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BackgroundTuberculum sellae meningioma (TSM), a common benign tumor in the sellae region, usually causes neurological deficits, such as vision impairment, by squeezing the peripheral neurovascular structures. Surgical management is recommended as the optimal strategy for TSM treatment and vision restoration. However, it remains challenging to resect TSM in the traditional transcranial approach (TCA). Recently, the endoscopic endonasal approach (EEA) has emerged as an effective option in skull base surgeries. Besides the effectivity, the advantages and limitations of EEA in TSM surgery remain controversial.ObjectWe compared the surgical outcomes and complications between TCA and EEA surgeries to identify the principles in TSM surgical management.MethodsRetrospective analysis was performed on the patients, who underwent TSM surgery in Wuhan Union Hospital between January 2017 and December 2021. The patients were assigned to TCA or EEA group according to the surgery they experienced. All patients were analyzed with the extent of tumor resection, vision outcome, postoperative complications, and follow-up results.ResultsA total of 112 patients were enrolled in this study, including 78 in TCA group and 34 in EEA group. The mean follow-up was 20.5 months (range 3–36 months). There were no statistically significant differences in patient demographic data, preoperative symptoms, and tumor characteristics between TCA and EEA groups. Both TCA and EEA surgeries are effective in TSM resection with relatively high gross total resection rates (85.9% in TCA vs. 91.2% in EEA, p > .05). Meanwhile, EEA surgery has a better outcome in vision restoration or stabilization than TCA surgery (74.6% in TCA vs. 93.1% in EEA, p

Glioblastoma multiforme (GBM) is the most malignant brain cancer with great heterogeneities in many aspects, such as prognosis, clinicopathological features, immune landscapes, and immunotherapeutic responses. Considering that gene interaction network is relatively stable in a healthy state but widely perturbed in cancers, we sought to explore the multidimensional heterogeneities of GBM through evaluating the degree of network perturbations. The gene interaction network perturbations of GBM samples (TCGA cohort) and normal samples (GTEx database) were characterized by edge perturbations, which were quantized through evaluating the change in relative gene expression value. An unsupervised consensus clustering analysis was performed to identify edge perturbation-based clusters of GBM samples. Results revealed that the edge perturbation of GBM samples was stronger than that of normal samples. Four edge perturbation-based clusters of GBM samples were identified and showed prominent heterogeneities in prognosis, clinicopathological features, somatic genomic alterations, immune landscapes, and immunotherapeutic responses. In addition, a sample-specific perturbation of gene interaction score (SPGIScore) was constructed based on the differently expressed genes (DEGs) among four clusters, and exhibited a robust ability to predict prognosis. In conclusion, the bioinformatics approach based on sample-specific edge perturbation in gene interaction network provided a new perspective to understanding the multidimensional heterogeneities of GBM.

Background: Full endoscopic lumbar interbody fusion (Endo-LIF) is a representative recent emerging minimally invasive operation. The hidden blood loss (HBL) in an Endo-LIF procedure and its possible risk factors are still unclear. Methods: The blood loss (TBL) was calculated by Gross formula. Sex, age, BMI, hypertension, diabetes, ASA classification, fusion levels, surgical approach type, surgery time, preoperative RBC, HGB, Hct, PT, INR, APTT, Fg, postoperative mean arterial pressure, postoperative heart rate, Intraoperative blood loss (IBL), patient blood volume were included to investigate the possible risk factors by correlation analysis and multiple linear regression between variables and HBL. Results:Ninety-six patients (23 males, 73 females) who underwent Endo-LIF were retrospective analyzed in this study. The HBL was 240.11 (65.51, 460.31) mL (median [interquartile range]). Fusion levels (p = 0.002), age (p = 0.003), hypertension (p = 0.000), IBL (p = 0.012), PT (p = 0.016), preoperative HBG (p = 0.037) were the possible risk factors. Conclusion: Fusion levels, younger age, hypertension, prolonged PT, preoperative HBG are possible risk factors of HBL in an Endo-LIF procedure. More attention should be paid especially in multi-level minimally invasive surgery. The increase of fusion levels will lead to a considerable HBL.

Symptomatic lumbar disc herniation (LDH) is widely treated using percutaneous endoscopic lumbar discectomy (PELD). In the present PELD surgery, performing decompression under endoscope still takes a long time to explore the rupture site of annulus fibrosus, resulting in prolonged operation time and over‐invasion of the undegenerated annulus fibrosus. A wide range of intraoperative exploration also induces an iatrogenic injury of the normal annulus fibrosus, even aggravating intervertebral disc degeneration, which may lead to early postoperative recurrence in severe case. Hence, it is important to seek a precise decompression in PELD surgery. Under this kind of realization, more spinal surgeons possibly choose a disc staining before performing decompression. However, the classical disc staining technique still has its shortcomings. First of all, an appropriate dose of staining cannot be accurately mastered, even induces unqualified staining effect. Second, the duration of surgery and the times of fluoroscopy will be increased. Finally, what surgeons see under the endoscope is the staining result but not the staining process. Hence, this is accomplished more effectively by designing procedures that perform fully visible disc staining under spinal endoscope. There is no specific research to discuss the technique note of endoscopic staining in PELD surgery. We have come up with a new original technology of endoscopic staining with methylene blue injection in PELD for treatment of LDH.

ObjectiveThis study proposes to explore the protective effect of Zuo-Gui-Wan (ZGW) aqueous extract on spinal glucocorticoid-induced osteoporosis (GIOP) in vivo and in vitro, and the underlying mechanisms of ZGW in GIOP and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) were conducted.MethodsIn vivo, SD rats were randomly divided into three groups: control group (CON), dexamethasone (DEXM) group, and ZGW group, which were given vehicle, DEXM injection, and ZGW intragastric administration at the same time. Vertebral bone microarchitecture, biomechanics, histomorphology, serum AKP activity, and the autophagosome of osteoblasts were examined. The mRNA expressions of let-7f, autophagy-associated genes (mTORC1, Beclin-1, ATG12, ATG5, and LC3), Runx2, and CTSK were examined. In vitro, the let-7f overexpression/silencing vector was constructed and transfected to evaluate the osteogenic differentiation of BMSCs. Western blot was employed to detect the expression of autophagy-associated proteins (ULK2, ATG5, ATG12, Beclin-1, LC3).ResultsIn vivo, ZGW promoted the bone quantity, quality, and strength; alleviated histological damage; increased the serum AKP activity; and reduced the autophagosome number in osteoblasts. Moreover, ZGW increased the let-7f, mTORC1, and Runx2 mRNA expressions and reduced the Beclin-1, ATG12, ATG5, LC3, and CTSK mRNA expressions. In vitro, bioinformatics prediction and dual luciferase reporter gene assay verified that let-7f targeted the binding to ULK2 and negatively regulated the ULK2 expression. Furthermore, by let-7f overexpression/silencing, ZGW may promote osteoblast differentiation of BMSCs by regulating let-7f and autophagy as evidenced by Western blot (ULK2, ATG5, ATG12, Beclin-1, LC3).ConclusionsZGW may ameliorate GC-induced spinal osteoporosis by promoting osteoblast differentiation of BMSCs by activation of let-7f and suppression of autophagy.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is an acute and sometimes fatal cerebrovascular disease. The chronobiological patterns of aSAH are still unclear worldwide. This 15-year time-series study aims to clarify the chronobiological patterns including seasonal, monthly, weekly, and circadian distributions of aSAH. Methods: We retrospectively analyzed the medical records of aSAH patients in central China. To investigate seasonal and weekly distributions, we used the χ2 goodness-of-fit test to analyze the uniformity of the onset time. To explore monthly and circadian distributions, we established Fourier models to show the rhythmicity in chronobiological patterns. Subgroup analyses were conducted to assess the impact of age, gender, hypertension statuses, and aneurysmal characteristics (number, size, and location) on the chronobiological patterns of aSAH. Results: A total of 1469 patients with aSAH were recruited in the study. The seasonal and monthly distribution exhibited significantly higher incidence in winter and January/December and lower incidence in summer and July. The weekly distribution of aSAH onset showed no significant uneven variation. The circadian distribution of aSAH exhibited a significant pattern (p = 0.0145), with a morning peak around 8:00, and a late afternoon peak at 16:00–20.00. The circadian rhythmicity varied in subgroups of different ages, genders, and aneurysmal locations. Conclusion: The occurrence of aSAH exhibits significant circannual and circadian patterns among the Chinese population. Patients with aSAH of different ages, genders, and aneurysmal locations would present different chronobiological patterns.

