment regulation after SCI, we then focused the effects of OECs‐derived exosomes (OECs‐Exo) on microglial phenotypic regulation. We found that the extracted OECs‐Exo could be engulfed by microglia and partially reverse the LPS‐induced pro‐inflammatory polarization through inhibiting NF‐κB and c‐Jun signaling pathways in vitro. Furthermore, OECs‐Exo were found to inhibit the polarization of pro‐inflammatory macrophages/microglia while increased the numbers of anti‐inflammatory cells after SCI. Considering that the neuronal injury is closely related to the activation state of macrophages/microglia, co‐culture of microglia and neurons were performed. Neuronal death induced by LPS‐treated microglia could be significantly alleviated when microglia treated by LPS plus OECs‐Exo in vitro. After SCI, NeuN‐immunostaining and axonal tract‐tracing were performed to assess neuronal survival and axon preservation. Our data showed that the OECs‐Exo promoted the neuronal survival and axon preservation, and facilitated functional recovery after SCI. Our findings provide a promising therapeutic strategy for SCI based on exosome‐immunomodulation.

Mutations in the GJB2 gene encoding connexin26 (Cx26) protein are one of the most common causes of hereditary deafness. Previous studies have found that different Cx26-null mouse models have severe hearing loss and deformity of the organ of Corti (OC) as well as a reduction in microtubules in pillar cells (PCs). To explore the underlying mechanism of OC deformity caused by Cx26 downregulation further, we established Cx26 knockdown (KD) mouse models at postnatal days (P)0 and P8. The actin filaments contained in the pillar cells of mice in the P0 KD group were reduced by 54.85% and vinculin was increased by 22%, while the outer hair cells (OHCs) showed normal F-actin content. In the P8 KD group, PCs and OHCs of mice also showed almost normal F-actin content. The G-actin/F-actin ratio increased by 38% in the P0 KD group. No significant change was found in the mRNA or protein expression level of G-actin or the cadherin–catenin core complex in the P0 KD group at P6. Moreover, immunofluorescence showed that the intensity of LRRK2 was reduced by 97% in the P0 KD group at P6. Our results indicate that Cx26 is involved in the maturation of the cytoskeleton during the development of the OC at the early postnatal stage. The polymerization of G-actin into F-actin is prevented in Cx26 KD mice.

The role of the Slack (also known as Slo2.2, KNa1.1, or KCNT1) channel in pain-sensing is still in debate on which kind of pain it regulates. In the present study, we found that the Slack–/– mice exhibited decreased mechanical pain threshold but normal heat and cold pain sensitivity. Subsequently, X-gal staining, in situ hybridization, and immunofluorescence staining revealed high expression of the Slack channel in Isolectin B4 positive (IB4+) neurons in the dorsal root ganglion (DRG) and somatostatin-positive (SOM+) neurons in the spinal cord. Patch-clamp recordings indicated the firing frequency was increased in both small neurons in DRG and spinal SOM+ neurons in the Slack–/– mice whereas no obvious slow afterhyperpolarization was observed in both WT mice and Slack–/– mice. Furthermore, we found Kcnt1 gene expression in spinal SOM+ neurons in Slack–/– mice partially relieved the mechanical pain hypersensitivity of Slack–/– mice and decreased AP firing rates of the spinal SOM+ neurons. Finally, deletion of the Slack channel in spinal SOM+ neurons is sufficient to result in mechanical pain hypersensitivity in mice. In summary, our results suggest the important role of the Slack channel in the regulation of mechanical pain-sensing both in small neurons in DRG and SOM+ neurons in the spinal dorsal horn.

