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Background: B3 type thymoma is defined as a well-differentiated thymic carcinoma and is similar to a thymic carcinoma. However, the differences between them are not well defined. In addition, the data to compare the efficacy and safety of platinum-based chemotherapy as first-line therapy between B3 thymoma and thymic carcinoma are lacking. Methods: The efficacy and safety of platinum-based chemotherapy as first-line therapy was retrospectively compared between a group of 36 patients with type B3 thymoma and a group of 127 patients with thymic carcinoma treated between January 2009 and March 2022 at the Zhejiang Cancer Hospital. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events were analyzed. Results: The ORRs for B3 thymoma and thymic carcinoma were 36.1% and 28.3%, respectively (p = 0.370). Among all patients, the difference in PFS between B3 thymoma and thymic carcinoma was not significant (11.3 vs. 10.1 months, p = 0.118). The squamous carcinoma subgroup did not exhibit any differences in PFS compared to B3 thymoma (11.7 vs. 11.3 months, p = 0.161). The result for the non-squamous carcinoma subgroup was similar (6.5 vs. 11.3 months, p = 0.128). Furthermore, the OS values for B3 thymoma and thymic carcinoma were not significantly different (58.3 vs. 35.1 months, p = 0.067). However, there were differences in OS between B3 thymoma and non-squamous carcinoma (58.3 vs. 30.6 months, p = 0.031). Conclusions: B3 thymoma and especially squamous carcinoma patients may be treated using a similar therapy scheme as that utilized for thymic carcinoma.

Several genes on chromosome 1q21 region predict a high risk of multiple myeloma (MM); however, the underlying molecular pathology remains elusive. Overexpression, amplification, or activation of SET Domain Bifurcated 1 (SETDB1), which is located on 1q21, is closely associated with poor prognosis of many human solid malignancies. In our study, upregulation of SETDB1 might indicate an unfavorable prognosis of MM using bioinformatics analysis from GEO databases and MMRF-CoMMpass. Here, increased SETDB1 expression was observed in the plasma cells from newly diagnosed multiple myeloma patients compared to those from the normal controls. Meanwhile, SETDB1 overexpression was the result of increased copy numbers of SETDB1 gene. In MM patients, the Kaplan-Meier analysis was employed to demonstrate that increased SETDB1 expression was associated with shorter overall survival (OS) and event-free survival (EFS). Besides, we conducted multifactorial cox regression analysis to state that SETDB1 expression was an independent biomarker for OS and EFS. MM patients with higher SETDB1 expression showed higher levels of beta-2 microglobulin (β2M), lactate dehydrogenase (LDH), and bone marrow biopsy plasma cells (BMPC) and lower levels of haemoglobin (HGB). Functional enrichment analysis suggested that SETDB1 could promote cell cycle progression in myeloma. Finally, we observed that SETDB1 was distinctly correlated with tumor immunity in MM. SETDB1 expression in myeloma cells was positively correlated with CD56dim natural killer cells but negatively correlated with infiltrating levels of type17 T helper cells, effector memory CD8 T cells, activated dendritic cells, and natural killer T cells from whole bone marrow (WBM) biopsies. Taken together, these results indicated that SETDB1 could be used as a novel biomarker for predicting the prognosis of MM patients.

Background : Cardiogenic shock (CS) is the leading cause of the death in patients with ST elevation myocardial infarction (STEMI). Thyroid dysfunction is related to prognosis of patients with myocardial infarction. Hence, the aim of this study is to explore the relationship between thyroid hormones (free triiodothyronine [FT3] and free thyroxine [FT4]) and CS. Method : A total of 1270 patients with STEMI treated with percutaneous coronary intervention (PCI) were consecutively enrolled in our study. Patients were classified into two groups according to with or without CS during hospitalization. Stepwise multivariate logistic analysis was conducted to investigate the association of thyroid hormones and CS. Restricted cubic spline method was employed to further explore relationship between CS and thyroid hormones. Results : Patients who developed CS (n=103) had lower FT3 and higher FT4 on admission. The stepwise logistic analysis showed both FT3 (P=0.038) and FT4 (P=0.024) were independently related to CS. Restricted cubic splines indicated that lower FT3 ( 1.25 ng/dl) was correlated with higher prevalence of CS. Over 2.5 years’ follow-up, patients (n=294) with low FT3 ( =0.88 ng/dl) had the highest all-cause mortality (18.2%), whereas patients (n=293) with high FT3 and low FT4 had the lowest all-cause mortality (3.8%) (P for trend Conclusions : Both FT3 and FT4 are independently associated with in-hospital CS development in patients with STEMI treated with PCI. Patients with lower range of FT3 and upper range of FT4 had the worst outcomes in a long-term follow-up.

Chondrosarcoma (CHS) is the second most common bone malignant tumor and currently has limited treatment options. We have recently demonstrated that thioredoxin interacting protein (TXNIP) plays a crucial role in the oncogenesis of bone sarcoma, yet its implication in CHS is underdetermined. In the present study, we first found that knockdown of TXNIP promotes the proliferation of CHS cell largely through increasing their glycolytic metabolism, which is well-known as Warburg effect for providing energy. Consistent with our previous report that YAP is fundamental for CHS cell growth, herein we revealed that YAP functioned as an upstream molecule of TXNIP, and that YAP negatively regulated TXNIP mRNA and protein expression both in vitro and in vivo. Mechanistically, although knockdown of YAP upregulated both the nuclear and cytoplasmic TXNIP expression, we did not observe any obvious interaction between YAP and TXNIP; instead, miRNA-524-5p was demonstrated to be required for YAP-regulated TXNIP expression and thus controlling CHS cell growth. Together, our study reveals that TXNIP is a tumor suppressor in terms of CHS, and that the YAP/miRNA-524-5p/TXNIP signaling axis may provide a novel clue for CHS targeted therapy.

To identify the potential factors responsible for the individual variability of dabigatran, we investigated the genetic variations associated with clinical outcomes and pharmacodynamics (PD) in Chinese patients with nonvalvular atrial fibrillation (NVAF).Chinese patients with NVAF taking dabigatran etexilate with therapeutic doses were enrolled. The primary (bleeding events) and secondary (thromboembolic and major adverse cardiac events) outcomes for a 2-year follow-up were evaluated. Peak and trough PD parameters (anti-FIIa activity, activated partial thromboplastin time and prothrombin time) were detected. Whole-exome sequencing, genome-wide sequencing and candidate gene association analyses were performed.There were 170 patients with NVAF treated with dabigatran (110 mg twice daily) who were finally included. Two single-nucleotide polymorphisms (SNPs) were significantly related with bleeding, which include UBASH3B rs2276408 (odds ratio [OR] = 8.79, 95% confidence interval [CI]: 2.99-25.83, p = 7.77 × 10Genetic variations indeed affected bleeding and PD in Chinese patients with NVAF treated with dabigatran. The functions of these suggestive genes and SNPs might further be explored and verified in more in vivo and in vitro investigations.

Background Anemia is relatively common in cancer patients, and baseline anemia is associated with poor survival in patients with non-small cell lung cancer (NSCLC). However, there is a lack of large-sample studies of patients with NSCLC with epidermal growth factor receptor (EGFR) mutations. Methods We retrospectively analyzed anemia‑related data for patients with NSCLC and EGFR mutations who were admitted to Zhejiang Cancer Hospital from January 2013 to June 2019 and treated with targeted therapy. The patients’ clinicopathological features were evaluated by χ2 tests and the relationships between clinical characteristics and prognosis were investigated using Kaplan–Meier and multivariate Cox regression analyses. Results A total of 2,029 patients treated with EGFR-tyrosine kinase inhibitors (TKIs) were finally enrolled in this study, of whom 24.6% had baseline anemia. Patients without baseline anemia had longer median overall survival (OS) than patients with baseline anemia (36.10 vs. 29.10 months, P = 0.001), and patients with grade P EGFR mutations. Conclusions Baseline anemia is a significant factor predicting a poor prognosis in terms of OS in patients with NSCLC and EGFR mutations treated with targeted therapy. A higher grade of baseline anemia may also be related to shorter OS. And a higher risk of EGFR-mutated patients who had received targeted therapy could also be observed.