Abstract Chimeric antigen receptor-based T-cell immunotherapy is a promising strategy for treatment of hematological malignant tumors; however, its efficacy towards solid cancer remains challenging. We therefore focused on developing nanobody-based CAR-T cells that treat the solid tumor. CD105 expression is upregulated on neoangiogenic endothelial and cancer cells. CD105 has been developed as a drug target. Here we show the generation of a CD105-specific nanobody, an anti-human CD105 CAR-T cells, by inserting the sequences for anti-CD105 nanobody-linked standard cassette genes into AAVS1 site using CRISPR/Cas9 technology. Co-culture with CD105+ target cells led to the activation of anti-CD105 CAR-T cells that displayed the typically activated cytotoxic T-cell characters, ability to proliferate, the production of pro-inflammatory cytokines, and the specific killing efficacy against CD105+ target cells in vitro. The in vivo treatment with anti-CD105 CAR-T cells significantly inhibited the growth of implanted CD105+ tumors, reduced tumor weight, and prolonged the survival time of tumor-bearing NOD/SCID mice. Nanobody-based CAR-T cells can therefore function as an antitumor agent in human tumor xenograft models. Our findings determined that the strategy of nanobody-based CAR-T cells engineered by CRISPR/Cas9 system has a certain potential to treat solid tumor through targeting CD105 antigen.

The secreting function of pituitary adenomas (PAs) plays a critical role in making the treatment strategies. However, Magnetic Resonance Imaging (MRI) analysis for pituitary adenomas is labor intensive and highly variable among radiologists. In this work, by applying convolutional neural network (CNN), we built a segmentation and classification model to help distinguish functioning pituitary adenomas from non-functioning subtypes with 3D MRI images from 185 patients with PAs (two centers). Specifically, the classification model adopts the concept of transfer learning and uses the pre-trained segmentation model to extract deep features from conventional MRI images. As a result, both segmentation and classification models obtained high performance in two internal validation datasets and an external testing dataset (for segmentation model: Dice score = 0.8188, 0.8091 and 0.8093 respectively; for classification model: AUROC = 0.8063, 0.7881 and 0.8478, respectively). In addition, the classification model considers the attention mechanism for better model interpretation. Taken together, this work provides the first deep learning-based tumor region segmentation and classification models of PAs, which enables early diagnosis and subtyping PAs from MRI images.

Oblique lumbar interbody fusion (OLIF) has been driven to the maturity stage in recent years. However, postoperative symptoms such as thigh paresthesia resulting from intraoperative retraction of the psoas major (PM) have sometimes occurred. The aim of this study was to assess the different positions and morphology of PM muscles and their relationship with clinical outcomes after OLIF by introducing the Moro zones. Patients who underwent L4-5 OLIF at our institution between April 2019 and June 2021 were reviewed and all data were recorded. All patients were grouped by Moro zones into a Moro A cohort and a Moro I and II cohort based on the front edges of their left PM muscles. A total of 94 patients were recruited, including 57 in the Moro A group and 37 in the Moro I and II group. Postoperative thigh pain or numbness occurred in 12 (21.1%) and 2 (5.4%) patients in the Moro A group and the Moro I and II group, respectively. There was no difference in the psoas major transverse diameter (PMTD) between groups preoperatively, while longer PMTD was revealed postoperatively in the Moro A group. The operating window (OW) and psoas major sagittal diameter (PMSD) showed significant differences within and between groups. Thirteen patients had teardrop-shaped PM muscles, with 92.3% in the Moro A group showing significantly worse clinical scores at 1-week follow-up. The Moro zones of the PM affected the short-term outcomes after OLIF. Preoperative measurements and analysis of OW, PMSD and PM morphology should be performed as necessary to predict short-term outcomes.

ObjectiveCraniopharyngioma has always been a challenge for the neurosurgeon, and there is no consensus on optimal treatment. The objective of this study was to compare surgical outcomes and complications between transcranial surgery (TCS) and endoscopic endonasal surgery (EES) of craniopharyngiomas.MethodsA retrospective review of patients who underwent craniopharyngioma resection at Wuhan Union Hospital between January 2010 and December 2019 was performed. A total of 273 patients were enrolled in this retrospective study. All patients were analyzed with surgical effects, endocrinologic outcomes, complications, and follow-up results.ResultsA total of 185 patients underwent TCS and 88 underwent EES. There were no significant differences in patient demographic data, preoperative symptoms, and tumor characteristics between the two groups. The mean follow-up was 30.5 months (range 8–51 months). The EES group had a greater gross total resection (GTR) rate (89.8% EES vs. 77.3% TCS, p < 0.05) and lower rate of hypopituitarism (53.4% EES vs. 68.1% TCS, p < 0.05) and diabetes insipidus (DI) (51.1% EES vs. 72.4% TCS, p < 0.05). More postoperative cerebrospinal fluid (CSF) leaks occurred in the EES group (4.5% EES vs. 0% TCS, p < 0.05). More patients in the EES group with preoperative visual deficits experienced improvement after surgery (74.5% EES vs. 56.3% TCS, p < 0.05). There were statistical differences in the recurrence rates (12.5% EES vs. 23.8% TCS, p < 0.05) between the 2 groups.ConclusionThese data support the view that EES is a safe and effective minimally invasive surgery compared to TCS. Compared to TCS, EES has fewer surgical complications and a lower recurrence rate.

Benzalkonium chloride (BC) is widely used for disinfection in food industry. However, prolonged exposure to BC may lead to the emergence of BC adapted strains of Listeria monocytogenes, an important foodborne pathogen. Until now, two communication systems, the LuxS/AI-2 system and the Agr system, have been identified in L. monocytogenes. This study aimed to investigate the role of communication systems in BC adaptation and the effect of BC adaptation on two communication systems and the communication-controlled behaviors in L. monocytogenes. Results demonstrated that the Agr system rather than the LuxS system plays an important role in BC adaptation of L. monocytogenes. Neither luxS expression nor AI-2 production was affected by BC adaptation. On the other hand, the expression of the agr operon and the activity of the agr promoter were significantly increased after BC adaptation. BC adaptation enhanced biofilm formation of L. monocytogenes. However, swarming motility was reduced by BC adaptation. Data from qRT-PCR showed that flagella-mediated motility-related genes (flaA, motA, and motB) were downregulated in BC adapted strains. BC adaptation increased the ability of L. monocytogenes to adhere to and invade Caco-2 cells but did not affect the hemolytic activity. Compared with the wild-type strains, the expression levels of virulence genes prfA, plcA, mpl, actA, and plcB increased more than 2-fold in BC adapted strains; however, lower than 2-fold changes in the expression of hemolysis-associated gene hly were observed. Our study suggests that BC adaptation could increase the expression of the Agr system and enhance biofilm formation, invasion, and virulence of L. monocytogenes, which brings about threats to food safety and public health. Therefore, effective measures should be taken to avoid the emergence of BC adapted strains of L. monocytogenes.