Functionalization and bestowing high values upon bioactive tea polysaccharides have been focused recently. For this purpose, the immune activation effect on RAW264.7 macrophages promoted by Lu’an Guapian polysaccharide (LGP-1, 2.35 × 105 Da) was investigated firstly. LGP-1 was obtained and characterized via DEAE 52 ion exchange column, high performance liquid chromatography and atomic force microscope. Immunological assay manifested a remarkable promotion effect on macrophages. LGP-1 could significantly stimulate the phagocytosis of macrophages, promote NO generation and trigger TNF-α, IL-6, IL-1β release dose-dependently. Fluorescence labeling tests confirmed the production level of reactive oxygen species increased obviously. Western blot results demonstrated that the treated macrophages were able to increase PI3K expression and p65 nuclear translocation, indicated that LGP-1 enhanced macrophage immunity via PI3K/AKT and NF-κB signaling pathways. Moreover, TLR4 was involved in the process. These results made clear that LGP-1 could be explored as a bioactive substance applied in functional foods.

Abstract Background Hepatocellular carcinoma (HCC) is a major health problem and a primary cause of cancer‐related death worldwide. Although great advances have achieved recently by large‐scale high‐throughput analysis, the precise molecular mechanism underlying HCC progression remains to be clearly elucidated. We investigated the relationship between Tescalcin (TESC), a candidate oncogene, and clinicopathological features of HCC patients and explored the role of TECS in HCC development. Methods To identify new genes involved in HCC development, we analyzed The Cancer Genome Atlas liver cancer database, and TESC was selected for further investigation. HCC tissue microarray analysis for TESC and its association with clinicopathological features were performed to investigate its clinical significance. TESC was knocked down by using short‐hairpin RNAs. Cell proliferation was analyzed by WST‐1 assay and cell counting. Cell apoptosis was tested by fluorescence‐activated cell sorting. A subcutaneous xenograft tumor model in nude mice was established to determine the in vivo function of TESC. Affymetrix microarray was used to identify its molecular mechanism. Results TESC was significantly increased in HCC tissues compared with the adjacent normal liver tissues. High expression of TESC was detected in 61 of 172 HCC patients by tissue microarray. Large tumor (> 5 cm) and elevated total bilirubin were associated with high TESC expression (both P

Nucleotide-binding oligomerization domain(NOD)-like receptor family contains Pryrin domain protein 3(NLRP3)inflammasome, which is an intracellular protein complex. Large release of ROS can activate the production of intracellular NLRP3 inflammasome. It consists of NLRP3, a cysteine protease recruitment domain(ASC),and a pro-caspase-1 precursor, can activate caspase-1 while being assembled. Then, the cytokines interleukin-1 and interleukin-18(pro-Il-1/18)are cleaved into mature forms by caspase-1 to perform their pro-inflammatory functions. pyroptosis refers to the programmed cell death of Caspase-1-dependent cells mediated by inflammasome. This article reviews the structure and function of NLRP3 inflammasome, its relationship with pyroptosis, and the research progress in ophthalmic diseases.

Abstract Background The influence of perioperative blood transfusion (PBT) on postsurgical survival of patients with different stage of hepatocellular carcinoma (HCC) is not well clarified. This study aimed to evaluate the impact of PBT on survival outcomes of different stage of HCC patients. Methods Consecutive patients who underwent liver resection for HCC between January 2009 and November 2015 were identified from an HCC prospective database in authors’ center. The survival outcomes were compared between patients receiving PBT and those without PBT before and after propensity score matching (PSM) in different stage subsets. Cox regression analysis was performed to verify the impact of PBT on outcomes of HCC. Results Among 1255 patients included, 804 (64.1%) were Barcelona Clinic Liver Cancer (BCLC) stage 0-A, and 347 (27.6%) received PBT. Before PSM, patients with PBT had worse disease free survival (DFS) and overall survival (OS) compared with those without PBT in both BCLC 0-A subset and BCLC B-C subset (all P

Abstract We aimed to explore the molecular substrate underlying EGFR‐TKI resistance and investigate the effects of N‐acetylcysteine (NAC) on reversing EGFR‐TKI resistance. In the current research, the effects of NAC in combination with gefitinib on reversing gefitinib resistance were examined using CCK‐8 assay, combination index (CI) method, matrigel invasion assay, wound‐healing assay, flow cytometry, western blot, and quantitative real‐time PCR (qRT‐PCR). CCK8 assay showed that NAC plus gefitinib combination overcame EGFR‐TKI resistance in non‐small cell lung cancer (NSCLC) cells by lowering the value of half maximal inhibitory concentration (IC50). CI calculations demonstrated a synergistic effect between the two drugs (CI