Decreased cytotoxicity of natural killer (NK) cells has been shown in multiple myeloma (MM). However, the underlying molecular mechanisms remain unclear. Here, by using single-cell RNA sequencing analysis and in vitro experiments, we aim to uncover and validate molecularly distinctive insights into identifying regulators for NK cell exhaustion and provide potential targets for novel immune therapies in MM.Single-cell RNA sequencing was conducted in the bone marrow and peripheral blood samples from 10 newly diagnosed MM patients and three healthy volunteers. Based on the cluster-defining differentially expressed genes, we named and estimated functional states of each cluster via bioinformatics analyses. Functional significance of key findings obtained from sequencing analysis was examined in a series of in vitro experiments, including luciferase reporter assay, lentiviral expression vector construction, NK cell transfection, RT-qPCR, flow cytometry, and cytotoxicity assay.We classified NK cells into seven distinct clusters and confirmed that a subset of ZNF683In summary, our findings uncover an important mechanism of ZNF683

Phagocyte oxidase plays an essential role in the first line of host defense against pathogens. It oxidizes intracellular NADPH to reduce extracellular oxygen to produce superoxide anions that participate in pathogen killing. The resting phagocyte oxidase is a heterodimeric complex formed by two transmembrane proteins NOX2 and p22. Despite the physiological importance of this complex, its structure remains elusive. Here, we reported the cryo-EM structure of the functional human NOX2-p22 complex in nanodisc in the resting state. NOX2 shows a canonical 6-TM architecture of NOX and p22 has four transmembrane helices. M3, M4, and M5 of NOX2, and M1 and M4 helices of p22 are involved in the heterodimer formation. Dehydrogenase (DH) domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain, leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the DH in a productive docked conformation.

Objective One barrier hindering high frequency brain signals (HFBS, >80 Hz) from wide clinical applications is that the brain generates both pathological and physiological HFBS. This study was to find specific biomarkers for localizing epileptogenic zones (EZs). Methods Twenty three children with drug-resistant epilepsy and age/sex matched healthy controls were studied with magnetoencephalography (MEG). High frequency oscillations (HFOs, > 4 oscillatory waveforms) and high frequency spikes (HFSs, > 1 spiky or sharp waveforms) in 80–250 Hz and 250–600 Hz bands were blindly detected with an artificial intelligence method and validated with visual inspection. The magnitude of HFOs and HFSs were quantified with spectral analyses. Sources of HFSs and HFOs were localized and compared with clinical EZs determined by invasive recordings and surgical outcomes. Results HFOs in 80–250 Hz and 250–600 Hz were identified in both epilepsy patients (18/23, 12/23, respectively) and healthy controls (6/23, 4/23, respectively). HFSs in 80–250 Hz and 250–600 Hz were detected in patients (16/23, 11/23, respectively) but not in healthy controls. A combination of HFOs and HFSs localized EZs for 22 (22/23, 96%) patients. Conclusions The results indicate, for the first time, that HFSs are a newer and more specific biomarker than HFOs for localizing EZs because HFOs appeared in both epilepsy patients and healthy controls while HFSs appeared only in epilepsy patients.

To explore the effect of personalized digital analog assisted acetabular prosthesis precise implantation in hip dysplasia.From February 2017 to July 2019, 11 patients(12 hips) with hip dysplasia underwent total hip arthroplasty, including 4 males(5 hips) and 7 females(7 hips), aged from 27 to 61 years old, with an average of (46.64±12.93) years old;Crowe classification:8 hips in typeⅠ and 4 hips in typeⅡ. The preoperative thin-layer CT scan was imported into Mimics 10.01 software. The appropriate size and placement angle of acetabular prosthesis were selected through preoperative simulation, and the acetabular bone defect was understood to determine whether structural bone grafting was needed during the operation. The length of both lower limbs, the anteversion angle of acetabular prosthesis, the abduction angle, the height of acetabular rotation center and the horizontal distance of hip joint center before and after the operation were measured, and the postoperative dislocation, bone graft healing and acetabular cup loosening were observed. The hip Harris score was used to evaluate the joint function.All patients were followed up for 18 to 30 months with an average of (23.45±3.70) months. There was no prosthesis dislocation, loosening and bone graft healing after operation. One case had numbness in the innervation area due to the traction of sciatic nerve during operation, and was treated with neurotrophic drugs and recovered one month after operation. The length difference of both lower limbs decreased from (31.73±5.98) mm before operation to (4.73±1.90) mm 3 months after operation (Through preoperative personalized digital analog reconstruction of acetabulum in patients with hip dysplasia, we can better understand the acetabular defect, help to evaluate the size and placement angle of acetabular prosthesis and whether structural bone grafting is needed, and obtain satisfactory clinical curative effect.

Pulmonary sarcomatoid carcinoma (PSC) is an aggressive and poorly differentiated type of non-small cell lung carcinoma. Because of the rarity of PSC, the efficacy and toxicity of immunotherapy remain unclear. Hence, the aim of this study was to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) for the treatment of advanced PSC. The study cohort was limited to 33 patients with pathologically confirmed PSC treated with ICIs in four hospitals in China from March 2018 to March 2022. Expression of programmed death ligand 1 (PD-L1) was detected by immunohistochemical analysis. Categorical variables were compared with the Fisher exact test and survival analysis was conducted with the Kaplan-Meier method. Of the 33 PSC patients, 8 (24.2%) received monotherapy with ICIs and 25 (75.8%) received combination therapy with ICIs. The objective response rate (ORR) and disease control rate (DCR) were 36.4% and 78.8%, respectively. The median durations of progression-free survival (PFS) and overall survival (OS) were 6.07 and 21.33 months, respectively. PD-L1 status in 16 available samples was assessed, which included 30.3% PD-L1-positive patients. The ORRs for PD-L1-positive vs. -negative patients were 50.0% and 90.0%, the DCR was 33.3% and 83.3%, and the median PFS was 17.50 and 6.07 months, respectively (p=0.812). The median OS was not reached in PD-L1-positive and -negative patients (p=0.655). The incidence of immune-related adverse (irAEs) was 48.5% and mainly included grade 1 or 2 (39.4%), while the incidence of grade 3 or 4 was 9.1%. Pneumonia (9.1%) and skin rash (9.1%) were the most frequent irAEs. Immunotherapy with ICIs was a promising regimen to improve the prognosis of patients with advanced PSC.

Ferroptosis is a novel type of cell death depending on iron and is strongly related to the development of tumors. Hepatocellular carcinoma (HCC) is a malignancy with high incidence. Despite some reports demonstrating the relation between ferroptosis-related genes and HCC, more details have not been excavated. In the present study, we collected and analyzed HCC patients' datasets from the TCGA-LIHC project and ICGC portal, respectively. Through the bioinformatic methods, we screened 126 differentially expressed genes. Then a prognostic model was established with four genes (GPX2, MT3, PRDX1, and SRXN1). PRDX1 is the hub gene of the prognosis model and has a high expression in hepatocellular carcinoma tumor tissue and cell lines. We further found that silencing PRDX1 increased the accumulation of ferrous ions and lipid peroxidation accumulation in HEPG2 cells and promoted ferroptosis in hepatocellular carcinoma. In conclusion, the study demonstrated the four-gene signature can be used to predict HCC prognosis. It also revealed the potential function of the ferroptosis-related gene PRDX1 in HCC, which can be a biomarker of the prediction for HCC outcome.

Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. They are involved in many crucial biological processes and human diseases, especially in thyroid diseases. DUOXs are protein complexes co-assembled from the catalytic DUOX subunits and the auxiliary DUOXA subunits and their activities are regulated by intracellular calcium concentrations. Here, we report the cryo-EM structures of human DUOX1-DUOXA1 complex in both high-calcium and low-calcium states. These structures reveal the DUOX1 complex is a symmetric 2:2 hetero-tetramer stabilized by extensive inter-subunit interactions. Substrate NADPH and cofactor FAD are sandwiched between transmembrane domain and the cytosolic dehydrogenase domain of DUOX. In the presence of calcium ions, intracellular EF-hand modules might enhance the catalytic activity of DUOX by stabilizing the dehydrogenase domain in a conformation that allows electron transfer., Dual oxidases (DUOXs), assembled from the catalytic DUOX and the auxiliary DUOXA subunits, produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen in a calcium-activated manner. Here authors report the cryo-EM structures of human DUOX1-DUOXA1 complex in both high-calcium and low-calcium states.

Background Sepsis is a life-threatening multi-organ dysfunction caused by the dysregulated host response to infection. Sepsis remains a major global concern with high mortality and morbidity, while management of sepsis patients relies heavily on early recognition and rapid stratification. This study aims to identify the crucial genes and biomarkers for sepsis which could guide clinicians to make rapid diagnosis and prognostication. Methods Preliminary analysis of multiple global datasets, including 170 samples from patients with sepsis and 110 healthy control samples, revealed common differentially expressed genes (DEGs) in peripheral blood of patients with sepsis. After Gene Oncology (GO) and pathway analysis, the Weighted Gene Correlation Network Analysis (WGCNA) was used to screen for genes most related with clinical diagnosis. Also, the Protein-Protein Interaction Network (PPI Network) was constructed based on the DEGs and the hub genes were found. The results of WGCNA and PPI network were compared and one shared gene was discovered. Then more datasets of 728 experimental samples and 355 control samples were used to prove the diagnostic and prognostic value of this gene. Last, we used real-time PCR to confirm the bioinformatic results. Results Four hundred forty-four common differentially expressed genes in the blood of sepsis patients from different ethnicities were identified. Fifteen genes most related with clinical diagnosis were found by WGCNA, and 24 hub genes with most node degrees were identified by PPI network. ARG1 turned out to be the unique overlapped gene. Further analysis using more datasets showed that ARG1 was not only sharply up-regulated in sepsis than in healthy controls, but also significantly high-expressed in septic shock than in non-septic shock, significantly high-expressed in severe or lethal sepsis than in uncomplicated sepsis, and significantly high-expressed in non-responders than in responders upon early treatment. These all demonstrate the performance of ARG1 as a key biomarker. Last, the up-regulation of ARG1 in the blood was confirmed experimentally. Conclusions We identified crucial genes that may play significant roles in sepsis by WGCNA and PPI network. ARG1 was the only overlapped gene in both results and could be used to make an accurate diagnosis, discriminate the severity and predict the treatment response of sepsis.

We aimed to explore the treatment efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for lung squamous cell carcinoma (SCC) patients and identify potential beneficial subgroups of EGFR-mutated lung SCC patients in this study. Between February 1st, 2013 and December 1st, 2021, 657 advanced lung SCC patients were enrolled at Zhejiang Cancer Hospital. Amplification refractory mutation system PCR or next-generation sequencing were used to detect gene abnormality. Clinicopathological features were analyzed by chi-square test and the clinical results of lung SCC patients who received first-generation EGFR-TKI were analyzed by the Kaplan-Meier method. Lung SCC patients harboring EGFR mutation accounted for 11.0% in this study. Of 657 lung SCC patients, the median PFS and OS of 116 patients who received targeted therapy were 3.6 months and 16.2 months, patients treated with targeted therapy had similar OS to patients without targeted therapy (p=0.839). Of 110 lung SCC patients who received first-generation EGFR-TKI, EGFR-mutated patients had long PFS (p=0.000) but similar OS (p=0.472) than patients with EGFR wide type. EGFR-mutated SCC patients who received first-generation EGFR-TKI as a first-line benefit are equal to patients who received first-generation EGFR-TKI as the second line or beyond according to similar PFS (p=0.311) and OS (p=0.721) between them. In addition, there was also no significant difference in PFS (p=0.376) and OS (p=0.205) between patients with exon 19 deletion and L858R point mutation. Lung SCC patients harboring EGFR mutation received first-generation EGFR-TKI had better clinical survival than patients with EGFR wide type.

Non-small-cell lung cancer (NSCLC) has a high incidence and mortality worldwide. Moreover, it needs more accurate means for predicting prognosis and treatments. Pyroptosis is a novel form of cell death about inflammation which was highly related to the occurrence and development of tumors. Despite having some studies about pyroptosis-related genes (PRGs) and cancer, the correlation has not been explored enough between PRGs and immune in NSCLC. In this study, we constructed a PRG model by WGCNA to access the prognosis value PRGs have. The testing cohort ( n = 464 ) with four datasets from the GEO database conducted a survival analysis to confirm the stability of the prognostic model. The risk score and age are examined as independent prognostic factors. Based on the PRGs, we found multiple pathways enriched in immune in NSCLC. Separating samples into three subtypes by consensus cluster analysis, Cluster 3 was identified as immune-inflamed phenotype with an optimistic prognostic outcome. A three-gene PRG signature (BNIP3, CASP9, and CAPN1) was identified, and BNIP3 was identified as the core gene. Knockdown of BNIP3 significantly inhibited the growth of H358 cells and induced pyroptosis. In conclusion, the model construction based on PRGs provides novel insights into the prediction of NSCLC prognosis, and BNIP3 can serve as a diagnostic biomarker for NSCLC.

Background The diagnosis between benign and malignant gallbladder lesions is sometimes difficult. The objective of this study is to assess whether contrast-enhanced ultrasound (CEUS) and contrast-enhanced harmonic endoscopic ultrasound (CH-EUS) can be an accurate method for detecting gallbladder malignancy and to determine which imaging signs can be indicative of malignancy. Methods A study search of PubMed, Elsevier, and Sciencedirect was performed in May 2019. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve were used to examine the accuracy of CEUS and CH-EUS. Results Twenty-one studies were included in the meta-analysis. The pooled sensitivities of CEUS and CH-EUS were 0.81 (0.75–0.86) and 0.92 (0.86–0.95); the specificities were 0.94 (0.90–0.96) and 0.89 (0.69–0. 97); the DORs were 64 (32–127) and 89 (22–354); and the area under the SROC curves were 0.90 (0.87–0.92) and 0.92 (0.90–0.94). On CEUS, the diagnostic criterion for gallbladder malignancy according to four features were analyzed. Sensitivity and specificity were 0.75 (0.65–0.83) and 0.98 (0.85–1.00) for integrity of gallbladder wall; 0.69 (0.55–0.81) and 0.89 (0.77–0.95) for heterogeneous enhancement; 0.81 (0.71–0.88) and 0.88 (0.76–0.94) for irregular vessels; and 0.81 (0.66–0.91) and 0.75 (0.59–0.86) for washout time within 28 s. On CH-EUS, heterogeneous enhancement could be indicative of malignant lesions with a sensitivity of 0.94 (0.85–0.97); and the specificity was 0.92 (0.71–0.98). Conclusions CEUS and CH-EUS are promising and reliable imaging modalities with a high sensitivity and specificity for the diagnosis of gallbladder malignancy. CH-EUS might be more sensitive than CEUS with a higher sensitivity. In addition, irregular tralesional vessels and washout time within 28 s on CEUS and heterogeneous enhancement on CH-EUS are indicative of malignancy. However, larger scale and well-designed studies are warranted to verify our results.