Localization of defect sites is a major challenge for surgical repair of cerebrospinal fluid (CSF) leaks. Here, we report a case in which we applied a 3-dimensional (3D) printed model to accurately identify the defect sites and facilitate the successful repair of a cranial CSF leak. A 37-year-old female patient diagnosed with recurrent nasopharyngeal carcinoma suffered CSF rhinorrhea and severe bacterial meningitis. Lumbar drainage and antibiotic administration failed to control the condition. In addition to high resolution computed tomography and magnetic resonance imaging, we applied a 3D printed model of the skull to improve the understanding of the osseous destruction at the skull base and aid in accurately localizing the defect sites of the right middle fossa. Accordingly, a right temporalis pedicled flap combined with an autogenous fascia lata flap was applied to cover the defect sites. The leak stopped postoperatively, and meningitis was relieved by enhanced antibacterial treatment. As a complement to high resolution computed tomography and magnetic resonance imaging, a 3D printed model may improve localization of complex defect sites and surgical planning by allowing preoperative visualization of the skull condition.

RPP25, a 25 kDa protein subunit of ribonuclease P (RNase P), is a protein-coding gene. Disorders associated with RPP25 include chromosome 15Q24 deletion syndrome and diffuse scleroderma, while systemic sclerosis can be complicated by malignancy. However, the functional role of RPP25 expression in glioblastoma multiforme (GBM) is unclear. In this study, comprehensive bioinformatics analysis was used to evaluate the impact of RPP25 on GBM occurrence and prognosis. Differential analysis of multiple databases showed that RPP25 was commonly highly expressed in multiple cancers but lowly expressed in GBM. Survival prognostic results showed that RPP25 was prognostically relevant in six tumors (CESC, GBM, LAML, LUAD, SKCM, and UVM), but high RPP25 expression was significantly associated with poor patient prognosis except for CESC. Analysis of RPP25 expression in GBM alone revealed that RPP25 was significantly downregulated in GBM compared with normal tissue. Receiver operating characteristic (ROC) combined with Kaplan-Meier (KM) analysis and Cox regression analysis showed that high RPP25 expression was a prognostic risk factor for GBM and had a predictive value for the 1-year, 2-year, and 3-year survival of GBM patients. In addition, the expression of RPP25 was correlated with the level of immune cell infiltration. The gene set enrichment analysis (GSEA) results showed that RPP25 was mainly associated with signalling pathways related to tumor progression and tumor metabolism.

Abstract Background Adjacent segment disease (ASD) is a well-known complication after interbody fusion. Pedicle screw-rod revision possesses sufficient strength and rigidity. However, is a surgical segment with rigid fixation necessary for ASD reoperation? This study aimed to investigate the biomechanical effect of different instrumentation on lateral lumbar interbody fusion (LLIF) for ASD treatment. Methods A validated L2~5 finite element (FE) model was modified for simulation. ASD was considered the level cranial to the upper-instrumented segment (L3/4). Bone graft fusion in LLIF with bilateral pedicle screw (BPS) fixation occurred at L4/5. The ASD segment for each group underwent a) LLIF + posterior extension of BPS, b) PLIF + posterior extension of BPS, c) LLIF + lateral screw, and d) stand-alone LLIF. The L3/4 range of motion (ROM), interbody cage stress and strain, screw-bone interface stress, cage-endplate interface stress, and L2/3 nucleus pulposus of intradiscal pressure (NP-IDP) analysis were calculated for comparisons among the four models. Results All reconstructive models displayed decreased motion at L3/4. Under each loading condition, the difference was not significant between models a and b, which provided the maximum ROM reduction (73.8 to 97.7% and 68.3 to 98.4%, respectively). Model c also provided a significant ROM reduction (64.9 to 77.5%). Model d provided a minimal restriction of the ROM (18.3 to 90.1%), which exceeded that of model a by 13.1 times for flexion-extension, 10.3 times for lateral bending and 4.8 times for rotation. Model b generated greater cage stress than other models, particularly for flexion. The maximum displacement of the cage and the peak stress of the cage-endplate interface were found to be the highest in model d under all loading conditions. For the screw-bone interface, the stress was much greater with lateral instrumentation than with posterior instrumentation. Conclusions Stand-alone LLIF is likely to have limited stability, particularly for lateral bending and axial rotation. Posterior extension of BPS can provide reliable stability and excellent protective effects on instrumentation and endplates. However, LLIF with the use of an in situ screw may be an alternative for ASD reoperation.

Background: Anlotinib is a multi-target anti-angiogenic agent. This retrospective study aimed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide for the treatment of recurrent high-grade glioma.Materials and Methods: The clinical data of patients with recurrent high-grade glioma treated with anlotinib alone or in combination with temozolomide in our cancer center were collected and analyzed. Treatment response was evaluated according to the response assessment for neuro-oncology criteria. Progression-free survival, progression-free survival at 6 months, overall survival, and overall survival at 12 months were evaluated by Kaplan–Meier method and compared by log-rank test.Results: Between August 2019 and December 2020, 31 patients with recurrent high-grade glioma (21 of grade 4 and 10 of grade 3) were enrolled in this study. Seventeen patients received anlotinib alone and 14 received anlotinib plus temozolomide. All patients were heavily treated, the median lines of previous treatments were 2, and the median Karnofsky score was 60. At the data cutoff date, the median progression-free survival was 4.5 months and the progression-free survival at 6 months was 43.5%. The median overall survival was 7.7 months, and the overall survival at 12 months was 26.7%. The progression-free survival at 6 months and the overall survival at 12 months for 21 patients with grade 4 glioma was 40.2 and 27.9%, respectively. The tumor objective response rate was 41.9% in all patients and 33.3% in patients with grade 4 glioma. No grade 3 or worse treatment-related adverse events were recorded during the treatment.Conclusion: Anlotinib alone or in combination with temozolomide showed encouraging efficacy and favorable tolerability in patients with recurrent high-grade glioma who had been heavily treated.

Glioma is the most common malignancy of the central nervous system. Although advances in surgical resection, adjuvant radiotherapy, and chemotherapy have been achieved in the last decades, the prognosis of gliomas is still dismal. COL5A1 is one of the collagen members with minor content but prominent functions. The present study examined the biological functions, prognostic value, and gene-associated tumor-infiltrating immune cells of COL5A1 through experiments and bioinformatics analysis. We found that the overexpression of COL5A1 was positively correlated with the increasing tumor malignancies and indicated poor prognosis in gliomas. Moreover, downregulation of COL5A1 could inhibit proliferation and migration of glioma cells and enhance their temozolomide sensitivities in vitro. Further bioinformatic analysis revealed that COL5A1 and its co-expressed genes participated in a number of pathways and biological processes involved in glioma progression. Finally, we evaluated the tumor-infiltrating immune cells of gliomas depending on COL5A1 and found that the percentages of the dendritic cells, which were known as the central mediator of tumor microenvironment in gliomas, were positively associated with the expression levels of COL5A1. Taken together, COL5A1 is an important biomarker and potential therapeutic target of gliomas.

