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Abstract This study investigated the possible mechanisms of microRNA-124a on the differentiation of bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanism. β-Thiol ethanol induced Notch1 mRNA expression, microRNA-124a inhibitor reduced the effects of β-thiol ethanol on Notch1 mRNA expression in BMSCs. Baicalin induced Hes1 mRNA expression, and microRNA-124a inhibitor reduced the effects of baicalin on Hes1 mRNA expression in BMSCs. Si-Notch1 suppressed Hes1 mRNA expression in BMSCs. Baicalin increased the effects of Notch1 on Hes1 mRNA expression in BMSCs. Si-Notch1 increased cell growth of BMSCs. Baicalin reduced the effects of si-Notch1 on cell growth and the differentiation of BMSCs. We demonstrated that microRNA-124a promoted the differentiation of BMSCs into neurons through Notch/Hes1 signal pathway.

As the global population ages, the incidence of Parkinson's Disease (PD) continues to rise, imposing significant social and economic burdens. Mangiferin (MGF), a polyphenolic, bioactive compound has been shown to play a role in the prevention and treatment of PD. This study investigates the neuroprotective effects of MGF in an MPTP-induced zebrafish model of PD through transcriptome analysis. Initially, optimal concentrations for modeling were determined using various MPTP and MGF combinations. The zebrafish were then divided into control, MPTP-treated, and MGF co-treated groups. Subsequent evaluations included hatching rates, mortality rates, growth and development conditions, spontaneous motor abilities, as well as measurements of enzymatic activities of SOD, CAT, and levels of GSH. Ultimately, the therapeutic efficacy of MGF on the PD model in zebrafish was assessed through transcriptome sequencing. The results demonstrated that MPTP treatment induced PD-associated symptoms in zebrafish, while MGF treatment significantly improved the motor abilities and survival rates of the PD model zebrafish, effectively reducing oxidative stress and ameliorating PD symptoms. Transcriptome sequencing further revealed that MGF may mitigate mitochondrial-related oxidative stress in PD zebrafish by modulating the expression of critical genes including lrrk2, vps35, atp13a, dnajc6, and uchl1. Differential gene expression analysis indicated that these genes are primarily involved in vital signaling pathways, such as neuroactive ligand-receptor interaction, and the calcium signaling pathway. In summary, our study provides robust scientific evidence supporting MGF as a potential therapeutic candidate for PD by preserving mitochondrial homeostasis and elucidating its mechanisms of action.

Abstract Background With the implementation of lung cancer screening programs, an increasing number of pulmonary nodules have been detected.Video-assisted thoracoscopic surgery (VATS) could provide adequate tissue specimens for pathological analysis, and has few postoperative complications.However, locating the nodules intraoperatively by palpation can be difficult for thoracic surgeons. The preoperative pulmonary nodule localization technique is a very effective method.We compared the safety and effectiveness of two methods for the preoperative localization of pulmonary ground glass nodules. Methods From October 2020 to April 2021, 133 patients who underwent CT-guided single pulmonary nodule localization were retrospectively reviewed. All patients underwent video-assisted thoracoscopic surgery (VATS) after successful localization. Statistical analysis was used to evaluate the localization accuracy, safety, information related to surgery and postoperative pathology information. The aim of this study was to evaluate the clinical effects of the two localization needles. Results The mean maximal transverse nodule diameters in the four-hook needle and hook wire groups were 8.97 ± 3.85 mm and 9.00 ± 3.19 mm, respectively (P = 0.967). The localization times in the four-hook needle and hook wire groups were 20.58 ± 2.65 min and 21.43 ± 3.06 min, respectively (P = 0.09). The dislodgement rate was significantly higher in the hook wire group than in the four-hook needle group (7.46% vs. 0, P = 0.024). The mean patient pain scores based on the visual analog scale in the four-hook needle and hook wire groups were 2.87 ± 0.67 and 6.10 ± 2.39, respectively (P = 0.000). All ground glass nodules (GGNs) were successfully resected by VATS. Conclusions Preoperative pulmonary nodule localization with both a four-hook needle and hook wire is safe, convenient and effective.

PurposeSphingosine-1-phosphate (S1P) is a signaling lipid involved in many biological processes, including inflammatory and immune regulatory responses. The study aimed to determine whether admission S1P levels are associated with disease severity and prognosis after spontaneous intracerebral hemorrhage (ICH).MethodsData of 134 patients with spontaneous ICH and 120 healthy controls were obtained from Biological Resource Sample Database of Intracerebral Hemorrhage at the First Affiliated Hospital of Zhengzhou University. Plasma S1P levels were measured. Regression analyses were used to analyze the association between S1P levels and admission and 90-day modified Rankin scale (mRS) scores. Receiver operating characteristic (ROC) curves assessed the predictive value of S1P levels for ICH severity and prognosis.ResultsPatients with ICH exhibited elevated plasma S1P levels compared to the control group (median 286.95 vs. 239.80 ng/mL, p