Abstract Background Patients with hepatocellular carcinoma (HCC) undergoing surgical resection still have a high 5-year recurrence rate (~ 60%). With the development of laparoscopic hepatectomy (LH), few studies have compared the efficacy between LH and traditional surgical approach on HCC. The objective of this study was to establish a nomogram to evaluate the risk of recurrence in HCC patients who underwent LH. Methods The clinical data of 432 patients, pathologically diagnosed with HCC, underwent LH as initial treatment and had surgical margin > 1 cm were collected. The significance of their clinicopathological features to recurrence-free survival (RFS) was assessed, based on which a nomogram was constructed using a training cohort (n = 324) and was internally validated using a temporal validation cohort (n = 108). Results Hepatitis B surface antigen (hazard ratio [HR], 1.838; P = 0.044), tumor number (HR, 1.774; P = 0.003), tumor thrombus (HR, 2.356; P = 0.003), cancer cell differentiation (HR, 0.745; P = 0.080), and microvascular tumor invasion (HR, 1.673; P =0.007) were found to be independent risk factors for RFS in the training cohort, and were used for constructing the nomogram. The C-index for RFS prediction in the training cohort using the nomogram was 0.786, which was higher than that of the 8th edition of the American Joint Committee on Cancer TNM classification (C-index, 0.698) and the Barcelona Clinic Liver Cancer staging system (C-index, 0.632). A high consistency between the nomogram prediction and actual observation was also demonstrated by a calibration curve. An improved predictive benefit in RFS and higher threshold probability of the nomogram were determined by receiver operating characteristic curve analysis, which was also confirmed in the validation cohort compared to other systems. Conclusions We constructed and validated a nomogram able to quantify the risk of recurrence after initial LH for HCC patients, which can be clinically implemented in assisting the planification of individual postoperative surveillance protocols.

Abstract Background Endovascular treatment has been recognized as the first line therapy for renal artery aneurysm (RAA). However, RAA related with malignancies had been sporadically reported in the literature. Stent insertion should be contraindicated for RAAs with malignant etiology, whereas surgery be optimal. Case presentation A 40-year-old female underwent covered stent insertion to exclude the left RAA for suspected Takayasu arteritis in a reginal hospital. Three months later the RAA recurred with sign of threatened rupture, and the patient was transferred for salvage embolization with coils and thrombin injection. However, 20 days after the embolization procedure, multiple painful subcutaneous nodules developed in her flanks. Undifferentiated sarcoma was revealed by the pathological biopsy of the nodules. The RAA in this case was most likely related with the malignancy. Conclusion Malignancy was the most likely etiology behind recurrent aneurysm in this case. Definite diagnosis is mandatory for interventional radiologists before stent insertion for treatment of RAA.

Cardio-cerebrovascular diseases, as a major cause of health loss all over the world, contribute to an important part of the global burden of disease. A large number of traditional Chinese medicines have been proved effective both clinically and in pharmacological investigations, with the acceleration of the modernization of Chinese medicine. Sinomenine is the main active constituent of sinomenium acutum and has been generally used in therapies of rheumatoid arthritis and neuralgia. Varieties of pharmacological effects of sinomenine in cardio-cerebrovascular system have been discovered recently, suggesting an inspiring application prospect of sinomenine in cardio-cerebrovascular diseases. Sinomenine may retard the progression of atherosclerosis by attenuating endothelial inflammation, regulating immune cells function, and inhibiting the proliferation of vascular smooth muscle cells. Sinomenine also alleviates chronic cardiac allograft rejection relying on its anti-inflammatory and anti-hyperplastic activities and suppresses autoimmune myocarditis by immunosuppression. Prevention of myocardial or cerebral ischemia-reperfusion injury by sinomenine is associated with its modulation of cardiomyocyte death, inflammation, calcium overload, and oxidative stress. The regulatory effects on vasodilation and electrophysiology make sinomenine a promising drug to treat hypertension and arrhythmia. Here, in this review, we will illustrate the pharmacological activities of sinomenine in cardio-cerebrovascular system and elaborate the underlying mechanisms, as well as give an overview of the potential therapeutic roles of sinomenine in cardio-cerebrovascular diseases, trying to provide clues and bases for its clinical usage.