Background: The incidence of Clostridioides difficile infection (CDI) has increased in recent years in patients with inflammatory bowel disease (IBD). C. difficile is a toxin-producing bacterium, and CDI results in the worsening of underlying IBD, increasing the risk of IBD treatment failure, surgery, and hospitalization. Because the symptoms of CDI overlap with those of IBD, it is challenging to make a differential diagnosis. Therefore, early, rapid, and reliable diagnostic tools that can identify CDI in IBD patients would be valuable to clinicians. Methods: This study retrospectively collected 135 patients with IBD. Among them, 44 patients were diagnosed with CDI, and 42 patients were diagnosed with viral or fungal infections. A total of 49 patients without infections were defined as the control group. The diagnostic values of procalcitonin (PCT), C-reactive protein (CRP), and white blood cell (WBC) count in the peripheral blood were examined. Results: In this study, PCT levels were significantly higher in patients with CDI than in non-CDI patients (including patients with viral/fungal infections and the control group; p < 0.001 and p < 0.05, respectively). CRP levels were significantly higher in patients with CDI than in non-CDI patients (p < 0.05). The area under the curve (AUC) of PCT and WBC count were compared using DeLong’s test: the AUCs of PCT vs. CRP for the detection of the IBD–CDI group and the control group was 0.826 [95% confidence interval (CI) 0.743–0.909] vs. 0.663 [95% confidence interval (CI) 0.551–0.774] (p < 0.05), respectively. WBC count was inferior as a diagnostic tool for CDI. The sensitivity was 59.09% (95% CI: 43.2% to 73.7%), the specificity was 89.80% (95% CI: 77.8% to 96.6%), and the positive likelihood ratio LR (+) was 5.79 for PCT for the diagnosis of CDI. Conclusions: The present study demonstrates the superiority of PCT over CRP and WBC count for the rapid diagnosis of CDI in IBD patients.

Brain cancers are among the top causes of death worldwide. Although, the survival rates vary widely depending on the type of the tumor, early diagnosis could generally benefit in better prognosis outcomes of the brain cancer patients. Conventionally, neuroimaging and biopsy are the most widely used approaches in diagnosis, subtyping, and prognosis monitoring of brain cancers, while emerging liquid biopsy assays using peripheral blood or cerebrospinal fluid have demonstrated many favorable characteristics in this task, especially due to their minimally invasive and easiness in sampling nature. Here, we review the recent studies in the liquid biopsy of brain cancers. We discuss the methodologies and performances of various assays on diagnosis, tumor subtyping, relapse prediction as well as prognosis monitoring in brain cancers, which approaches have made a big step toward clinical benefits of brain cancer patients.

Cell death is a common phenomenon in the progression of Alzheimer’s disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Moreover, several hallmarks of AD pathogenesis were consistent with the characteristics of ferroptosis, such as excess iron accumulation, elevated lipid peroxides, and reactive oxygen species (ROS), reduced glutathione (GSH), and glutathione peroxidase 4 (GPX4) levels. Besides, some ferroptosis inhibitors can relieve AD-related pathological symptoms in AD mice and exhibit potential clinical benefits in AD patients. Therefore, ferroptosis is gradually being considered as a distinct cell death mechanism in the pathogenesis of AD. However, direct evidence is still lacking. In this review, we summarize the features of ferroptosis in AD, its underlying mechanisms in AD pathology, and review the application of ferroptosis inhibitors in both AD clinical trials and mice/cell models, to provide valuable information for future treatment and prevention of this devastating disease.

BackgroundMeningioma invasion can be preoperatively recognized by radiomics features, which significantly contributes to treatment decision-making. Here, we aimed to evaluate the comparative performance of radiomics signatures derived from varying regions of interests (ROIs) in predicting BI and ascertaining the optimal width of the peritumoral regions needed for accurate analysis.MethodsFive hundred and five patients from Wuhan Union Hospital (internal cohort) and 214 cases from Taihe Hospital (external validation cohort) pathologically diagnosed as meningioma were included in our study. Feature selection was performed from 1,015 radiomics features respectively obtained from nine different ROIs (brain-tumor interface (BTI)2–5mm; whole tumor; the amalgamation of the two regions) on contrast-enhanced T1-weighted imaging using least-absolute shrinkage and selection operator and random forest. Principal component analysis with varimax rotation was employed for feature reduction. Receiver operator curve was utilized for assessing discrimination of the classifier. Furthermore, clinical index was used to detect the predictive power.ResultsModel obtained from BTI4mm ROI has the maximum AUC in the training set (0.891 (0.85, 0.932)), internal validation set (0.851 (0.743, 0.96)), and external validation set (0.881 (0.833, 0.928)) and displayed statistically significant results between nine radiomics models. The most predictive radiomics features are almost entirely generated from GLCM and GLDM statistics. The addition of PEV to radiomics features (BTI4mm) enhanced model discrimination of invasive meningiomas.ConclusionsThe combined model (radiomics classifier with BTI4mm ROI + PEV) had greater diagnostic performance than other models and its clinical application may positively contribute to the management of meningioma patients.

Background: Vertebrobasilar dolichoectasia (VBD) is one of the rare causes of trigeminal neuralgia (TN). The common surgical treatments for patients with TN caused by VBD (VBD-TN) are microvascular decompression (MVD) and Gamma Knife radiosurgery (GKRS). However, the therapeutic effects of the two methods have not been clinically compared, so this study was performed to evaluate the treatment outcomes of MVD and GKRS for patients with VBD-TN.Methods: The retrospective study was performed from March 2011 to March 2019 in Wuhan Union Hospital. A total of 80 patients diagnosed with VBD-TN were included in this study, and they were divided into the MVD group (n = 46) and GKRS group (n = 34) according to the surgical methods. The imaging data, intraoperative findings, treatment outcomes, and complications of the two groups were analyzed and compared. Meanwhile, the influencing factors of the treatment effect are also explored on the two groups.Results: Patients who underwent MVD were younger than patients who underwent GKRS (median ages were 61.1 and 65.4 years old, respectively, p = 0.03). The median follow-up was 61.1 months for the MVD group and 56.8 months for the GKRS group. The favorable outcomes [Barrow Neurological Institute (BNI) pain score, BNI scores I–II] occurred in 97.8% of patients treated with MVD and in 78.9% of patients treated with GKRS (p = 0.009). The favorable outcomes in the percentage of patients after MVD 1, 3, 5, and 7 years were 95.7, 85.1, 74.2, and 74.2%, respectively, whereas the corresponding percentages after GKRS were 76.5, 66.2, 56.6, and 47.2%, respectively (p = 0.031). The postoperative complications (except facial numbness) in the MVD group were higher than those in the GKRS group (p = 0.036), but the incidence of new and worsening facial numbness was lower in the GKRS group (p < 0.001).Conclusions: MVD is superior to GKRS in obtaining and maintaining favorable outcomes for patients with VBD-TN, but it also comes with more complications other than facial numbness. Thus, the treatment program can be tailored to a patient's unique condition and wishes.

Objective To evaluate the influence of insufficient bone cement distribution on outcomes following percutaneous vertebroplasty (PVP). Methods This retrospective matched-cohort study included patients 50–90 years of age who had undergone PVP for single level vertebral compression fractures (VCFs) from February 2015 to December 2018. Insufficient (Group A)/sufficient (Group B) distribution of bone cement in the fracture area was assessed from pre- and post-operative computed tomography (CT) images. Assessments were before, 3-days post-procedure, and at the last follow-up visit (≥12 months). Result Of the 270 eligible patients, there were 54 matched pairs. On post-operative day 3 and at the last follow-up visit, significantly greater visual analogue scale (VAS) pain scores and Oswestry Disability Index (ODI) scores were obtained in Group B over Group A, while kyphotic angles (KAs) and vertebral height (VH) loss were significantly larger in Group A compared with Group B. Incidence of asymptomatic cement leakage and re-collapse of cemented vertebrae were also greater in Group A compared with Group B. Conclusions Insufficient cement distribution may relate to less pain relief and result in progressive vertebral collapse and kyphotic deformity post-PVP.