Acute myeloid leukemia (AML) represents as a prevalent and formidable hematological malignancy, characterized by notably low 5-year survival rates. Ferroptosis has been found to be correlated with cancer initiation, therapeutic response, and clinical outcome. Nevertheless, the involvement of Ferroptosis-related genes (FRGs) in AML remains ambiguous. Five independent AML cohorts totaling 1,470 (GSE37642, GSE12417, GSE10358, Beat-AML, and TCGA-AML) patients with clinical information were used to systematically investigated the influence of these FRGs expression on outcome and tumor microenvironment. The integration of these datasets led to the subdivision into training and validation sets. Nineteen FRGs were identified as correlated with the overall survival (OS) of AML patients, primarily enriched in ferroptosis, fatty acid metabolism, and leukemia-related signaling pathways. The prognostic signature, consisting of 11 FRGs, was formulated using LASSO-Cox stepwise regression analysis. Patients with high-risk scores exhibited reduced survival compared to those in the low-risk group. The receiver operating characteristic (ROC) analysis underscored the signature's robust predictive accuracy. The high predictive efficacy was confirmed by both internal and external validation datasets. Leukemia and signaling related to immune regulation were mainly enriched pathways of the differentially expressed genes by comparing high- and low-risk groups. The immune composition deconvolution might indicate an immunosuppressive niche in the high-risk patients. The pRRophetic algorithm exploration unveiled chemical drugs with potentially sensitivity among patients in both groups. Collectively, our study developed a ferroptosis-derived prognostic signature that provides the OS prediction and identifies the immune microenvironment for AML patients on large-scale AML cohorts.

Abstract Background Ischemic stroke is one of the most serious global public health problems. However, the performance of current therapeutic regimens is limited due to their poor target specificity, narrow therapeutic time window, and compromised therapeutic effect. To overcome these barriers, we designed an ischemia-homing bioengineered nano-scavenger by camouflaging a catalase (CAT)-loaded self-assembled tannic acid (TA) nanoparticle with a M2-type microglia membrane (TPC@M2 NPs) for ischemic stroke treatment. Results The TPC@M2 NPs can on-demand release TA molecules to chelate excessive Fe2+, while acid-responsively liberating CAT to synergistically scavenge multiple ROS (·OH, ·O2 −, and H2O2). Besides, the M2 microglia membrane not only can be served as bioinspired therapeutic agents to repolarize M1 microglia into M2 phenotype but also endows the nano-scavenger with ischemia-homing and BBB-crossing capabilities. Conclusions The nano-scavenger for specific clearance of multiple pathogenic elements to alleviate inflammation and protect neurons holds great promise for combating ischemic stroke and other inflammation-related diseases.

PurposeWe aimed to explore the difference in coagulation function between healthy individuals and patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis and its relationship with disease severity.MethodsWe retrospectively compared coagulation function in 161 patients with first-attack anti-NMDAR encephalitis and 178 healthy individuals. The association between D-dimer levels and disease severity was analyzed using binary logistic regression. Receiver operating characteristic (ROC) curves were used to analyze the predictive value of D-dimer levels for the severity of anti-NMDAR encephalitis.ResultsCompared to control individuals, patients with anti-NMDAR encephalitis had higher D-dimer levels (median 0.14 vs. 0.05 mg/L, p < 0.001), blood white blood cell (WBC) count (median 8.54 vs. 5.95 × 109/L, p < 0.001), and neutrophil count (median 6.14 vs. 3.1 × 109/L, p < 0.001). D-dimers (median 0.22 vs. 0.10 mg/L, p < 0.001), blood WBC count (median 9.70 vs. 7.70 × 109/L, p < 0.001), neutrophil count (median 7.50 vs. 4.80 × 109/L, p < 0.001), and C-reactive protein (median 2.61 vs. 1.50 mg/l, p = 0.017) were higher; however, eosinophils (median 0.02 vs. 0.06 × 109/L, p < 0.001), and blood calcium (median 2.26 vs. 2.31 mmol/L, p = 0.003) were lower in patients with severe forms of anti-NMDAR encephalitis than in those with mild to moderate forms, and were associated with initial modified Rankin Scale scores. Multivariate analysis showed that D-dimer levels were significantly associated with severity [odds ratio =2.631, 95% confidence interval (CI) = 1.018–6.802, p = 0.046]. The ROC curve was used to analyze the predictive value of D-dimer levels for disease severity. The area under the curve was 0.716 (95% CI = 0.64–0.80, p < 0.001), and the best cut-off value was D-dimer = 0.147 mg/L (sensitivity 0.651; specificity, 0.705).ConclusionSerum D-dimer and neutrophil levels were independent predictors of disease severity in patients with first-attack anti-NMDAR encephalitis.