Objective: A considerable part of COVID-19 patients were found to be re-positive in the SARS-CoV-2 RT-PCR test after discharge. Early prediction of re-positive COVID-19 cases is of critical importance in determining the isolation period and developing clinical protocols.Materials and Methods: Ninety-one patients discharged from Wanzhou Three Gorges Central Hospital, Chongqing, China, from February 10, 2020 to March 3, 2020 were administered nasopharyngeal swab SARS-CoV-2 tests within 12–14 days, and 50 eligible patients (32 male and 18 female) with completed data were enrolled. Average age was 48 ± 11.5 years. All patients underwent non-enhanced chest CT on admission. A total of 568 radiomics features were extracted from the CT images, and 17 clinical factors were collected based on the medical record. Student's t-test and support vector machine–based recursive feature elimination (SVM-RFE) method were used to determine an optimal subset of features for the discriminative model development.Results: After Student's t-test, 62 radiomics features showed significant inter-group differences (p < 0.05) between the re-positive and negative cases, and none of the clinical features showed significant differences. These significant features were further selected by SVM-RFE algorithm, and a more compact feature subset containing only two radiomics features was finally determined, achieving the best predictive performance with the accuracy and area under the curve of 72.6% and 0.773 for the identification of the re-positive case.Conclusion: The proposed radiomics method has preliminarily shown potential in identifying the re-positive cases among the recovered COVID-19 patients after discharge. More strategies are to be integrated into the current pipeline to improve its precision, and a larger database with multi-clinical enrollment is required to extensively verify its performance.

Background/ObjectiveWe aimed to explore the prognostic value of regression rate (RR) of plasma Epstein–Barr virus (EBV) DNA after induction chemotherapy (IC) in patients with stages II–IVA nasopharyngeal carcinoma (NPC).MethodsEligible patients receiving IC followed by concurrent chemoradiotherapy were included. The cut-off value of pre-treatment EBV DNA (pre-IC DNA) and RR were identified by receiver operating curve (ROC). Recursive partitioning analysis (RPA) was applied to create new staging. Harrell’s c-index and time-independent ROC were employed to compare different RPA staging.ResultsIn total, 1,184 patients were included. The cut-off values of pre-IC DNA and RR were 16,200 copies/ml and 95.127% for patients receiving two cycles, and 5,520 copies/ml and 99.994% for those receiving three cycles. Notably, we only focused on patients receiving two cycles of IC. Patients with a RR >95.127% had significantly better 5-year overall survival (OS) than those with a RR ≤95.127% (86.2% vs. 54.3%, P

TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase.

AIM: To evaluate the effects of etanercept on the expression of Fas, tumor necrosis factor-alpha (TNF-α) and caspase-8 in the early stage of the apoptotic pathway in diabetic rats, and to explore the therapeutic effect of etanercept on diabetic retinopathy. METHODS: A total of 60 Sprague-Dawley (SD) rats were randomly and evenly divided into 3 groups with 20 rats each, including control group, and diabetic groups with or without treatment. Streptozotocin (STZ)-induced diabetic rats were established for diabetic groups. Blood glucose and body weight were measured weekly. All the rats were sacrificed at the 12wk after treatment. The expressions of Fas, TNF-α and caspase-8 in rat retina were quantitatively detected by PCR and Western blot. The leakage of Evan blue was adopted to measure the retinal vascular leakage quantitatively, and to compare it among different groups. TUNEL method was used to compare the amount of apoptotic bodies quantitatively in rat retina ganglion cells under electron microscope. RESULTS: The expressions of Fas, TNF-α and caspase-8 in each group were compared via PCR and Western blot, in which the diabetic group with treatment was lower than those without treatment (P