BackgroundGiven the similarities in clinical manifestations of cystic-solid pituitary adenomas (CS-PAs) and craniopharyngiomas (CPs), this study aims to establish and validate a nomogram based on preoperative imaging features and blood indices to differentiate between CS-PAs and CPs.MethodsA departmental database was searched to identify patients who had undergone tumor resection between January 2012 and December 2020, and those diagnosed with CS-PAs or CPs by histopathology were included. Preoperative magnetic resonance imaging (MRI) features as well as blood indices were retrieved and analyzed. Radiological features were extracted from the tumor on contrast-enhanced T1 (CE-T1) weighted and T2 weighted sequences. The two independent samples t-test and principal component analysis (PCA) were used for feature selection, data dimension reduction, and radiomics signature building. Next, the radiomics signature was put in five classification models for exploring the best classifier with superior identification performance. Multivariate logistic regression analysis was then used to establish a radiomic-clinical model containing radiomics and hematological features, and the model was presented as a nomogram. The performance of the radiomics-clinical model was assessed by calibration curve, clinical effectiveness as well as internal validation.ResultsA total of 272 patients were included in this study: 201 with CS-PAs and 71 with CPs. These patients were randomized into training set (n=182) and test set (n=90). The radiomics signature, which consisted of 18 features after dimensionality reduction, showed superior discrimination performance in 5 different classification models. The area under the curve (AUC) values of the training set and the test set obtained by the radiomics signature are 0.92 and 0.88 in the logistic regression model, 0.90 and 0.85 in the Ridge classifier, 0.88 and 0.82 in the stochastic gradient descent (SGD) classifier, 0.78 and 0.85 in the linear support vector classification (Linear SVC), 0.93 and 0.86 in the multilayers perceptron (MLP) classifier, respectively. The predictive factors of the nomogram included radiomic signature, age, WBC count, and FIB. The nomogram showed good discrimination performance (with an AUC of 0.93 in the training set and 0.90 in the test set) and good calibration. Moreover, decision curve analysis (DCA) demonstrated satisfactory clinical effectiveness of the proposed radiomic-clinical nomogram.ConclusionsA personalized nomogram containing radiomics signature and blood indices was proposed in this study. This nomogram is simple yet effective in differentiating between CS-PAs and CPs and thus can be used in routine clinical practice.

BackgroundGlioma is the most common malignant brain tumor in adults, with its tumor-promoting immune microenvironment always being intricate to handle with. Amounts of evidence has accumulated to suggest that alternative splicing (AS) is related to tumor immune microenvironment. However, comprehensive analysis of immune-related AS events and their clinical significance are still lacking in glioma.MethodsAS events and transcriptome data of 653 glioma patients were downloaded online. ssGSEA was performed on transcriptome data of 653 patients to divided them into low, medium and high immune cell infiltration groups. Immune-related AS events were filtrated based on this grouping. Then lasso Cox regression analysis and multivariate Cox regression analysis were done to achieve an immune-related AS events prognostic signature for glioma. Kaplan-Meier analysis, ROC analyses, univariate Cox regression and multivariate Cox regression were performed to reveal the independent prognostic role of this signature. Meanwhile, a nomogram was constructed to achieved better prognostic value for glioma patients. Besides, functional enrichment analyses and correlation analyses with immune cells infiltration were used to validated the immune-related characteristic of this signature.Results36 immune-related AS events were achieved based on the grouping mentioned above. A nine-immune-related alternative splicing event signature was built for glioma patients. This signature showed an independent prognostic value and a nomogram containing gender, age, Karnofsky performance score, grade, IDH status, MGMT promoter status and risk score derived from the signature was constructed with a higher predictive ability for overall survival. Association with the infiltration of immune cell subtypes was validated and functional enrichment analysis found that the signature was mainly enriched in immune-related and pro-tumor functions.ConclusionOur research presented all immune-related AS events in glioma, identified an immune-related prognostic AS events risk model and a nomogram was constructed to predict the prognosis individually and more precisely. Tight connection was verified between this signature and clinical characteristics. Also, immune cells infiltration and immune checkpoints expression level were proved to link to risk scores, which enhanced the understanding of relationship between AS events and glioma immune microenvironment, firstly revealing the potential role of AS in immunotherapy of glioma.

Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are implicated in the regulation of tumor cell ferroptosis. However, the prognostic value of ferroptosis-related lncRNAs has never been comprehensively explored in glioma. In this study, the transcriptomic data and clinical information of glioma patients were downloaded from TCGA, CGGA and Rembrandt databases. We identified 24 prognostic ferroptosis-related lncRNAs, 15 of which (SNAI3-AS1, GDNF-AS1, WDFY3-AS2, CPB2-AS1, WAC-AS1, SLC25A21-AS1, ARHGEF26-AS1, LINC00641, LINC00844, MIR155HG, MIR22HG, PVT1, SNHG18, PAXIP1-AS2, and SBF2-AS1) were used to construct a ferroptosis-related lncRNAs signature (FRLS) according to the least absolute shrinkage and selection operator (LASSO) regression. The validity of this FRLS was verified in training (TCGA) and validation (CGGA and Rembrandt) cohorts, respectively. The Kaplan-Meier curves revealed a significant distinction of overall survival (OS) between the high- and low-risk groups. The receiver operating characteristic (ROC) curves exhibited robust prognostic capacity of this FRLS. A nomogram with improved accuracy for predicting OS was established based on independent prognostic factors (FRLS, age, and WHO grade). Besides, patients in the high-risk group had higher immune, stroma, and ESTIMATE scores, lower tumor purity, higher infiltration of immunosuppressive cells, and higher expression of immune checkpoints. Patients in the low-risk group benefited significantly from radiotherapy, while no survival benefit of radiotherapy was observed for those in the high-risk group. In conclusion, we identified the prognostic ferroptosis-related lncRNAs in glioma, and constructed a prognostic signature which was associated with the immune landscape of glioma microenvironment and radiotherapy response.

Background: The outbreak of novel coronavirus disease 2019 (COVID-19) has caused public panic and psychological health problems, especially in medical staff. We aimed to investigate the psychological effect of the COVID-19 outbreak on medical staff.Methods: A cross-sectional study was conducted to examine the psychological impact of medical staff working in COVID-19 designated hospitals from February to March 2020 in China. We assessed psychological health problems using the Symptom Check List 90 (SCL-90).Results: Among 656 medical staff, 244 were frontline medical staff and 412 general medical staff. The prevalence of psychological health problems was 19.7%. The SCL-90 scores in frontline medical staff were significantly higher than that in general medical staff (mean: 141.22 vs. 129.54, P < 0.05). Furthermore, gender [odds ratio (OR) = 1.53, 95% CI = (1.02, 2.30), P = 0.042 for female vs. male] and the burden of current work [OR = 7.55, 95% CI = (3.75, 15.21), P < 0.001 for high burden; OR = 2.76, 95% CI = (1.80, 4.24), P < 0.001 for moderate burden vs. low burden] were associated with increased risk of poor psychological status.Conclusions: Medical staff experienced a high risk of psychological health problems during the outbreak of COVID-19, especially for frontline medical staff. Psychological health services are expected to arrange for medical staff in future unexpected infectious disease outbreaks.

Abstract Background Breast cancer is one of the most common malignancies and the major cause of cancer-related death in women. Although the importance of PIWI-interacting RNAs (piRNAs) in cancer has been increasingly recognized, few studies have been explored the functional mechanism of piRNAs in breast cancer development and progression. Methods We examined the top 20 highly expressed piRNAs based on the analysis of TCGA breast cancer data in two patient cohorts to test the roles of piRNAs in breast cancer. The effects of piRNA-36,712 on the malignant phenotypes and chemosensitivity of breast cancer cells were detected in vitro and in vivo. MS2-RIP and reporter gene assays were conducted to identify the interaction and regulation among piRNA-36,712, miRNAs and SEPW1P. Kaplan-Meier estimate with log-rank test was used to compare patient survival by different piRNA-36,712 expression levels. Results We found piRNA-36,712 level was significantly lower in breast cancer than in normal breast tissues and low level was correlated with poor clinical outcome in patients. Functional studies demonstrated that piRNA-36,712 interacts with RNAs produced by SEPW1P, a retroprocessed pseudogene of SEPW1, and subsequently inhibits SEPW1 expression through competition of SEPW1 mRNA with SEPW1P RNA for microRNA-7 and microRNA-324. We also found that higher SEPW1 expression due to downregulation of piRNA-36,712 in breast cancer may suppress P53, leading to the upregulated Slug but decreased P21 and E-cadherin levels, thus promoting cancer cell proliferation, invasion and migration. Furthermore, we found that piRNA-36,712 had synergistic anticancer effects with the paclitaxel and doxorubicin, two chemotherapeutic agents for breast cancer. Conclusions These findings suggest that piRNA-36,712 is a novel tumor suppressor and may serve as a potential predictor for the prognosis of breast cancer patients.