BackgroundThe coexistence of neuromyelitis optica spectrum disorder (NMOSD) and connective tissue disease (CTD) is well recognized. The purpose of this study was to investigate and compare the characteristics of first attack NMOSD with and without CTD.MethodsA total of 113 Patients with NMOSD were included and were divided into two groups based on the presence of co-occurring CTD. Their demographic, clinical, laboratory, and image characteristics were obtained through inpatient medical records and follow-ups. Kaplan–Meier survival analysis was used to analyze the effect of CTD in NMOSD patients at the time of first recurrence. The risk factors that could predict complications of NMOSD with CTD was analyzed by binary logistic regression. The ability of homocysteine (Hcy) to predict the coexistence of NMOSD and CTD was analyzed and evaluated by the receiver operating characteristic curve.ResultsThe demographic data, clinical features, cerebrospinal fluid analysis, and MRI findings, except relapse events (including relapse rate, number of recurrences, and time of first recurrence), were similar between the two groups. The serum lymphocyte-to-monocyte ratio and albumin levels were lower (P < 0.05), while serum erythrocyte sedimentation rate and Hcy levels were higher in patients with NMOSD with CTD than in those without CTD (P < 0.001). Kaplan–Meier survival analysis showed that the time of first recurrence in NMOSD patients complicated with CTD was earlier than that of without CTD (log rank test P = 0.035). Logistic regression revealed that serum Hcy levels (OR 1.296, 95% CI, 1.050–1.601, P = 0.016) were independently associated with the occurrence of NMOSD with CTD. The receiver operating characteristic curve area was 0.738 (95% CI, 0.616–0.859; P < 0.001) for Hcy levels. Considering the Hcy concentration of 14.07 μmol/L as the cutoff value, the sensitivity and specificity of predicting the coexistence of first-attack NMOSD and CTD were 56 and 89.8%, respectively.ConclusionsWhen the first-attack NMOSD patients are complicated with CTD, they have a higher recurrence rate, more recurrences, earlier first recurrence, higher serum Hcy levels, and enhanced systemic inflammatory reactions. Furthermore, Hcy levels may help to screen for CTD in patients with first-attack NMOSD.

Alcohol use disorder (AUD) is one of the most common substance use disorders contributing to both behavioral and cognitive impairments in patients with AUD. Recent neuroimaging studies point out that AUD is a typical disorder featured by altered functional connectivity. However, the details about how voxel-wise functional coordination remain unknown. Here, we adopted a newly proposed method named functional connectivity density (FCD) to depict altered voxel-wise functional coordination in AUD. The novel functional imaging technique, FCD, provides a comprehensive analytical method for brain's “scale-free” networks. We applied resting-state functional MRI (rs-fMRI) toward subjects to obtain their FCD, including global FCD (gFCD), local FCD (lFCD), and long-range FCD (lrFCD). Sixty-one patients with AUD and 29 healthy controls (HC) were recruited, and patients with AUD were further divided into alcohol-related cognitive impairment group (ARCI, n = 11) and non-cognitive impairment group (AUD-NCI, n = 50). All subjects were asked to stay stationary during the scan in order to calculate the resting-state gFCD, lFCD, and lrFCD values, and further investigate the abnormal connectivity alterations among AUD-NCI, ARCI, and HC. Compared to HC, both AUD groups exhibited significantly altered gFCD in the left inferior occipital lobe, left calcarine, altered lFCD in right lingual, and altered lrFCD in ventromedial frontal gyrus (VMPFC). It is notable that gFCD of the ARCI group was found to be significantly deviated from AUD-NCI and HC in left medial frontal gyrus, which changes probably contributed by the impairment in cognition. In addition, no significant differences in gFCD were found between ARCI and HC in left parahippocampal, while ARCI and HC were profoundly deviated from AUD-NCI, possibly reflecting a compensation of cognition impairment. Further analysis showed that within patients with AUD, gFCD values in left medial frontal gyrus are negatively correlated with MMSE scores, while lFCD values in left inferior occipital lobe are positively related to ADS scores. In conclusion, patients with AUD exhibited significantly altered functional connectivity patterns mainly in several left hemisphere brain regions, while patients with AUD with or without cognitive impairment also demonstrated intergroup FCD differences which correlated with symptom severity, and patients with AUD cognitive impairment would suffer less severe alcohol dependence. This difference in symptom severity probably served as a compensation for cognitive impairment, suggesting a difference in pathological pathways. These findings assisted future AUD studies by providing insight into possible pathological mechanisms.

