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Ruoran Wang,1 Min He,2 Jing Zhang,1 Shaobo Wang,3 Jianguo Xu1 1Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 3Department of Infectious Diseases, Xi’an Hospital of Traditional Chinese Medicine, Xi’an, Shannxi Province, People’s Republic of ChinaCorrespondence: Jianguo XuDepartment of Neurosurgery, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, People’s Republic of ChinaEmail xujg@scu.edu.cnShaobo WangDepartment of Infectious Diseases, Xi’an Hospital of Traditional Chinese Medicine, No. 69, Fengcheng 8th Road, Xi’an, 710016, People’s Republic of ChinaEmail 1307799083@qq.comBackground: As an inflammation-based marker, red cell distribution width to platelet ratio (RPR) has been verified to be associated with disease severity and outcome in many clinical settings. We designed this study to evaluate the prognostic value of RPR in patients with traumatic brain injury (TBI).Methods: A total of 420 patients admitted with TBI were included in this study. Laboratory and clinical data were collected from an electronic medical record system. Univariate and multivariate logistic regression analyses were sequentially performed to discover risk factors of in-hospital mortality. Receiver operating characteristic (ROC) curves were drawn to confirm the predictive value of different markers including RPR in training set and testing set.Results: Non-survivors had higher level of RPR than survivors (P< 0.001). Logistic regression analysis showed that RPR was significantly associated with mortality even after adjusting for confounding factors (P< 0.001). The area under the ROC curve (AUC) value of Glasgow Coma Scale (GCS) for predicting mortality was 0.761 and 0775 in training set and testing set, respectively. And the constructed predictive model incorporating RPR had the highest AUC value of 0.858 and 0.884 in training set and testing set.Conclusion: RPR is significantly associated with mortality in TBI patients. Utilizing RPR to construct a predictive model is valuable to evaluate prognosis of TBI patients.Keywords: red cell distribution to platelet ratio, traumatic brain injury, prognosis, marker

Ischemic stroke is still the major cause of disability worldwide. Although vascular endothelial growth factor (VEGF) is able to promote both angiogenesis and functional recovery, its use is limited by needle-induced injury, nonhomogenous VEGF distribution, and limited VEGF retention in the brain after intracranial or intravenous injection. Here, we first present a gelatin methacryloyl (GelMA) microneedle (MN)-based platform for the sustained and controlled local delivery of an adeno-associated virus (AAV) expressing human VEGF (AAV-VEGF) that achieves homogenous distribution and high transfection efficiency in ischemic brains. An ischemic stroke model was established in adult rats, and MNs loaded with AAV-VEGF were epicortically inserted into both the ischemic core and penumbra of these rats one day after the onset of ischemia. One week later, the inflammatory response and microneedle biocompatibility were assessed by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence. Eight weeks later, angiogenesis and neural stem cell proliferation and migration were assessed. GelMA MN implantation did not elicit an obvious inflammatory response and had good biocompatibility in the brain. AAV-green fluorescent protein (GFP)-loaded MNs could achieve successful transfection and homogeneous distribution in the brain cortex three weeks postoperatively. MNs loaded with AAV-VEGF increased VEGF expression and enhanced functional angiogenesis and neurogenesis. In summary, MNs might emerge as a promising platform for delivering various therapeutics to treat ischemic stroke and repair other neurologically diseased tissues.