About 1% of the population around the world suffers from epilepsy. The success of epilepsy surgery depends critically on pre-operative localization of epileptogenic zones. High frequency oscillations including ripples (80-250 Hz) and fast ripples (250-500 Hz) are commonly used as biomarkers to localize epileptogenic zones. Recent literature demonstrated that fast ripples indicate epileptogenic zones better than ripples. Thus, it is crucial to accurately detect fast ripples from ripples signals of magnetoencephalography for improving outcome of epilepsy surgery. This paper proposes an automatic and accurate ripple and fast ripple detection method that employs virtual sample generation and neural networks with an attention mechanism. We evaluate our proposed detector on patient data with 50 ripples and 50 fast ripples labeled by two experts. The experimental results show that our new detector outperforms multiple traditional machine learning models. In particular, our method can achieve a mean accuracy of 89.3% and an average area under the receiver operating characteristic curve of 0.88 in 50 repeats of random subsampling validation. In addition, we experimentally demonstrate the effectiveness of virtual sample generation, attention mechanism, and architecture of neural network models.

Retinal neovascularization (RNV) is a common pathological feature in many kinds of fundus oculi diseases. Sometimes RNV can even lead to severe vision loss. Oxidative injury is one of the main predisposing factors for RNV occurrence and development. The specific mechanism may be closely related to the special structural tissues of the retina. Retinal astrocytes (RACs) are mesenchymal cells located in the retinal neuroepithelial layer. RACs have an intimate anatomical relationship with microvascular endothelial cells. They have a variety of functions, but little is known about the mechanisms by which RACs regulate the function of endothelial cells. The molecules secreted by RACs, such as exosomes, have recently received a lot of attention and may provide potential clues to address the RAC‐mediated modulation of endothelial cells. In this study, we aimed to preliminarily explore the mechanisms of how RAC exosomes generated under oxidative stress are involved in the regulation of endothelial function. Our results showed that the apoptosis and autophagy levels in RACs were positively correlated with the oxidative stress level, and the exosomes generated from RACs under normal and oxidative stress conditions had different effects on the proliferation and migration of endothelial cells. However, the effect of RACs on endothelial cell function could be markedly reversed by the autophagy inhibitor 3‐methyladenine or the exosome inhibitor GW4869. Therefore, oxidative stress can lead to increased autophagy in RACs and can further promote RACs to regulate endothelial cell function by releasing exosomes., Highlights 1.tBHP‐induced oxidative stress can increase the level of autophagy in retinal (RAC) astrocytes.2.RAC with high‐autophagy level has a completely opposite effect on HUVEC functions when compared with normal RAC.3.RACs under different states have different effects on endothelial cell functions by releasing exosomes

To identify abnormal functional connectivity of the default mode network in cingulate gyrus epilepsy, which may yield new information about the default mode network and suggest a new cingulate gyrus epilepsy biomarker. Fifteen patients with cingulate gyrus epilepsy (mean age = 21 years) and 15 healthy controls (mean age = 24 years) were studied in the resting state using magnetoencephalography. Twelve brain areas of interest in the default mode network were extracted and investigated with multifrequency signals that included alpha (α, 8–13 Hz), beta (β, 14–30 Hz), and gamma (γ, 31–80 Hz) band oscillations. Patients with cingulate gyrus epilepsy had significantly greater connectivity in all three frequency bands (α, β, γ). A frequency‐specific elevation of functional connectivity was found in patients compared to controls. The greater functional connectivity in the γ band was significantly more prominent than that of the α and β bands. Patients with cingulate gyrus epilepsy and controls differed significantly in functional connectivity between the left angular gyrus and left posterior cingulate cortex in the α, β, and γ bands. The results of the node degree analysis were similar to those of the functional connectivity analysis. Our findings reveal for the first time that brain activity in the γ band may play a key role in the default mode network in cingulate gyrus epilepsy. Altered functional connectivity of the left angular gyrus and left posterior cingulate cortex may be a new biomarker for cingulate gyrus epilepsy.

Rivaroxaban is a novel oral anticoagulant widely used for thromboprophylaxis in patients with non-valvular atrial fibrillation (NVAF). The present study aimed to develop a population pharmacokinetic (PPK) model for rivaroxaban in Chinese patients with NVAF.We performed a prospective multicenter study. The plasma concentration of rivaroxaban was directly detected by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and indirectly by rivaroxaban-calibrated chromogenic anti-Xa assay (STAA total of 150 patients from five centers were recruited, including 263 plasma concentrations detected by HPLC-MS/MS, 2626 gene polymorphisms, and 131 plasma concentrations detected by anti-Xa assay. In our study, an oral one-compartment model was used to describe the pharmacokinetics of rivaroxaban in patients with NVAF. In the final model, the estimated apparent clearance (CL/F) and volume of distribution (V/F) were 5.79 L/h (relative standard error [RSE] 4.4%) and 51.5 L (RSE 5.0%), respectively. Covariates in the final model included creatinine clearance, total bilirubin, rs4728709, and body weight. The simulation results showed that in the 15 mg once-daily dosing regimen, in most instances the maximum plasma concentration at steady state (COur study was the first multicenter PPK model for rivaroxaban in Chinese patients with NVAF (Alfalfa-RIVAAF-PPK). The study found that 15 mg once daily may be suitable as the principal rivaroxaban dose for Chinese patients with NVAF. For patients with the rs4728709 mutation, it may be necessary to examine insufficient anticoagulation. We found that the rivaroxaban-calibrated chromogenic anti-Xa assay and HPLC-MS/MS method were highly linearly correlated. Prospective studies with larger sample sizes and real-world studies are needed for further verification.

Background Migraine is a common and disabling primary headache, which is associated with a wide range of psychiatric comorbidities. However, the mechanisms of emotion processing in migraine are not fully understood yet. The present study aimed to investigate the neural network during neutral, positive, and negative emotional stimuli in the migraine patients. Methods A total of 24 migraine patients and 24 age- and sex-matching healthy controls were enrolled in this study. Neuromagnetic brain activity was recorded using a whole-head magnetoencephalography (MEG) system upon exposure to human facial expression stimuli. MEG data were analyzed in multi-frequency ranges from 1 to 100 Hz. Results The migraine patients exhibited a significant enhancement in the effective connectivity from the prefrontal lobe to the temporal cortex during the negative emotional stimuli in the gamma frequency (30–90 Hz). Graph theory analysis revealed that the migraine patients had an increased degree and clustering coefficient of connectivity in the delta frequency range (1–4 Hz) upon exposure to positive emotional stimuli and an increased degree of connectivity in the delta frequency range (1–4 Hz) upon exposure to negative emotional stimuli. Clinical correlation analysis showed that the history, attack frequency, duration, and neuropsychological scales of the migraine patients had a negative correlation with the network parameters in certain frequency ranges. Conclusions The results suggested that the individuals with migraine showed deviant effective connectivity in viewing the human facial expressions in multi-frequencies. The prefrontal-temporal pathway might be related to the altered negative emotional modulation in migraine. These findings suggested that migraine might be characterized by more universal altered cerebral processing of negative stimuli. Since the significant result in this study was frequency-specific, more independent replicative studies are needed to confirm these results, and to elucidate the neurocircuitry underlying the association between migraine and emotional conditions.

ATP-sensitive potassium channels (K

Evidence of the acute effects of air pollutants on ischemic heart disease (IHD) hospitalizations based on the entire population of a megacity in central China is lacking. All IHD hospitalization records from 2017 to 2018 were obtained from the Wuhan Information Center of Health and Family Planning. Daily air pollutant concentrations and meteorological data were synchronously collected from the Wuhan Environmental Protection Bureau. A time-series study using generalized additive models was conducted to systematically examine the associations between air pollutants and IHD hospitalizations. Stratified analyses by gender, age, season, hypertension, diabetes, and hyperlipidemia were performed. In total, 139,616 IHD hospitalizations were included. Short-term exposure to air pollutants was positively associated with IHD hospitalizations. The age group ≥76 was at higher exposure risk, and the associations appeared to be more evident in cold seasons. PM2.5 and PM10 appeared to have greater effects on males and those without hypertension or diabetes, whereas NO2 and SO2 had greater effects on females and those with hypertension or diabetes. The risk of IHD hospitalization due to air pollutants was greater in people without hyperlipidemia. Our study provides new evidence of the effects of air pollution on the increased incidence of IHD in central China.