Head and neck squamous cell carcinoma (HNSCC) represents one of the most prevalent and malignant tumors of epithelial origins with unfavorable outcomes. Increasing evidence has shown that dysregulated long non-coding RNAs (lncRNAs) correlate with tumorigenesis and genomic instability (GI), while the roles of GI-related lncRNAs in the tumor immune microenvironment (TIME) and predicting cancer therapy are still yet to be clarified. In this study, transcriptome and somatic mutation profiles with clinical parameters were obtained from the TCGA database. Patients were classified into GI-like and genomic stable (GS)-like groups according to the top 25% and bottom 25% cumulative counts of somatic mutations. Differentially expressed lncRNAs (DElncRNAs) between GI- and GS-like groups were identified as GI-related lncRNAs. These lncRNA-related coding genes were enriched in cancer-related KEGG pathways. Patients totaling 499 with clinical information were randomly divided into the training and validation sets. A total of 18 DElncRNAs screened by univariate Cox regression analysis were associated with overall survival (OS) in the training set. A GI-related lncRNA signature that comprised 10 DElncRNAs was generated through least absolute shrinkage and selection operator (Lasso)-Cox regression analysis. Patients in the high-risk group have significantly decreased OS vs. patients in the low-risk group, which was verified in internal validation and entire HNSCC sets. Integrated HNSCC sets from GEO confirmed the notable survival stratification of the signature. The time-dependent receiver operating characteristic curve demonstrated that the signature was reliable. In addition, the signature retained a strong performance of OS prediction for patients with various clinicopathological features. Cell composition analysis showed high anti-tumor immunity in the low-risk group which was evidenced by increased infiltrating CD8+ T cells and natural killer cells and reduced cancer-associated fibroblasts, which was convinced by immune signatures analysis via ssGSEA algorithm. T helper/IFNγ signaling, co-stimulatory, and co-inhibitory signatures showed increased expression in the low-risk group. Low-risk patients were predicted to be beneficial to immunotherapy, which was confirmed by patients with progressive disease who had high risk scores vs. complete remission patients. Furthermore, the drugs that might be sensitive to HNSCC were identified. In summary, the novel prognostic GILncRNA signature provided a promising approach for characterizing the TIME and predicting therapeutic strategies for HNSCC patients.

Abstract Background It is difficult to predict lymph node metastasis in patients with early lung cancer. Pure ground glass opacity (GGO) on computed tomography indicates an early-stage adenocarcinoma that can be removed by limited resection or lobectomy without the need for mediastinal lymph node dissection or sampling, and lung adenocarcinoma with GGO therefore has a good prognosis. We examined the incidence and risk factors of lymph node metastasis in patients with clinical stage IA lung adenocarcinoma. Methods We retrospectively analyzed clinical data for 327 patients with stage IA peripheral lung cancer treated in our hospital from March 2014 to December 2018. The patients were divided into four groups according to computed tomography signs. Lobectomy and systematic lymph node dissection were performed in all patients. Correlations between lymph node metastasis and clinical pathological factors were analyzed by logistic regression. Results Among the 327 patients, 26 (7.95%) had lymph node metastasis. No patients with pure GGO or GGO-dominant types had lymph node metastasis. Logistic regression identified tumor diameter, solid content, plasma carcinoembryonic antigen (CEA) level, pathological type, lymphovascular invasion, and pleural invasion as factors related to the presence of lymph node metastasis. Conclusions Tumor diameter, solid component ratio, plasma CEA level, pathological type, vascular tumor thrombus, and pleural invasion are possible independent risk factors for lymph node metastasis in patients with stage IA lung adenocarcinoma. In contrast, lymph node metastasis is rare in patients with pure GGO or GGO-dominant lung adenocarcinoma.

Abstract In the tumor vascular system, the vascular structure is disordered, the morphology is abnormal, and the structure of the blood vessel walls is incomplete, leading to leakage of the blood vessel wall, elevated interstitial fluid pressure, and elevated blood flow resistance. These alterations lead to local microenvironmental changes, which mainly manifest as a lack of oxygen and acidosis, further affecting the efficacy of chemotherapy drugs. Antiangiogenic drugs can normalize the abnormalities caused by tumor angiogenesis, thereby transferring oxygen and drugs to tumor cells more efficiently through normalized blood vessels and enhancing the efficacy of chemotherapy drugs. Apatinib is a specific VEGFR‐2 inhibitor that blocks the transmission of the VEGF/VEGFR‐2 signaling pathway. In this study, we constructed a nude mouse xenograft model of lung cancer and administered apatinib at different doses and times to detect the normalization of reactive blood vessels through VEGF, α‐SMA, college‐IV, HIF‐1α, and MMP. The ultrastructure of tumor blood vessels was observed by electron microscopy, and the dose and timing of apatinib‐induced normalization of lung cancer in nude mice were confirmed. Then, we observed the inhibitory effect of apatinib combined with pemetrexed on transplanted tumors of lung cancer cells in nude mice at different time points and observed whether combination pemetrexed chemotherapy showed more significant effects in the time window of vascular normalization induced by apatinib. The inhibition of the growth of transplanted tumors was examined. Then 20 patients with advanced non–small cell lung cancer were enrolled, and apatinib sequential chemotherapy drugs were applied as a third‐line chemotherapy regimen to observe its clinical efficacy.