Background and Aim: Guidelines recommend adjuvant treatment for patients with high-grade gliomas and low-grade gliomas with high risk of progression. In clinical practice, however, treatments may not conform to these suggested guidelines. In this study, we reviewed the treatments and outcomes in patients with gliomas at Sun Yat-Sen University Cancer Center (SYSUCC), China. Materials and Methods: Medical records and radiologic images of 1215 glioma patients who underwent surgery at the center from 2000 to 2017 were retrospectively reviewed, and their clinicopathological characteristics, treatment method, and overall survival (OS) were analyzed. The study was approved by the Ethics Committee of SYSUCC on February 20, 2019 (approval No. GZR2019-219). Results: A total of 1001 patients diagnosed with glioma (initially World Health Organization 2007 criteria, then 2016 criteria) were enrolled, including 90 patients with Grade I, 307 Grade II, 239 Grade III, and 365 Grade IV gliomas. A total of 331 of 604 patients with high-grade glioma (54.8%) and 159 of 397 with low-grade glioma (40.1%) received postsurgical radiotherapy, and 285 patients with high-grade tumors (47.1%) and 80 with low-grade tumors (20.2%) received adjuvant chemotherapy. The median OS was 17.5 months for Grade IV and 43.1 months for Grade III gliomas. The median OS of patients with low-grade glioma was not reached. The 5-year survival rates of patients with Grades I, II, III, and IV gliomas were 94.7%, 73.7%, 45.7%, and 18.6%, respectively. Multivariate analysis identified onset age, preoperative seizure, tumor location, pathological subtype, resection extent, and postsurgical treatment as independent predictors of OS in patients with high-grade gliomas. Patients with high-grade glioma who received postsurgical treatment had better survival than those without adjuvant therapy (Grade III: 52.6 vs. 20.3 months, P = 0.012; Grade IV: 22.6 vs. 12.1 months, P < 0.001). Among patients with diffuse low-grade gliomas, age, performance status, preoperative seizure, Ki-67 index, tumor subtype, and resection extent were associated with clinical outcomes. Conclusion: Glioma patients are not always treated according to guidelines. Although standard care may lead to favorable prognoses, individualized treatments may be more acceptable and result in better outcomes and should thus be considered in routine clinical practice.

Background and Aim: Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in a lower survival. Dianhydrogalactitol (VAL-083) is a novel bi-functional DNA-targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. Subjects and Methods: The study has two parts: part 1 is a dose–escalation and induction format to enroll up to ten patients in which they received VAL-083 at 20, 30, or 40 mg/m2 per day for 3 days every 21 days concurrently with standard radiation treatment and VAL-083 for up to eight additional cycles. Part 2 comprises an expansion phase to enroll up to twenty additional patients. This study was performed with approval by the Institutional Review Board of Sun Yat-sen University Cancer Center (B2016-058-01) on January 13, 2017, and registered with the ClinicalTrials.gov (NCT03050736) on February 13, 2017. Results: After completion of dose escalation, VAL-083, 30 mg/m2 per day, in combination with radiation therapy, was generally safe and well tolerated. At the cutoff date, 23 patients had been enrolled, 14 of whom had been treated in the expansion phase. Consistent with prior studies, myelosuppression was the most common adverse event. Pharmacokinetic assessment indicated that the levels of VAL-083 were as high in the cerebrospinal fluid as in plasma, 2 h postinfusion. Of the 22 patients who had reached their four precycle magnetic resonance imaging assessments, 12 were assessed with disease progression, with a median progression-free survival of 9.9 (95% confidence interval 7.3–12.0) months for all the patients studied. Conclusion: These preliminary data support VAL-083 as a potentially valuable treatment option for newly diagnosed GBM.

Listeria monocytogenes is a major foodborne pathogen that can cause listeriosis in humans and animals. Andrographolide is known as a natural antibiotic and exhibits good antibacterial activity. We aimed to investigate the effect of andrographolide on two quorum-sensing (QS) systems, LuxS/AI-2 and Agr/AIP of L. monocytogenes, as well as QS-controlled phenotypes in this study. Our results showed that neither luxS expression nor AI-2 production was affected by andrographolide. Nevertheless, andrographolide significantly reduced the expression levels of the agr genes and the activity of the agr promoter P2. Results from the crystal violet staining method, confocal laser scanning microscopy (CLSM), and field emission scanning electron microscopy (FE-SEM) demonstrated that andrographolide remarkably inhibited the biofilm-forming ability of L. monocytogenes 10403S. The preformed biofilms were eradicated when exposed to andrographolide, and reduced surviving cells were also observed in treated biofilms. L. monocytogenes treated with andrographolide exhibited decreased ability to secrete LLO and adhere to and invade Caco-2 cells. Therefore, andrographolide is a potential QS inhibitor by targeting the Agr QS system to reduce biofilm formation and virulence of L. monocytogenes.

BackgroundProteins containing the caspase recruitment domain (CARD) play critical roles in cell apoptosis and immunity. However, the impact of CARD genes in tumor immune cell infiltration, responsiveness to checkpoint immunotherapy, and clinical outcomes of gliomas remains unclear. Here, we explore using CARD genes to depict the immune microenvironment and predict the responsiveness of gliomas to anti-PD-1 therapy.MethodsThe genome and transcriptome data of 231 patients with isocitrate dehydrogenase wild-type (IDH-wt) gliomas were retrieved from The Cancer Genome Atlas (TCGA) database to screen CARD genes associated with T lymphocyte infiltration in gliomas. Weighted co-expression network and LASSO penalized regression were employed to generate a CARD-associated risk score (CARS). Two independent and publicly available datasets were used to validate the effectiveness of CARS.ResultsThe CARS divided the 231 glioma patients into high- and low-risk subgroups with distinct immune microenvironment and molecular features. The high-risk group had high CARS and was characterized by enrichment of dysfunctional T lymphocytes in a profound immunosuppressive microenvironment, whereas the low-risk group had low CARS and exhibited an immune exclusion genotype. Moreover, signaling aberrations including upregulation of PI3K/Akt/mTOR, NF-κB, and TGF-β were found in the high-risk group. In contrast, the activated WNT pathway was more evident in the low-risk group. Furthermore, we found that an elevated CARS indicated a decreased overall survival for IDH-wt gliomas under standard care but a clinical benefit from checkpoint immunotherapy.ConclusionThis study developed an immune- and prognosis-relevant risk score, which could be used to enhance our understanding of the heterogeneity of immune microenvironment of gliomas and facilitate to identify patients who will benefit from checkpoint immunotherapy.

Development of strategies for mitigating the severity of COVID-19 is now a top public health priority. We sought to assess strategies for mitigating the COVID-19 outbreak in a hospital setting via the use of non-pharmaceutical interventions. We developed an individual-based model for COVID-19 transmission in a hospital setting. We calibrated the model using data of a COVID-19 outbreak in a hospital unit in Wuhan. The calibrated model was used to simulate different intervention scenarios and estimate the impact of different interventions on outbreak size and workday loss. The use of high-efficacy facial masks was shown to be able to reduce infection cases and workday loss by 80% (90% credible interval (CrI): 73.1–85.7%) and 87% (CrI: 80.0–92.5%), respectively. The use of social distancing alone, through reduced contacts between healthcare workers, had a marginal impact on the outbreak. Our results also indicated that a quarantine policy should be coupled with other interventions to achieve its effect. The effectiveness of all these interventions was shown to increase with their early implementation. Our analysis shows that a COVID-19 outbreak in a hospital's non-COVID-19 unit can be controlled or mitigated by the use of existing non-pharmaceutical measures.