Abstract Background Whether PD-L1/PD-1 expression plays a significant role in the prognosis of NPC is still controversial. The present study mainly aimed to investigate the prognostic significance of PD-L1/PD-1 expression in patients with NPC. Methods A systematical research was performed in the PubMed, Web of Science, EMBASE, and the Cochrane Library databases up to January 06, 2019. Eighteen studies met eligible criteria were included in the meta-analysis. Quality assessment of included articles was evaluated by Newcastle–Ottawa quality assessment scale (NOS). Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were used to elucidated the primary endpoint, overall survival (OS), and the secondary endpoints. Furthermore, the relationship between clinicopathological features of NPC and PD-L1/PD-1 expression was estimated by relative ratios (RRs) and 95% CIs. Results A total of 1836 patients from 15 included studies concerning PD-L1 and 678 patients from six studies regarding PD-1 were included in the meta-analysis. Pooled results revealed that PD-L1 expression in NPC did not correlate with OS (HR 1.34 95% CI 0.93–1.93, p = 0.11), DFS (HR 1.82, 95% CI 0.86–3.85, p = 0.12), PFS (HR 1.19, 95% CI 0.46–3.08, p = 0.72), and DMFS (HR 2.26, 95% CI 0.60–8.56, p = 0.23). Meanwhile, no statistically significant differences existed between the expression level of PD-1 in tumor infiltrating lymphocytes (TILs) and the OS in NPC, with the pooled HR 1.29 (95% CI 0.68–2.42, p = 0.44). In subgroup analysis, higher expression of PD-L1 in immune cells correlated with better OS in patients with NPC, with a pooled HR 0.68 (95% CI 0.47–0.99, p = 0.04). Among the clinicopathological features included in our study, we found that the positive expression of PD-L1 in NPC associated with the higher expression of PD-1 (RR 1.25, 95% CI 1.02–1.52, p = 0.03). Conclusions Our meta-analysis indicated that higher/positive expression of PD-L1/PD-1 may not serve as suitable biomarkers for the prognosis of NPC, which was not in consistent with some previous studies about the prognostic value of PD-L1/PD-1 in other types of tumors. Despite the positive results in subgroup analysis and study about clinicopathological features, it may still need corroboration of prospective and large-scale studies.

The macrophage-related immune response is an important component of the cochlear response to different exogenous stresses, including noise, ototoxic antibiotics, toxins, or viral infection. However, the role of the immune response in hereditary deafness caused by genetic mutations is rarely explored. GJB2, encoding connexin 26 (Cx26), is the most common deafness gene of hereditary deafness. In this study, two distinct Cx26-null mouse models were established to investigate the types and underlying mechanisms of immune responses. In a systemic Cx26-null model, macrophage recruitment was observed, associated with extensive cell degeneration of the cochlear epithelium. In a targeted-cell Cx26-null model, knockout of Cx26 was restricted to specific supporting cells (SCs), which led to preferential loss of local outer hair cells (OHCs). This local OHC loss can also induce a macrophage-related immune response. Common inflammatory factors, including TNF-α, IL-1β, Icam-1, Mif, Cx3cr1, Tlr4, Ccl2, and Ccr2, did not change significantly, while mRNA of Cx3cl1 was upregulated. Quantitative immunofluorescence showed that the protein expression of CX3CL1 in Deiters cells, a type of SC coupled with OHCs, increased significantly after OHC death. OHC loss caused the secondary death of spiral ganglion neurons (SGNs), while the remaining SGNs expressed high levels of CX3CL1 with infiltrated macrophages. Taken together, our results indicate that CX3CL1 signaling regulates macrophage recruitment and that enhancement of macrophage antigen-presenting function is associated with cell degeneration in Cx26-null mice.