ObjectiveThis study assessed the effects of repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) on serum neurofilament light chain (NfL) levels, alcohol consumption, craving, and psychological impairment in participants with alcohol use disorder (AUD).MethodsParticipants with AUD were randomly assigned to receive one of two treatments (active or sham rTMS). All participants received 10 daily active or sham rTMS sessions over the left DLPFC for 2 weeks, with follow-up visits at baseline and immediately after the completion of the treatments. Serum samples were obtained before and after the intervention. Days of heavy drinking, visual analog scale (VAS) scores, and mental health component scores (MCSs) of the Medical Outcomes Study 36-Item Short Form Health Survey were used to assess the effects of rTMS.ResultsActive rTMS had a significant effect on reducing days of heavy drinking, alcohol craving, and serum NfL levels, and improved social functioning and mental health. The improvement with active rTMS was significantly greater than that with sham rTMS. Correlation analysis revealed that the reduction in the baseline drinking level was positively correlated with declines in the VAS and NfL levels but not with psychological scores.ConclusionRepetitive transcranial magnetic stimulation of the left DLPFC was associated with reducing alcohol consumption and craving in patients with AUD and positively impacted neuropsychological and social function. Serum NfL levels may be useful as an early serological indicator of alcohol-induced brain injury.

The most common symptom of patients with alcohol use disorders (AUD) is cognitive impairment that negatively affects abstinence. Presently, there is a lack of indicators for early diagnosis of alcohol-related cognitive impairment (ARCI). We aimed to assess the cognitive deficits in AUD patients with the help of a specific imaging marker for ARCI. Data-driven dynamic and static global signal topography (GST) methods were applied to explore the cross-talks between local and global neuronal activities in the AUD brain. Twenty-six ARCI, 54 AUD without cognitive impairment (AUD-NCI), and gender/age-matched 40 healthy control (HC) subjects were recruited for this study. We found that there was no significant difference with respect to voxel-based morphometry (VBM) and static GST between AUD-NCI and ARCI groups. And in dynamic GST measurements, the AUD-NCI patients had the highest coefficient of variation (CV) at the right insula, followed by ARCI and the HC subjects. In precuneus, the order was reversed. There was no significant correlation between the dynamic GST and behavioral scores or alcohol consumption. These results suggested that dynamic GST might have potential implications in understanding AUD pathogenesis and disease management.

ObjectiveTo discover the levels of NLR family pyrin domain-containing 3 (NLRP3) in the cerebrospinal fluid (CSF) from adult patients with community-acquired bacterial meningitis (CABM).MethodsWe enrolled 34 patients with CABM, 20 patients with viral meningitis (VM), and 25 patients with non-inflammatory neurological disease. Data on standard clinical parameters, scores, and outcomes were obtained from clinical records, and inflammasome levels in the CSF were measured by an enzyme-linked immunosorbent assay. The area under the receiver operating characteristic curve (AUROC) was used to quantify the diagnostic and prognostic performance of CSF NLRP3 as a biomarker of CABM.ResultsThe levels of NLRP3 were elevated in the CSF of patients with CABM, but levels for ASC, caspase-1, or other inflammasomes did not vary significantly. CSF NLRP3 was positively correlated with clinical severity and with the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte count, albumin quotient (Qalb), and immunoglobulin G quotient (QIgG). Patients with unfavorable outcomes had higher levels of NLRP3 in the CSF, which were correlated with several blood indicators, including NLR, PLR, and lymphocyte and monocyte counts.ConclusionsOur results suggested that the level of CSF NLRP3 could represent the severity of CABM in adults. CSF NLRP3 may be a good biomarker for the diagnosis of CABM and for the discrimination between CABM and VM. It may also be a better biomarker for predicting the prognosis of adult patients with CABM when compared to the NLR or the lymphocyte and monocyte counts.

ObjectiveTo analyze and compare different clinical, laboratory, and magnetic resonance imaging characteristics between pediatric and adult patients with first-attack myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and to explore predictive factors for severity at disease onset.MethodsPatients diagnosed with MOGAD at the First Affiliated Hospital of Zhengzhou University from January 2013 to August 2021 were enrolled in this retrospective study. Age at disease onset, sex, comorbidities, laboratory tests, magnetic resonance imaging (MRI) characteristics, and Expanded Disability Status Scale (EDSS) scores were collected and analyzed. The association between risk factors and initial EDSS scores at disease onset was analyzed using logistic regression models and Spearman correlation analyses. A receiver-operating characteristic (ROC) curve analysis was used to evaluate the predictive ability of the uric acid and homocysteine (Hcy) levels for the severity of neurological dysfunction at the onset of MOGAD.ResultsSixty-seven patients (female, n=34; male, n=33) with first-attack MOGAD were included in this study. The mean age at onset was 26.43 ± 18.22 years (range: 3–79 years). Among patients