Background: Healthcare workers (HCWs) are at the forefront of fighting against the COVID-19 pandemic. However, they are at high risk of acquiring the pathogen from infected patients and transmitting to other HCWs. We aimed to investigate risk factors for nosocomial COVID-19 infection among HCWs in a non-COVID-19 hospital yard. Methods: Retrospective data collection on demographics, lifestyles, contact status with infected subjects for 118 HCWs (including 12 COVID-19 HCWs) at Union Hospital of Wuhan, China. Sleep quality and working pressure were evaluated by the Pittsburgh Sleep Quality Index (PSQI) and The Nurse Stress Index (NSI), respectively. The follow-up duration was from Dec 25, 2019, to Feb 15, 2020. Results: A high proportion of COVID-19 HCWs had engaged in night shift-work (75.0% vs. 40.6%) and felt working under pressure (66.7% vs. 32.1%) than uninfected HCWs. SARS-CoV-2 infected HCWs had significantly higher scores of PSQI and NSI than uninfected HCWs (P

BackgroundMedulloblastoma is the common pediatric malignant tumor with poor prognosis in cerebellum. However, MB is always with clinical heterogeneity. To provide patients with more clinically beneficial treatment strategies, there is a pressing need to develop a new prognostic prediction model as a supplement to the prediction outcomes of clinical judgment.Materials and MethodsFour datasets of mRNA expression and clinical data were downloaded from gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) were identified and functionally enriched among GSE50161, GSE74195, GSE86574. Then we used STRING and Cytoscape to constructed and analyze protein-protein interaction network (PPI) and hub genes. Univariate cox regression analysis was performed to identify overall survival-related hub genes in an unique dataset from GSE85217 as train cohort. Lasso Cox regression model was used to construct the prognostic gene signature. Time-dependent receiver operating characteristic (ROC), Kaplan–Meier curve, univariate and multivariate Cox regression analysis were used to assess the prognostic capacity of the twelve-gene signature. A unique dataset from GSE85217 was downloaded to further validate the results. Finally, we established the nomogram by using the gene signature and validated it with ROC curve. Gene set enrichment analysis (GSEA) was carried out to further investigate its potential molecular mechanism. Besides, the twelve genes expression at the mRNA and protein levels was validated using external database such as Oncomine, cBioportal and HPA, respectively.ResultsA twelve-gene signature comprising FOXM1, NEK2, CCT2, ACTL6A, EIF4A3, CCND2, ABL1, SYNCRIP, ITGB1, NRXN2, ENAH, and UMPS was established to predict overall survival of medulloblastoma. The ROC curve showed good performance in survival prediction in both the train cohort and the validation cohort. The twelve-gene signature could stratify patients into a high risk and low risk group which had significantly different survival. Univariate and multivariate Cox regression revealed that the twelve-gene signature was an independent prognostic factor in medulloblastoma. Nomogram, which included twelve-gene signatures, was established and showed some clinical benefit.ConclusionOur study identified a twelve-gene signature and established a prognostic nomogram that reliably predicts overall survival in medulloblastoma. The above results will help us to better analyze the pathogenesis and treatment of medulloblastoma in the future.

Background: Forkhead box protein f1 (Foxf1) is associated with cell differentiation, and may be a key player in bone homoeostasis. However, the effect of Foxf1 on osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) and ovariectomy-induced bone loss, as well as its clinical implications, is unknown. Methods: By quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, we assayed Foxf1 expression in bone tissue, BMSCs, and bone marrow-derived macrophages (BMMs), derived from ovariectomised (OVX) mice, and during osteogenic differentiation and osteoclast differentiation. Using a loss-of-function approach (small interfering RNA [siRNA]-mediated knockdown) in vitro, we examined whether Foxf1 regulates osteoblast differentiation of BMSCs via the Wnt/β-catenin signalling pathway. Furthermore, we assessed the anabolic effect of Foxf1 knockdown (siFoxf1) in OVX mice in vivo. We also assayed the expression of Foxf1 in bone tissue derived from postmenopausal osteoporosis (PMOP) patients and its link with bone mineral density (BMD). Finally, we examined the effect of Foxf1 knockdown on the osteoblastic differentiation of human BMSCs. Findings: Foxf1 expression was significantly increased in bone extract and BMSCs from OVX mice and gradually decreased during osteoblastic differentiation of BMSCs but did not differ significantly in OVX mouse-derived BMMs or during osteoclast differentiation. In vitro, Foxf1 knockdown markedly increased the expression of osteoblast specific genes, alkaline phosphatase (ALP) activity, and mineralisation. Moreover, siFoxf1 activated the Wnt/β-catenin signalling pathway. The siFoxf1-induced increase in osteogenic differentiation was partly rescued by inhibitor of Wnt signalling (DKK1). In OVX mice, Foxf1 siRNA significantly reduced bone loss by enhancing bone formation. Foxf1 expression levels negatively correlated with reduced bone mass and bone formation in bone tissue from PMOP patients. Finally, Foxf1 knockdown significantly promoted osteogenesis by human BMSCs. Interpretation: Our findings indicate that Foxf1 knockdown promotes BMSC osteogenesis and prevents OVX-induced bone loss. Therefore, Foxf1 has potential as a biomarker of osteogenesis and may be a therapeutic target for PMOP. Keywords: Foxf1, Osteogenic differentiation, Mesenchymal stem cells, Postmenopausal osteoporosis, Bone metabolism

Abstract Background Pituitary adenoma (PA) is a common intracranial tumor and surgical treatment is considered to be the best treatment for most patients. The extended endoscopic endonasal approach (EEEA) has been used to treat increasing numbers of patients with PA in recent years. We conducted this study to evaluate the safety and efficacy of this approach for PA resection. Methods We performed a retrospective analysis of all patients who underwent an EEEA to remove PA by a binostril, four-handed technique between October 2013 and April 2016 in our department. The medical information of the patients including gender, age, tumor size, hormone level, clinical outcome, and complications were collected and analyzed. Results From a total of 593 pituitary adenoma surgeries, 171 patients (101 male and 70 female, mean age 47.4 ± 12.8 years) underwent EEEA, including 96 with functional adenomas (56.14%) and 75 with nonfunctional adenomas (43.86%). The most common symptoms were headache and vision change. Gross total resection was achieved in 126 patients (73.68%). Common complications were hyposmia or anosmia, diabetes insipidus, hypopituitarism, postoperative cerebrospinal fluid leak, cerebral hemorrhage, and epistaxis. The mean duration of follow-up was 14.6 months (range: 6–31 months). Conclusions The application of EEEA for PA resection by a binostril, four-handed technique provided great surgical freedom with minimal invasion, and resulted in few complications. EEEA is a secure and effective surgical method that could be used for the majority of PAs.