Background Colorectal cancer (CRC) is a heterogeneous disease with different responses to targeted therapies due to various factors, and the treatment effect differs significantly between individuals. Personalize medical treatment (PMT) is a method that takes individual patient characteristics into consideration, making it the most effective way to deal with this issue. Patient similarity and clustering analysis is an important aspect of PMT. This paper describes how to build a knowledge base using formal concept analysis (FCA), which clusters patients based on their similarity and preserves the relations between clusters in hierarchical structural form. Methods Prognostic factors (attributes) of 2442 CRC patients, including patient age, cancer cell differentiation, lymphatic invasion and metastasis stages were used to build a formal context in FCA. A concept was defined as a set of patients with their shared attributes. The formal context was formed based on the similarity scores between each concept identified from the dataset, which can be used as a knowledge base. Results A hierarchical knowledge base was constructed along with the clinical records of the diagnosed CRC patients. For each new patient, a similarity score to each existing concept in the knowledge base can be retrieved with different similarity calculations. The ranked similarity scores that are associated with the concepts can offer references for treatment plans. Conclusions Patients that share the same concept indicates the potential similar effect from same clinical procedures or treatments. In conjunction with a clinician’s ability to undergo flexible analyses and apply appropriate judgement, the knowledge base allows faster and more effective decisions to be made for patient treatment and care.

Magnetoencephalography (MEG) based on optically pumped magnetometers (OPMs) opens up new opportunities for brain research. However, OPM recordings are associated with artifacts. We describe a new artifact reduction method, frequency specific signal space classification (FSSSC), to improve the signal-to-noise ratio of OPM recordings.FSSSC was based on time-frequency analysis and signal space classification (SSC). SSC was accomplished by computing the orthogonality of the brain signal and artifact. A dipole phantom was used to determine if the method could remove artifacts and improve accuracy of source localization. Auditory evoked magnetic fields (AEFs) from human subjects were used to assess the usefulness of artifact reduction in the study of brain function because bilateral AEFs have proven a good benchmark for testing new methods. OPM data from empty room recordings were used to estimate magnetic artifacts. The effectiveness of FSSSC was assessed in waveforms, spectrograms, and covariance domains.MEG recordings from phantom tests show that FSSSC can remove artifacts, normalize waveforms, and significantly improve source localization accuracy. MEG signals from human subjects show that FSSC can reveal auditory evoked magnetic responses overshadowed and distorted by artifacts. The present study demonstrates FSSSC is effective at removing artifacts in OPM recordings. This can facilitate the analyses of waveforms, spectrograms, and covariance. The accuracy of source localization of OPM recordings can be significantly improved by FSSSC.Brain responses distorted by artifacts can be restored. The results of the present study strongly support that artifact reduction is very important in order for OPMs to become a viable alternative to conventional MEG.

Immune checkpoint inhibitors (ICIs) have made breakthrough progress in the treatment of various malignant tumors. However, only some patients receiving ICIs obtain long-lasting clinical effects, and some patients still do not achieve remission. Improving the treatment benefits of this part of the population has become a concern of clinicians. IL-1 signaling plays an important role in the tumor microenvironment (TME). However, the relationship between the IL-1 signaling mutation status and the prognosis of colon adenocarcinoma (COAD) patients receiving ICIs has not been reported. We downloaded the data of a COAD cohort receiving ICIs, including prognostic data and mutation data. Additionally, we downloaded the data of a COAD cohort from The Cancer Genome Atlas (TCGA) database, including clinical data, expression data and mutation data. Gene set enrichment analysis (GSEA) was used to assess differences in the activity of some key physiological pathways between the IL-1 signaling mutated-type (IL-1-MT) and IL-1 signaling wild-type (IL-1-WT) groups. The CIBERSORT algorithm was used to evaluate the contents of immune cells in the TME of COAD patients. The multivariate Cox regression model results suggested that IL-1-MT can be used as an independent predictor of a better prognosis in COAD patients receiving ICIs (P = 0.03, HR = 0.269, 95% CI: 0.082-0.883). Additionally, IL-1-MT COAD patients had significantly longer overall survival (OS) (log-rank P = 0.015). CIBERSORT analysis showed that the IL-1-MT group had high infiltration levels of activated dendritic cells (DCs), M1 macrophages, neutrophils, activated natural killer (NK) cells, activated CD4+ memory T cells and CD8+ T cells. Similarly, the IL-1-MT group had significantly upregulated immunogenicity, including in terms of the tumor mutation burden (TMB), neoantigen load (NAL) and number of mutations in DNA damage repair (DDR) signaling. GSEA showed that the IL-1-MT group was highly enriched in the immune response and proinflammatory mediators. Additionally, the expression levels of immune-related genes, immune checkpoint molecules and immune-related signatures were significantly higher in the IL-1-MT group than in the IL-1-WT group. IL-1-MT may be an independent predictor of a good prognosis in COAD patients receiving ICIs, with significantly longer OS in IL-1-MT COAD patients. Additionally, IL-1-MT was associated with significantly increased immunogenicity, activated immune cell and inflammatory mediator levels and immune response-related scores.

TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels that are involved in many physiological processes. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal segmental glomerulosclerosis (FSGS) in humans, but their pathogenic mechanism remains elusive. Here, we report the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. Based on these structures and accompanying electrophysiological studies, we identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. These calcium sensors are also structurally and functionally conserved in TRPC6. We uncovered that the GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. Furthermore, structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets reveal different conformations of the transmembrane domain, providing templates for further structure-based drug design targeting TRPC6-related diseases such as FSGS.

Age-related cataract (ARC) is the most common cause of severe visual impairment and blindness. The precise mechanisms of ARC are not completely understood, but it is well accepted that oxidative damage plays an important role in the disease pathogenesis. BLM, the key enzyme of the double-strand break repair (DSBR) pathway, is part of a family of DNA unwinding enzymes and has a crucial role in multiple steps of the DNA recombination, replication and repair processes. We have recently shown that BLM-rs1063147 is initially associated with nuclear ARC in a cross-section study. Therefore, we wanted to study the effects of BLM on ARC progression. In ARC patients, BLM transcription in lens capsules was decreased, so did the BLM protein, and after UVB irradiation, BLM mRNA and protein levels were increased in SRA01/04 cells. Upon silencing BLM in SRA01/04 cells and rat lens, cell vitality and apoptosis were altered, and the rat lens opacification was considerable. In conclusion, BLM can regulate cataract progression by influencing cell vitality and apoptosis.

High-frequency oscillations (HFOs) are spontaneous magnetoencephalography (MEG) patterns that have been acknowledged as a putative biomarker to identify epileptic foci. Correct detection of HFOs in the MEG signals is crucial for the accurate and timely clinical evaluation. Since the visual examination of HFOs is time-consuming, error-prone, and with poor inter-reviewer reliability, an automatic HFOs detector is highly desirable in clinical practice. However, the existing approaches for HFOs detection may not be applicable for MEG signals with noisy background activity. Therefore, we employ the stacked sparse autoencoder (SSAE) and propose an SSAE-based MEG HFOs (SMO) detector to facilitate the clinical detection of HFOs. To the best of our knowledge, this is the first attempt to conduct HFOs detection in MEG using deep learning methods. After configuration optimization, our proposed SMO detector is outperformed other classic peer models by achieving 89.9% in accuracy, 88.2% in sensitivity, and 91.6% in specificity. Furthermore, we have tested the performance consistency of our model using various validation schemes. The distribution of performance metrics demonstrates that our model can achieve steady performance.