PurposeTo assess the impact of comorbidity on treatment outcomes in patients with locally recurrent nasopharyngeal carcinoma (lrNPC) using intensity-modulated radiotherapy (IMRT) and to develop a nomogram that combines prognostic factors to predict clinical outcome and guide individual treatment.MethodsThis was a retrospective analysis of patients with lrNPC who were reirradiated with IMRT between 2003 and 2014. Comorbidity was evaluated by Adult Comorbidity Evaluation-27 grading (ACE-27). The significant prognostic factors (P < 0.05) by multivariate analysis using the Cox regression model were adopted into the nomogram model. Harrell concordance index (C-index) calibration curves were applied to assess this model.ResultsBetween 2003 and 2014, 469 lrNPC patients treated in our institution were enrolled. Significant comorbidity (moderate or severe grade) was present in 17.1% of patients by ACE-27. Patients with no or mild comorbidity had a 5-year overall survival (OS) rate of 36.2 versus 20.0% among those with comorbidity of moderate or severe grade (P < 0.0001). The chemotherapy used was not significantly different in patients with lrNPC (P > 0.05). For the rT3–4 patients, the 5-year OS rate in the chemotherapy + radiation therapy (RT) group was 30.0 versus 16.7% for RT only (P = 0.005). The rT3–4 patients with no or mild comorbidity were associated with a higher 5-year OS rate in the chemotherapy + RT group than in the RT only group (32.1 and 17.1%, respectively; P=0.003). However, for the rT3–4 patients with a comorbidity (moderate or severe grade), the 5-year OS rate in the chemotherapy + RT group vs. RT alone was not significantly different (15.7 vs. 15.0%, respectively; p > 0.05). Eight independent prognostic factors identified from multivariable analysis were fitted into a nomogram, including comorbidity. The C-index of the nomogram was 0.715. The area under curves (AUCs) for the prediction of 1-, 3-, and 5-year overall survival were 0.770, 0.764, and 0.780, respectively.ConclusionComorbidity is among eight important prognostic factors for patients undergoing reirradiation. We developed a nomogram for lrNPC patients to predict the probability of death after reirradiation and guide individualized management.

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the MYO15A gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the MYO15A gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the MYO15A gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the MYO15A gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.

Genetic testing is the gold standard for exploring the etiology of congenital hearing loss. Here, we enrolled 137 Chinese patients with congenital hearing loss to describe the molecular epidemiology by using 127 gene panel testing or 159 variant testing. Sixty-three deaf children received 127 gene panel testing, while seventy-four patients received 159 variant testing. By use of 127 gene panel testing, more mutant genes and variants were identified. The most frequent mutant genes were GJB2, SLC26A4, MYO15A, CDH23, and OTOF. By analyzing the patients who received 127 gene panel testing, we found that 51 deaf children carried variants which were not included in 159 variant testing. Therefore, a large number of patients would be misdiagnosed if only 159 variant testing is used. This study highlights the advantage of 127 gene panel testing, and it suggests that broader genetic testing should be done to identify the genetic etiology of congenital hearing loss.

The aim of this study was to investigate the role of high mobility group protein-1 (HMGB1) in the proliferation and migration of lung cancer cells. CCK-8 assays and colony formation assays were used to evaluate the effect of HMGB1 regulation on cancer cell viability and colony formation. Trans-well assays and wound healing assays were also performed. Our data showed that HMGB1 is upregulated in clinical lung cancer tissues compared with non-cancer tissues, and it is differentially expressed in lung cancer cell lines. The knockdown of HMGB1 in A549 lung cancer cells significantly reduced cell proliferation, viability and motility. In contrast, overexpression of HMGB1 in lung cancer H1299 cells significantly increased cell viability and motility. Western blotting showed that HMGB1 could promote epithelial-mesenchymal transition. The Wnt/β-catenin pathway was activated after overexpression of HMGB1 in H1299 cells, while it was inactivated by knocking down HMGB1 in A549 cells. These data suggest that HMGB1 promotes the proliferation and migration of lung cancer cells in vitro . The carcinogenic behavior of HMGB1 can be achieved by activating the Wnt/β-catenin pathway.