Background: Alcohol dependence, a global public health problem, leads to structural and functional damage in the brain. Alcohol dependence patients present complex and varied clinical manifestations and live with general complaints existing in contemporary society, making most people with alcohol dependence hard to identify. Therefore, it is important to find potential biomarkers for the diagnosis and evaluation of alcohol dependence. In the study, we explored potential biomarkers for the diagnosis and monitoring of diseases and evaluated brain structural changes in alcohol dependence patients.Methods: Enzyme-linked immunosorbent assay (ELSA) was employed to detect the expression of serum nucleotide-binding oligomerization domain containing 3 (NLRP3) and single-molecule array (Simoa) assay was used to detect the expression of serum neurofilament light (NfL) in 50 alcohol dependence patients and 50 controls with no drinking history. Alcohol consumption was measured by standard drinks. Neuropsychological assessments, including the Montreal cognitive assessment (MoCA), Pittsburgh sleep quality index (PSQI), generalized anxiety disorder (GAD-7), and patient health questionnaire-9 (PHQ-9), were conducted to evaluate cognitive function and psychological state. The degree of white matter lesions (WMLs) was rated using the Fazekas scale based on magnetic resonance imaging analysis. White matter structure was quantified using the voxel-based morphometry method. The correlations between NLRP3 levels, NfL levels, neuropsychological dysfunction, the degree of WMLs, and white matter volume (WMV) were analyzed in alcohol dependence patients.Results: Serum NLRP3 and NfL levels were higher in the alcohol dependence group. NLRP3 levels were irrelevant to monthly alcohol assumption as well as to the MoCA, PSQI, GAD-7, PHQ-9, and Fazekas scale scores and WMV. NfL levels were positively correlated with the PSQI and PHQ-9 scores as well as the degree of WMLs and negatively correlated with the MoCA scores and WMV. No associations were evident between NfL and monthly alcohol assumption and GAD-7 scores in the alcohol dependence group.Conclusion: This study supports the potential value of serum NfL as a non-invasive biomarker in alcohol dependence. The association with neuropsychological dysfunction and degree of WMLs has implications to use NfL as a promising biomarker to assess the severity of brain damage as well as the progression and prognosis of alcohol dependence.

Neuromyelitis optica spectrum disorders (NMOSDs) are inflammatory diseases with a high risk of recurrence and progressive disability, and it is crucial to find sensitive and reliable biomarkers for prognosis and the early prediction of relapse. Highly active NMOSD is defined as two or more clinical relapses within a 12-month period. In this study, we analyzed independent risk factors among patients with aquaporin-4 (AQP4)-IgG positive highly active NMOSD. In this retrospective study, we analyzed the data of 94 AQP4-IgG positive patients with highly active NMOSD and 105 AQP4-IgG positive controls with non-highly active NMOSD. In order to rule out possible effects of previous treatments (such as glucocorticoids, immunoglobulin, and immunosuppressants), we focused on the first-attack NMOSD patients admitted to our hospital. Clinical data, including the age of onset, gender, comorbidities, and serum analysis and cerebrospinal fluid (CSF) analysis results, were collected, after which logistic regression models were used to determine the associations between the clinical factors and relapse outcomes. The prevalence of connective tissue disease and the proportion of antinuclear antibody (ANA)-positivity were higher in the highly active NMOSD group than in the control group. The leukocyte counts, homocysteine (Hcy) levels, CSF leukocyte counts, protein concentrations, IgG indexes, and 24h IgG synthesis rates were also higher in the highly active NMOSD group. The results of multivariate analysis indicated that connective tissue disease comorbidity (OR = 5.953, 95% CI: 1.221–29.034, P = 0.027), Hcy levels (OR = 1.063, 95% CI: 1.003–1.126, P = 0.04), and 24h IgG synthesis rate (OR = 1.038, 95% CI: 1.003–1.075, P = 0.034) may be independent risk factors for AQP4-IgG positive highly active NMOSD relapse after adjusting for various variables. Comorbidity of connective tissue disease, Hcy levels, and 24h IgG synthesis rate may be independent risk factors for AQP4-IgG positive highly active NMOSD.

Background The aim of this study was to investigate the feasibility of using a combination of apatinib in the treatment of non‐small cell lung cancer. Apatinib is a tyrosine kinase inhibitor which selectivelyacts on vascular endothelial growth factor receptor 2 (VEGFR‐2) and has shown good efficacy in a variety of malignancies, but the drug resistance is fast in single drug therapy. Methods The inhibitory effect of apatinib and other drugs on lung cancer cells was determined by CCK‐8 test in vitro, and the IC50 value was determined. To establish a nude mouse xenograft model, observe the inhibitory effect of apatinib combined with other drugs on lung cancer xenografts in nude mice; immunohistochemical staining of tumor microvessel density and Ki67 expression in transplanted tumor tissues; Western blot analysis of related signaling pathways expression; immunohistochemistry was used to detect tumor microvessel density in other organs and to observe its safety. Results In this study, we found apatinib combined with pemetrexed, the first and third generation of epidermal growth factor receptor tyrosine kinase inhibitor, could synergistically inhibit the proliferation of non‐small cell lung cancer cell (NSCLC) lines, reduce the microvessel density and Ki67 protein levels of three non‐small cell lung cancer xenografts, and enhance anti‐tumor activity by synergistically inhibiting the MAPK‐ERK and PI3K‐AKT‐mTOR signaling pathway. Furthermore, there were no pathological abnormalities in the heart, brain, liver and kidney of each group. Conclusions The efficacy of apatinib combination is better than that of monotherapy, and there is no significant difference in toxicity of important organs, which suggests the feasibility of a combination of apatinib in the treatment of non‐small cell lung cancer.