TRPC5 channel is a nonselective cation channel that participates in diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression, and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here, we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 Å. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative diacylglycerol molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a nonconductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.

Magnetoencephalography (MEG) is a persuasive tool to study the human brain in physiology and psychology. It can be employed to obtain the inference of change between the external environment and the internal psychology, which requires us to recognize different single trial event-related magnetic fields (ERFs) originated from different functional areas of the brain. Current recognition methods for the single trial data are mainly used for event-related potentials (ERPs) in the electroencephalography (EEG). Although the MEG shares the same signal sources with the EEG, much less interference from the other brain tissues may give the MEG an edge in recognition of the ERFs. In this work, we propose a new recognition method for the single trial auditory evoked magnetic fields (AEFs) through enhancing the signal. We find that the signal strength of the single trial AEFs is concentrated in the primary auditory cortex of the temporal lobe, which can be clearly displayed in the 2D images. These 2D images are then recognized by an artificial neural network (ANN) with 100% accuracy, which realizes the automatic recognition for the single trial AEFs. The method not only may be combined with the source estimation algorithm to improve its accuracy but also paves the way for the implementation of the brain-computer interface (BCI) with the MEG.

Summary Objective To preliminarily explore death risk factors in primary melanoma patients. Method Competing risk model analysis was used using a large sample public cohort and Cox proportional hazard model was compared. Result In the competing risk model analysis, age, gender, ethnicity, stage, site, TMN stage and metastases were the independent risk factors of single primary melanoma (SPM) death. T stage had a particularly important impact on SPM death. T2 stage had a 3.212 times greater risk of interest event than T1 stage [hazard ratio (HR) = 3.212, 95%CI: 2.994–3.446], T3 stage was 5.747 times greater than that T1 stage (HR = 5.747, 95%CI: 5.337–6.187) and T4 stage had a 7.086 times than T1 stage (HR = 7.086, 95%CI: 6.514–7.708). Gender, ethnicity, stage, site, T stage and brain and liver metastases were the independent risk factors of multiple primary melanoma (MPM) death. When some groups had a very high death rate or the reference group had a very low death rate in competing events, the results of Cox proportional hazard model may not be as accurate as the results obtained by fine-Gray regression model. Conclusion Early diagnosis and therapy, and prevention of tumor progression and metastases of primary melanoma patients are important measures to improve its prognosis and survival.

Resting membrane potential determines the excitability of the cell and is essential for the cellular electrical activities. The NALCN channel mediates sodium leak currents, which positively adjust resting membrane potential towards depolarization. The NALCN channel is involved in several neurological processes and has been implicated in a spectrum of neurodevelopmental diseases. Here, we report the cryo-EM structure of rat NALCN and mouse FAM155A complex to 2.7 Å resolution. The structure reveals detailed interactions between NALCN and the extracellular cysteine-rich domain of FAM155A. We find that the non-canonical architecture of NALCN selectivity filter dictates its sodium selectivity and calcium block, and that the asymmetric arrangement of two functional voltage sensors confers the modulation by membrane potential. Moreover, mutations associated with human diseases map to the domain-domain interfaces or the pore domain of NALCN, intuitively suggesting their pathological mechanisms., The NALCN channel mediates sodium leak currents, which in turn adjusts resting membrane potential and neuronal excitability. Here the authors describe a cryo-EM structure of mammalian NALCN-FAM155A channel complex, showing how selectivity filter contributes to sodium permeation and calcium block and how the voltage sensors contribute to current modulation.

Background Extreme delta brush (EDB) is considered a potential marker for anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. The brain regions involved in EDB are unclear. Case presentation A 16-year-old woman with anti-NMDAR encephalitis who was experiencing psychosis was admitted. Electroencephalography (EEG) and magnetoencephalography (MEG) were used to analyze EDB in the patient. EDB on EEG could be disturbed by opening and closing the eyes, by occipital alpha rhythms and by sleep-wake cycles. The MEG results showed beta activity originating from bilateral superior parietal lobes. However, the delta wave originated from bilateral superior temporal gyri, the right middle temporal gyrus, the right inferior frontal gyrus, and the left inferior parietal lobe. Conclusions Delta wave and beta activity might originate from different brain regions. Beta activity might be transmitted forward to the frontotemporal lobe and superimposed with delta activity to form EDB on EEG.

The aim of this article is to introduce the recent advance on the studies of fungal keratitis published over past 5 years. We performed literature review of articles published on PubMed, Google Scholar, CNKI and Web of Science relevant to the diagnosis, pathogenesis and novel treatment of fungal keratitis. Excessive inflammation can lead to stromal damage and corneal opacification, hence the research on immune mechanism provides many potential therapeutic targets for fungal keratitis. Many researchers discussed the importance of earlier definitive diagnosis and were trying to find rapid and accurate diagnostic methods of pathogens. Develop new drug delivery systems and new routes of administration with better corneal penetration, prolonged ocular residence time, and better mucoadhesive properties is also one of the research hotspots. Additionally, many novel therapeutic agents and methods have been gradually applied in clinical ophthalmology. The diagnosis and treatment of fungal keratitis are still a challenge for ophthalmologist, and many researches provide new methods to conquer these problems.

Ureaplasma urealyticum and Ureaplasma parvum are the most common Ureaplasma species causing repeated or persistent infection of the urogenital tract. The host can mobilize innate and adaptive immunity to defend and eliminate pathogens. However, under certain conditions, the host's immune protection cannot completely clear Ureaplasma species. Ureaplasma species have evolved a complex and sophisticated escape mechanism in the long-term defense against host immune protection. This article summarizes the research progress on Ureaplasma species' immune escape mechanism from several aspects such as evading host autophagy mechanism, antagonizing host nutritional immunity and regulating host cell gene expression.

Introduction This study was aimed to explore the relationship between neural network changes in newly diagnosed children with Benign Childhood Epilepsy with Centrotemporal Spikes (BECTS) and cognitive impairment. Methods Children's cognition was evaluated using the Wechsler Intelligence Scale for Children‐Fourth Edition (WISC‐IV). Magnetoencephalographic (MEG) data of 18 healthy children and 22 BECTS patients were recorded in order to construct a functional connectivity (FC) network, which was quantified by graph theory (GT). Results The mean age of the control group was 7.94 ± 1.89 years, and the mean age of BECTS patients was 8.14 ± 1.73 years. Our results show that the WISC‐IV index scores in the BECTS group were significantly lower than those in the control group. Besides, the FC network pattern of BECTS patients changed significantly in the 12–30, 30–80, and 250–500 Hz frequency band. The local functional connections between posterior cingulate cortex (PCC) and frontal lobe varied significantly in 12–30, 80–250, and 250–500 Hz. Our GT analysis shows that the connection strength of BECTS patients increases significantly in the 12–30 Hz frequency band, the path length decreases significantly in the 12–30 Hz and 30–80 Hz frequency bands, with the clustering coefficient decreasing significantly in the 12–30 Hz, 30–80 Hz, and 250–500 Hz frequency bands. Correlation analysis showed that the full‐scale IQ (FSIQ) was positively correlated with the 12–30 Hz clustering coefficient, verbal comprehension index (VCI) was positively correlated with the 250–500 Hz clustering coefficient, perceptual reasoning index (PRI) was positively correlated with the 12–30 Hz clustering coefficient, and perceptual reasoning index (PSI) was negatively correlated with the 12–30 Hz path length. Conclusion There is a trend of cognitive impairment in patients with early BECTS. This trend of cognitive impairment in early BECTS children may be related to the changes in the FC network pattern., BECTS patients have a certain degree of cognitive dysfunction in the early stage of the disease. The functional connections of patients with early BECTS showed unbalanced brain topology, and the brain network pattern was tending to be randomized. This trend of cognitive decline in early BECTS children may be related to the change of FC network patterns.