Exophiala dermatitidis, a dematiaceous fungus typically found in decaying organic matter worldwide, is a rare cause of fungal infections. Cerebral phaeohyphomycosis is a sporadic but often fatal infection of the brain caused by E. dermatitidis. However, due to limited reports, little is known about its specific predisposing factors, clinical manifestation, and optimal treatment modality. Here, we report a clinical presentation and management of cerebral phaeohyphomycosis in a Chinese patient. An otherwise healthy, young male who was diagnosed with neck fungal lymphadenitis caused by E. dermatitidis 7 months prior and was treated with itraconazole, presented later with progressive intracranial hypertension and persistent coma. Culture of the neck lymphoid tissue produced growth of a black yeast-like fungus, which was identified as E. dermatitidis by sequencing of the ribosomal DNA internal transcribed spacer (ITS) domains. Accordingly, a cerebral biopsy was performed, and the pathological report showed mycelia and fungal granulomas. We also sequenced CARD9 in the patient and found him to be homozygous for loss-of-function mutation; his parents were heterozygous for the same mutation. This is a first case report of cerebral phaeohyphomycosis caused by E. dermatitidis in a CARD9-deficient Chinese patient. He eventually succumbed to brain herniation and severe lung infection with a poor response to therapy. Thus, previously healthy patients with unexplained invasive E. dermatitidis infection, at any age, should be tested for inherited CARD9 deficiency.

Listeria monocytogenes is an important food-borne pathogen that can persist in food processing environments and thus contaminate food products. Benzalkonium chloride (BC) is a common disinfectant widely used in food industry. Selective pressure associated with exposure to BC may result in adaptation to this agent in L. monocytogenes. In this study, the effect of BC adaptation on susceptibility to antimicrobial agents and tolerance to environmental stresses, as well as the role of efflux pumps in BC adaptation were investigated in Listeria monocytogenes. Exposure of L. monocytogenes to progressively increasing concentrations of BC led to adaptation not only to BC but also to several other antimicrobial agents with different modes of action, including cefotaxime, cephalothin, ciprofloxacin, and ethidium bromide (EtBr), indicating that the disinfectant BC has the ability to select for antibiotic resistance. Reserpine, an efflux pump inhibitor, reduced minimum inhibitory concentrations (MICs) of cephalosporins, ciprofloxacin, and EtBr in BC adapted strains, indicating that efflux pumps are involved in cross-adaptation to these antimicrobial agents. Our results showed that expression levels of the efflux pump MdrL in the BC adapted strains increased significantly relative to the corresponding wild-type strains (P < 0.05), with the highest increase in one BC adapted strain named HL06BCA. Moreover, the knockout mutant HL06BCAΔmdrL showed impaired growth compared to that of HL06BCA when exposed to 2 μg/ml of BC. It suggests that efflux pump MdrL is associated with BC adaptation in L. monocytogenes. However, we did not find mdrL to be associated with cross-adaptation to cephalosporins, ciprofloxacin, and EtBr in HL06BCA. Additionally, increased sensitivity to acid, alkali, osmotic, ethanol, and oxidative stresses was observed in most strains after repeated exposure to BC. These results suggest rotation of different disinfectant is helpful to maintain high effectiveness of BC toward L. monocytogenes and ethanol and hydrogen peroxide are at least the appropriate candidates.

Efflux is a primary fluoroquinolone resistance mechanism in Listeria monocytogenes. In the present study, ciprofloxacin resistant strains were selected by exposure of sensitive strain to progressively increasing concentrations of ciprofloxacin and then the roles of efflux pumps Lde and MdrL in the development of resistance to ciprofloxacin were also investigated in L. monocytogenes. Ciprofloxacin sensitive strain of L. monocytogenes exhibited reduced susceptibility to this antibiotic after induction. Cross-resistance to ethidium bromide (EtBr) was observed in ciprofloxacin-induced strains. However, cross-resistance to benzalkonium chloride (BC) did not occur in this study. Compared to the wild-type strain HL06, the expression levels of lde were increased in four ciprofloxacin-induced strains. The single-gene deletion mutants of lde and mdrL from the ciprofloxacin-induced resistant strain HL06CIP4 were constructed. However, decreased minimum inhibitory concentration (MIC) of ciprofloxacin was observed only in HL06CIP4Δlde compared to that of the parental strain HL06CIP4. Ciprofloxacin uptake appeared to be obviously increased in HL06CIP4Δlde in relative to HL06CIP4. These evidences suggested that efflux pump Lde is involved in ciprofloxacin resistance in L. monocytogenes HL06CIP4. The deletion of lexA had no effect on the expression levels of lde in HL06CIP4 in the absence or presence of ciprofloxacin, indicating that LexA was not involved in the regulation of efflux pump Lde in L. monocytogenes.

The aim of this study was to examine the presence of genes responsible for resistance to quaternary ammonium compounds (QACs) and the association of qac genes with class 1 integrons in Proteus mirabilis isolated from cooked meat products. A total of 52 P. mirabilis isolates (29.2%) were detected from 178 samples, and their minimum inhibitory concentrations (MICs) of benzalkonium chloride (BC) ranged from 4 to >32 μg/mL. The isolates with BC MICs of 24 μg/mL were observed most frequently. PCR assays indicated that mdfA, ydgE/ydgF, qacE, qacEΔ1, emrE, sugE(c), and sugE(p) were commonly present (32.7%–100%) in these isolates, but qacH was less prevalent (3.8%). Five groups of resistance gene cassettes were identified in 10 intI1-positive isolates. An unusual gene cassette array dfrA32-ereA-aadA2 was found in one foodborne isolate of P. mirabilis. Two isolates harbored qacH- and sul3- associated non-classic integrons: aadA2-cmlA1-aadA1-qacH-IS440-sul3 and a new arrangement dfrA32-ereA1-aadA2-cmlA1-aadA1-qacH-IS440-sul3, which is first reported in P. mirabilis. Non-classic class 1 integrons were located on conjugative plasmids of 100 kb in two tested isolates. Our data showed that the QAC resistance genes were commonly present among P. mirabilis isolates from cooked meats and qacH was associated with non-classic class 1 integrons. The creation of transconjugants demonstrated that qacH-associated non-classic class 1 integrons were located on conjugative plasmids and therefore could facilitate the co-dissemination of disinfectant and antimicrobial resistance genes among bacteria, an increasing area of concern.

Pituitary tumors represent the most common intracranial neoplasms accompanying serious morbidity through mass effects and inappropriate secretion of pituitary hormones. Understanding the etiology of pituitary tumorigenesis will facilitate the development of satisfactory treatment for pituitary adenomas. Although the pathogenesis of pituitary adenomas is largely unknown, considerable evidence indicates that the pituitary tumorigenesis is a complex process involving multiple factors, including genetic and epigenetic changes. This review summarized the recent progress in the study of pituitary tumorigenesis, focusing on the role of tumor suppressor genes, oncogenes and microRNAs.

This study examined the effect of debagging time on color and flavor / taste compounds in the non-red apple cultivar 'Golden Delicious' and red cultivar 'Qinguan' at mid and late stages of fruit development. Debagging briefly improved the red color in both cultivars, the peel of 'Golden Delicious' presenting pale-pink hue. However, rapid anthocyanin accumulation occurred in apple peel at a specific time (after 179 days after flowering (DAF) in 'Qinguan') and was unaltered by debagging time in the red cultivar 'Qinguan'. Furthermore, untimely debagging had a detrimental effect on the content of anthocyanin. All sugars increased and organic acids decreased in apple pulp at mid to late stages of development. Bagging treatment reduced the content of most sugars and organic acids, as well as, the overall total. However, glucose and citric acid contents were higher in bagged fruit than non-bagged fruit; the maximum occurred in T7 treatment that was no-debagging at DAF 159 / 196 ('Golden delicious' / 'Qinguan'), i.e., 24.35 and 0.07 mg g-1 FW in 'Golden delicious', and 38.86 and 0.06 mg g-1 FW in 'Qinguan', respectively. In a word, bagging treatment can alter the pattern of peel color development in apple fruit; however, it remains difficult to alter the timing of rapid anthocyanin accumulation as it is regulated solely by development. Moreover, bagging treatment reduced the total accumulation of sugars and organic acids, and even the over total in pulp, but increased the glucose and citric acid contents in apple pulp.