Lakes are one of the natural reservoirs of antibiotic resistance genes (ARGs) in environments. Long retention times in lakes potentially allow ARGs to persist and may create increased opportunities for the emergence of resistant pathogens. In this study, we investigated the prevalence, source and dissemination risk of ARGs in the sediments of a typical urban lake, Lake Tai (China) which has been a drastic example of water pollution with eutrophication in the world due to its proliferated cyanobacterial blooms. High-throughput profilings of ARGs in the sediments of Lake Tai were characterized with metagenomic assembly, and were compared with those in other global lakes from Australia, Canada, Indonesia, Rwanda and the United States of America. The hosts of ARGs in the sediments of Lake Tai were explored based on the taxonomic annotation of ARG-carrying contigs and network analysis, and a novel recently-discovered crAssphage was employed for source tracking of resistance bacteria. Meanwhile, the potential resistome risk was identified by projecting the co-occurrence of acquired ARGs, mobile genetic elements (MGEs) and human bacterial pathogens into a three-dimensional exposure space. Results showed 321 ARG subtypes belonging to 21 ARG types were detected in the sediments of Lake Tai, dominated by multidrug, macrolide-lincosamide-streptogramin, bacitracin, quinolone, mupirocin and trimethoprim resistance genes. Relatively, the ARG levels in the sediments of Lake Tai were significantly higher than those in other global lakes. Source tracking showed the coverages of detected crAssphage in the sediments of Lake Tai were positively correlated with the total ARG coverage, suggesting the contribution of human fecal contamination to the prevalence of ARGs in this lake. It should be noted that the co-occurrence ratio of ARGs, MGEs and human pathogens in the sediments of Lake Tai was higher than that in other global lakes, likely indicating a higher risk for the resistance dissemination in the China's third largest freshwater lake. Keywords: Antibiotic resistance genes, Metagenomic assembly, Microbial source tracking, CrAssphage, Resistome risk, Lake Tai

Abstract Background N-acetylcysteine is a classic mucolytic agent. This study aimed to investigate the efficacy of N-acetylcysteine on reducing the risk of exacerbations in bronchiectasis patients. Methods A prospective, randomized, controlled trial was conducted between April 1, 2014 and December 31, 2016 in five general hospitals in Shandong Province, China. Adult bronchiectasis patients with at least two exacerbations in the past year were potentially eligible. Patients were randomly assigned to receive oral N-acetylcysteine (600 mg, twice daily, 12 months) or on-demand treatment. Results A total of 161 patients were eligible for randomization (81 to the N-acetylcysteine group and 80 to the control group). During the 12-month follow-up, the incidence of exacerbations in the N-acetylcysteine group was significantly lower than that in the control group (1.31 vs. 1.98 exacerbations per patient-year; risk ratio, 0.41; 95% CI, 0.17–0.66; P = 0.0011). The median number of exacerbations in the N-acetylcysteine group was 1 (0.5–2), compared with 2 (1–2) in the control group (U = − 2.95, P = 0.003). A total of 24.7% of the N-acetylcysteine group patients and 11.3% of the control group patients remained exacerbation-free throughout the 12-month follow-up (χ 2 = 4.924, P = 0.026). Compared with the control group, the volume of 24-h sputum in the N-acetylcysteine group was significantly reduced (t = − 3.091, P = 0.002). Additionally, the N-acetylcysteine group showed a significant improvement in the quality of life. No severe adverse events were reported in the intervention group. Conclusion The long-term use of N-acetylcysteine is able to reduce the risk of exacerbations for bronchiectasis patients in Shandong Province, China. The results of this study should be verified in a larger randomized controlled trial. Trial registration ClinicalTrials.gov (NCT02088216) (Registered date: March 5, 2014).

Ischemic stroke is one of the main central nervous system diseases and is associated with high disability and mortality rates. Recombinant tissue plasminogen activator (rt-PA) and mechanical thrombectomy are the optimal therapies available currently to restore blood flow in patients with stroke; however, their limitations are well recognized. Therefore, new treatments are urgently required to overcome these shortcomings. Recently, stem cell transplantation technology, involving the transplantation of induced pluripotent stem cells (iPSCs), has drawn the interest of neuroscientists and is considered to be a promising alternative for ischemic stroke treatment. iPSCs are a class of cells produced by introducing specific transcription factors into somatic cells, and are similar to embryonic stem cells in biological function. Here, we have reviewed the current applications of stem cells with a focus on iPSC therapy in ischemic stroke, including the neuroprotective mechanisms, development constraints, major challenges to overcome, and clinical prospects. Based on the current state of research, we believe that stem cells, especially iPSCs, will pave the way for future stroke treatment.