BACKGROUND: Neuromagnetic high frequency brain signals (HFBS, > 80 Hz) are a new biomarker for localization of epileptogenic zones (EZs) for pediatric epilepsy. METHODS: Twenty three children with drug-resistant epilepsy and age/sex matched healthy controls were studied with magnetoencephalography (MEG). Epileptic HFBS in 80-250 Hz and 250-600 Hz were quantitatively determined by comparing with normative controls in terms of kurtosis and skewness. Magnetic sources of epileptic HFBS were localized and then compared to clinical EZs determined by invasive recordings and surgical outcomes. RESULTS: Kurtosis and skewness of HFBS were significantly elevated in epilepsy patients compared to healthy controls (p < 0,001 and p < 0.0001, respectively). Sources of elevated MEG signals in comparison to normative data were co-localized to EZs for 22 (22/23, 96%) patients. CONCLUSIONS: The results indicate, for the first time, that epileptic HFBS can be noninvasively quantified by measuring kurtosis and skewness in MEG data. Magnetic source imaging based on kurtosis and skewness can accurately localize EZs. SIGNIFICANCE: Source imaging of kurtosis and skewness of MEG HFBS provides a novel way for preoperative localization of EZs for epilepsy surgery.

The giant cell tumor of tendon sheath (GCTTS) is a benign lesion most commonly attached to the tendons and bones of the fingers, hands, and wrists. The involvement of GCTTS to the foot is uncommon. The GCTTS invading tarsal bones and intertarsal joints is not described yet, and the appropriate diagnosis and treatment remain unclear. We report a case of GCTTS with the involvement of tarsal bones and intertarsal joint. Computed tomography scan and magnetic resonance imaging were used to further diagnose and evaluate the quality and range of tumor. The patient was treated with surgical excision of the tumor without application of bone graft. After adequate clearance of the tumor, the patient returned to an asymptomatic walk in 3 months. No malfunction, fracture, or tumor recurrence was found in 2-years follow-up. This report includes clinical, radiologic, histologic diagnostic, and surgical challenges in an unexpected lesion and a review of the literature.

Vitamin D regulates cell proliferation, inhibits cytokines release at sites of inflammation and reduces inflammatory responses. In this study, the aim was to investigate whether exogenous vitamin D attenuates LPS-induced lung injury via modulating epithelial cell proliferation, migration, apoptosis and epithelial mesenchymal transition (EMT). Murine and in vitro primary type II alveolar epithelial cell work were included in this study. In vivo, mice were mildly vitamin D deficient, 0.1, 1.5, 10 mg/kg 1,25(OH)2-vitamin D3 or 25(OH)-vitamin D3 was administrated by means of an intra-gastric injection for 14 days pre-intra-tracheal (IT) LPS, which remarkedly promoted alveolar epithelial type II cells proliferation, inhibited ATII cells apoptosis and inhibited EMT, with the outcome of attenuated LPS-induced lung injury. In vitro, vitamin D stimulated epithelial cell scratch wound repair, reduced primary ATII cells apoptosis as well. Vitamin D promoted primary human ATII cells proliferation through the PI3K/AKT signaling pathway and activation of vitamin D receptor (VDR). Moreover, vitamin D inhibited EMT in response to TGF-β, which was vitamin D receptor dependent. In conclusion, vitamin D attenuates lung injury via stimulating ATII cells proliferation and migration, reducing epithelial cell apoptosis and inhibits TGF-β induced EMT. Together, these results suggest that vitamin D has therapeutic potential for the resolution of ARDS.

Sterol O-acyltransferase 1 (SOAT1) is an endoplasmic reticulum (ER) resident, multi-transmembrane enzyme that belongs to the membrane-bound O-acyltransferase (MBOAT) family. It catalyzes the esterification of cholesterol to generate cholesteryl esters for cholesterol storage. SOAT1 is a target to treat several human diseases. However, its structure and mechanism remain elusive since its discovery. Here, we report the structure of human SOAT1 (hSOAT1) determined by cryo-EM. hSOAT1 is a tetramer consisted of a dimer of dimer. The structure of hSOAT1 dimer at 3.5 Å resolution reveals that a small molecule inhibitor CI-976 binds inside the catalytic chamber and blocks the accessibility of the active site residues H460, N421 and W420. Our results pave the way for future mechanistic study and rational drug design targeting hSOAT1 and other mammalian MBOAT family members., Sterol O-acyltransferase 1 (SOAT1, also named ACAT1) is an endoplasmic reticulum resident enzyme which catalyzes the esterification of cholesterol to generate cholesteryl esters. Here, authors report cryo-EM structures of human SOAT1 which reveal the binding site of the competitive inhibitor CI-976.

To evaluate the regulation of VEGF-Notch signaling pathway on proliferation and apoptosis of mesenchymal stem cells (MSC) in the patients with aplastic anemia (AA).The bone marrow specimens of AA patients were collected for isolation and identification of BM MSC. Westen blot was used to detect the expression of VEGF-Notch signaling pathway-related proteins (VEGF, VEGFR, Notch 1, Jagged 1, Delta-like 1 and Hes1). The VEGF (100 ng/ml) and DAPT (γ-secretase inhibitor, 10 μmol/L) were respectively added into MSC culture system in oder to activate and inhibit the signaling transduction of VEGF-Notch in BM MSC. The proliferation, apoptosis and cell cycle of MSC in AA patients were detected by CCK8 assay and flow cyfometry. The adipogenic differentiation of BM MSC was detected by oil red O staining.The VEGF-Notch signaling pathway was significantly inhibited in AA BM tissues and AA MSC (P＜0.05) detected by Western blot. The intervention of VEGF and DAPT significantly activated and inhibited VEGF-Notch signaling in AA MSC, respectively. CCK8 assay showed that VEGF intervention significantly promoted the proliferation of MSC in AA patients (P＜0.05). Flow cytometry showed that VEGF significantly inhibited apoptosis of MSCs by blocking S phase cells (P＜0.05).The activation of VEGF-Notch can restore the proliferation function of MSC in AA patients.VEGF-Notch信号通路对再生障碍性贫血患者骨髓MSC增殖和凋亡的作用.评估VEGF-Notch信号通路对再生障碍性贫血（aplastic anemia，AA）患者骨髓间充质干细胞（mesenchymal stem cell, MSC）增殖和凋亡的调节作用.收集再生障碍性贫血患者骨髓标本，进行骨髓MSC分离及鉴定，应用Western blot检测AA患者骨髓（BM）中VEGF-Notch信号通路相关蛋白（VEGF，VEGFR，Notch-1，Jagged1，Delta-like1和hes1）的表达。在MSC培养体系中分别加入VEGF（100 ng/ml）和DAPT（γ-secretase inhibitor）（10μmol/L），以活化和抑制MSC中的VEGF-Notch信号传导。利用细胞计数试剂盒8和流式细胞术评估AA患者MSC的细胞增殖、凋亡和细胞周期；应用油红0染色法检测成脂分化.AA患者MSC中VEGF-Notch信号通路受到明显抑制（P＜0.05）。VEGF和DAPT的干预分别激活和抑制AA患者MSC中的VEGF-Notch信号传导。CCK8检测结果显示，VEGF的干预明显促进MSC的增殖（P＜0.05）。流式细胞仪检测显示，VEGF通过阻断S期细胞显著抑制MSC的凋亡（P＜0.05）.VEGF-Notch信号通路的激活有可能恢复AA患者MSC的增殖功能.