Materials with designed gradient nanograins exhibit unprecedented mechanical properties, such as superior strength and ductility. In this study, a heterostructured 304 stainless steel with solely gradient dislocation structure (GDS) in micron-sized grains produced by cyclic-torsion processing was demonstrated to exhibit a substantially improved yield strength with slightly reduced uniform elongation, compared with its coarse grained counterparts. Microstructural observations reveal that multiple deformation mechanisms, associated with the formation of dense dislocation patterns, deformation twins and martensitic phase, are activated upon straining and contribute to the delocalized plastic deformation and the superior mechanical performance of the GDS 304 stainless steel.

Objective: To investigate prospective associations between triglyceride (TG) level and prognosis of first-attacked patients with neuromyelitis optica spectrum disorders (NMOSD).Methods: This retrospective study included 196 patients newly diagnosed with NMOSD from June 2014 to December 2018. Data of clinical parameters, including age of onset, sex, BMI, blood lipid levels, anti-aquaporin-4 status, serum glucose level, therapy regimens, comorbidities, initial Expanded Disability Status Scale (EDSS), relapses, and outcomes were collected. We used logistic regression models to examine the associations among relevant clinical factors and outcomes, and statistical analyses were performed using the SPSS 23.0 software.Results: Compared with the high TG group, residual EDSS was relatively lower in the normal TG group (median 1.0 vs. 2.0, P = 0.002). In the univariate analysis, TG level was positively correlated with outcomes (OR 1.75, 95% CI 1.18–2.60, P = 0.005) and relapses (OR 1.57, 95% CI 1.07–2.31, P = 0.02). Our stratified analysis suggested that patients with normal BMI (OR 4.90, 95% CI 2.10–11.44, P = 0.001) were closely correlated with poor recovery owing to increased TG level. In the multivariate analysis, a statistically significant association still existed between TG level and outcomes (OR 3.44, 95% CI 1.02–11.64; P = 0.040) after adjusting for various variables.Conclusions: In first-attacked NMOSD patients, TG level was positively associated with poor recovery. Early monitoring and treatment of elevated TG level in NMOSD patients are important.

Lung adenocarcinoma (LUAD) is one of the most lethal malignancies, posing a threat to human health. However, the molecular mechanisms underlying LUAD development remain largely unknown. In this study, we found that miR-1-3p was significantly downregulated in human LUAD tissues and cell lines and played an inhibitory role in LUAD cell tumorigenesis, as evidenced by the significantly reduced viability, migration, and invasion of LUAD cells in response to miR-1-3p overexpression. Mechanistically, microRNA (miR)-1-3p physically interacted with the 3′-untranslated region (UTR) of protein regulator of cytokinesis 1 (PRC1) mRNA, leading to downregulation of PRC1. Overexpression of PRC1 reversed the inhibitory effects of miR-1-3p on LUAD cell tumorigenesis, suggesting that the miR-1-3p/PRC1 axis is majorly involved in suppressing LUAD development and progression. Consistently, PRC1 was dramatically induced in LUAD tissues and cell lines as well as associated with a poor prognosis in LUAD patients. Taken together, our study identified the miR-1-3p/PRC1 axis as an important regulatory mechanism contributing to LUAD inhibition and provided valuable clues for the future development of therapeutic strategies against LUAD.

The clinical use of genetic variation in the evaluation of cancer risk is expanding, and thus understanding how determinants of cancer susceptibility identified in one population can be applied to another is of growing importance. However there is considerable debate on the relevance of ethnic background in clinical genetics, reflecting both the significance and complexity of genetic heritage. We address this via a systematic review of reported associations with cancer risk for 82 markers in 68 studies across six different cancer types, comparing association results between ethnic groups and examining linkage disequilibrium between risk alleles and nearby genetic loci. We find that the relevance of ethnic background depends on the question. If asked whether the association of variants with disease risk is conserved across ethnic boundaries, we find that the answer is yes, the majority of markers show insignificant variability in association with cancer risk across ethnic groups. However if the question is whether a significant association between a variant and cancer risk is likely to reproduce, the answer is no, most markers do not validate in an ethnic group other than the discovery cohort's ancestry. This lack of reproducibility is not attributable to studies being inadequately populated due to low allele frequency in other ethnic groups. Instead, differences in local genomic structure between ethnic groups are associated with the strength of association with cancer risk and therefore confound interpretation of the implied physiologic association tracked by the disease allele. This suggest that a biological association for cancer risk alleles may be broadly consistent across ethnic boundaries, but reproduction of a clinical study in another ethnic group is uncommon, in part due to confounding genomic architecture. As clinical studies are increasingly performed globally this has important implications for how cancer risk stratifiers should be studied and employed.