Radiation resistance is a serious issue in radiotherapy. Increasing evidence indicates that the human gut microbiome plays a role in the development of radiation resistance. Vitamin D is an important supplement for cancer patients treated with radiotherapy. Against this background, this paper reviewed research regarding the associations among vitamin D, microbiota dysbiosis, and radiation resistance. A hypothesis is developed to describe the relationships among vitamin D, the gut microbiota, and radiotherapy outcomes. Radiotherapy changes the composition of the gut microbiota, which in turn influence the serum level of vitamin D, and its distribution and metabolism in the body. Alteration of vitamin D level influences the patient response to radiotherapy, where the underlying mechanisms may be associated with the intestinal microenvironment, immune molecules in the intestines, gut microbiome metabolites, and signaling pathways associated with vitamin D receptors. Our understanding of the contribution of vitamin D and the gut microbiota to radiotherapy outcomes has been increasing gradually. A better understanding of the relationships among vitamin D, the gut microbiota, and radiotherapy outcomes will shed more light on radiation resistance, and also promote the development of new strategies for overcoming it, thus addressing an important challenge associated with the currently available radiotherapy modalities for cancer patients.

Purpose Long noncoding RNAs (lncRNAs) are important in disease progression and cellular functions. This study aimed to conduct global lncRNA profiling and characterize the role of lncRNA 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta 3-sence RNA 1 (PLCD3-OT1) in the progression of age-related cataract (ARC). Methods We performed lncRNA expression profiling of lens capsule from ARC groups and age-matched groups using high-throughput RNA-sequencing. Real-time PCR was conducted to detect the expression pattern of lncRNA and mRNA in the clinical samples and cell model. Assays of cell-counting kit-8, 5'-ethynyl-2'-deoxyuridine, TUNEL, and propidium iodide staining were used to detect cell viability, proliferation, apoptosis, and cell cycle. We also performed fluorescence in situ hybridization assay to detect the location of lncRNA, and verified the endogenous competitive RNA mechanism between miRNAs, lncRNAs, and target genes via double-luciferase reporter analyses. Results The expression of lncRNA PLCD3-OT1 and PLCD3 were significantly decreased in ARC. PLCD3-OT1 overexpression promoted the expression of PLCD3, cell viability, proliferation, and inhibited cell apoptosis upon oxidative stress, while knockdown of PLCD3 showed the opposite results. Mechanistically, PLCD3-OT1functions through positively regulation the expression of PLCD3. In addition, PLCD3-OT1 may act as a ceRNA to regulate the expression of PLCD3 through competition for miR-224-5p. Conclusions PLCD3-OT1 and PLCD3 may become potential therapeutic targets for the prognosis, diagnosis, and treatment of ARC.

Nucleotide exchange factor (GrpE), a highly conserved antigen, is rapidly expressed and upregulated when Ureaplasma urealyticum infects a host, which could act as a candidative vaccine if it can induce an anti-U. urealyticum immune reaction. Here, we evaluated the vaccine potential of recombinant GrpE protein adjuvanted by Freund's adjuvant (FA), to protect against U. urealyticum genital tract infection in a mouse model. After booster immunization in mice with FA, the GrpE can induced both humoral and cellular immune response after intramuscular injection into BALB/c mice. A strong humoral immune response was detected in the GrpE-immunized mice characterized by production of high titers of antigen-specific serum IgG (IgG1, IgG2a, and IgG3) antibodies. At the same time, the GrpE also induced a Th1-biased cytokine spectrum with high levels of IFN-γ and TNF-α after re-stimulation with immunogen GrpE in vitro, suggesting that GrpE could trigger the Th1 response when used for vaccination in the presence of FA. Although GrpE vaccination in the presence of a Th1-type adjuvant-induced had readily detectable Th1 responses, there wasn't increase inflammation in response to the infection. More importantly, the robust immune responses in mice after immunization with GrpE showed a significantly reduced U. urealyticum burden in cervical tissues. Histopathological analysis confirmed that tissues of GrpE-immunized BALB/c mice were protected against the pathological effects of U. urealyticum infection. In conclusion, this study preliminarily reveals GrpE protein as a promising new candidate vaccine for preventing U. urealyticum reproductive tract infection.

The brain undergoes enormous changes during childhood. Little is known about how the brain develops to serve word processing. The objective of the present study was to investigate the maturational changes of word processing in children and adolescents using magnetoencephalography (MEG). Responses to a word processing task were investigated in sixty healthy participants. Each participant was presented with simultaneous visual and auditory word pairs in "match" and "mismatch" conditions. The patterns of neuromagnetic activation from MEG recordings were analyzed at both sensor and source levels. Topography and source imaging revealed that word processing transitioned from bilateral connections to unilateral connections as age increased from 6 to 17 years old. Correlation analyses of language networks revealed that the path length of word processing networks negatively correlated with age (r = -0.833, p 0.0001), while the connection strength (r = 0.541, p 0.01) and the clustering coefficient (r = 0.705, p 0.001) of word processing networks were positively correlated with age. In addition, males had more visual connections, whereas females had more auditory connections. The correlations between gender and path length, gender and connection strength, and gender and clustering coefficient demonstrated a developmental trend without reaching statistical significance. The results indicate that the developmental trajectory of word processing is gender specific. Since the neuromagnetic signatures of these gender-specific paths to adult word processing were determined using non-invasive, objective, and quantitative methods, the results may play a key role in understanding language impairments in pediatric patients in the future.

Background Neurokinin1 (NK1) receptor has played a vital role in the development of tumor. However, NKP608 as a NK1 receptor antagonist whether has the effect of the resistance of colorectal cancer is still unclear. Thereby, in this study, we investigated the role of NKP608 on human colorectal cancer and explored the underlying mechanism. Methods The cell proliferation of colorectal cancer cells was detected by cell counting kit-8 (CCK8) assay, cell migration and invasion were assessed by transwell assay, the apoptotic ratio of cells was assessed by Annexin V-fluorescein isothiocyanate/propidium iodide stained and flow cytometry. The involvement of molecular mechanisms was examined by western blot. Results In this study, we found that NKP608 inhibited the proliferation, migration/invasion of HCT116 cells. In addition, NKP608 reduced expressions of Wnt-3a, β-catenin, Cyclin D1, and (vascular endothelial growth factor) VEGF while induced expression of E-Cadherin. Furthermore, flow cytometry analyzed that NKP608 induced apoptosis of HCT116 cells, consistently, western blotting detecting of apoptosis-related proteins revealed that NKP608 downregulated Bcl-2 while upregulated Bax and Active-Caspase-3. Conclusions Taken together, our results demonstrated that NKP608 inhibited colorectal cancer cell proliferation, migration and invasion via suppressing the Wnt/β-catenin signaling pathway. Therefore, NKP608 might represent a promising therapeutic agent in the treatment of colorectal cancer.

OBJECTIVE The understanding of childhood absence epilepsy (CAE) has been revolutionized over the past decade, but the biological mechanisms responsible for variable treatment outcomes are unknown. Our purpose in this prospective observational study was to determine how pretreatment ictal network pathways, defined using a combined electroencephalography (EEG)-functional magnetic resonance imaging (EEG-fMRI) and magnetoencephalography (MEG) effective connectivity analysis, were related to treatment response. METHODS Sixteen children with newly diagnosed and drug-naive CAE had 31 typical absence seizures during EEG-fMRI and 74 during MEG. The spatial extent of the pretreatment ictal network was defined using fMRI hemodynamic response with an event-related independent component analysis (eICA). This spatially defined pretreatment ictal network supplied prior information for MEG-effective connectivity analysis calculated using phase slope index (PSI). Treatment outcome was assessed 2 years following diagnosis and dichotomized to ethosuximide (ETX)-treatment responders (N = 11) or nonresponders (N = 5). Effective connectivity of the pretreatment ictal network was compared to the treatment response. RESULTS Patterns of pretreatment connectivity demonstrated strongest connections in the thalamus and posterior brain regions (parietal, posterior cingulate, angular gyrus, precuneus, and occipital) at delta frequencies and the frontal cortices at gamma frequencies (P