Introduction This aim of this study was to delineate current clinical scenarios of painful diabetic peripheral neuropathy (PDN) and associated anxiety and depression among patients in Mainland China, and to report current therapy and clinical practices. Methods A total of 1547 participants were enrolled in the study between 14 June 2018 and 11 November 2019. Recruitment was conducted using a multilevel sampling method. Participants’ demographics, medical histories, glucose parameters, Douleur Neuropathique 4 Questionnaire (DN4) scores, visual analogue scale (VAS) pain scores, Patient Health Questionnaire 9 (PHQ-9) scores, Generalised Anxiety Disorder 7 (GAD-7) scores and therapies were recorded. Results The male-to-female ratio was 1.09:1 (807:740), and the mean age at onset was 61.28 ± 11.23 years. The mean DN4 score (± standard deviation) was 4.91 ± 1.88. The frequencies of DN4 sub-item phenotypes were: numbness, 81%; tingling, 68.71%; pins and needles, 62.90%; burning, 53.59%; hypoaesthesia to touch, 50.16%; electronic shocks, 43.31%; hypoaesthesia to pinprick, 37.94%; brushing, 37.82%; painful cold, 29.61%; and itching, 25.86%. Age, diabetic duration, depression history, PHQ-9 score and GAD-7 score were identified as risk factors for VAS pain score. Peripheral artery disease (PAD) was a protective factor for VAS pain score. For all participants currently diagnosed with PDN and for those previously diagnosed PDN, fasting blood glucose (FBG) was a risk factor for VAS; there was no association between FBG and VAS pain score for PDN diagnosed within 3 months prior to recruitment. Utilisation rate of opium therapies among enrolled participants was 0.71% , contradiction of first-line guideline recommendation for pain relief accounted for 9.43% (33/350) and contradiction of second-line guideline recommendation for opium dosage form was 0.57% (2/350). Conclusion Moderate to severe neuropathic pain in PDN was identified in 73.11% of participants. Age, diabetic duration, depression history, PHQ-9 score, GAD-7 score and FBG were risk factors for VAS pain scores. PAD was protective factor. The majority of pain relief therapies prescribed were in accordance with guidelines. Trial registration ClinicalTrials.gov identifier, NCT03520608, retrospectively registered, 2018-05-11. Supplementary Information The online version contains supplementary material available at 10.1007/s40122-021-00281-w.

Background. miRNA is an essential factor in neuropathic pain. However, the underlying mechanism of miRNA in neuropathic pain remains unclear. Objective. To explore the potential role of miR-223 in neuropathic pain in a mice model of chronic sciatic nerve injury. Methods. Mice were divided into the sham group, CCI group, CCI + Lenti-vector group, and CCI + Lenti-miR-223 group. Flow cytometry was used to detect the neuronal apoptosis and the proportion of M1/M2 macrophages in each group. Western blot was used to detect the protein expression levels of ASC, caspase-1, IL-1β, and IL-18 in each group. Luciferase activity assay detects the binding of miR-223 and NLRP3. Macrophage chemotaxis experiments verified the anti-inflammatory effect of miR-223 in vitro. Results. The overexpression of miR-233 significantly reduced the neuropathic pain caused by CCI and reduced the apoptosis and inflammatory factor expression. miR-223 inhibits the expression of NLRP3 by directly binding to the 3′-untranslated region. Overexpression of miR-223 reduces the protein levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in the spinal cord of CCI mice, increases the proportion of M2-type macrophages, and reduces the proportion of M1-type macrophages. Conclusion. miR-223 may facilitate the development of neuropathic pain in CCI mice by inhibiting NLRP3-mediated neuroinflammation.

Haibo Teng,1,&ast; Zhiyong Liu,1,&ast; Ouying Yan,2 Wenbo He,1 Danyang Jie,3 Yuanwei Qie,4 Jianguo Xu1 1Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China; 3West China School of Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Health Management Center of West-China Fourth Hospital, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianguo XuDepartment of Neurosurgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaEmail xujg@scu.edu.cnBackground: Craniopharyngiomas (CPs) are relatively rare benign tumor located in the central nervous system (CNS). This study investigates the related risk factors of survival of craniopharyngiomas and develops a simple but detailed method predicting prognosis based on the Surveillance, Epidemiology, and End Results (SEER) database in order to improve the clinic management of CPs.Methods: Between 2004 and 2017, 1213 patients diagnosed with craniopharyngiomas registered at the program and were included in the SEER-21 registry database. Overall survival (OS) curves were plotted with the Kaplan–Meier method and significance was determined by Log rank test. Single- and multiple-factor regression analyses were made using Cox proportional hazards model to identify independent predictors related to OS. Subsequently, we developed a nomogram with those factors to predict 3-, 5- and 10-year OS of craniopharyngiomas patients.Results: We identified 1213 patients with craniopharyngioma. The OS rates at 3, 5, and 10 years after diagnosis were 89.1%, 86.2%, and 83%. Age, ethnicity, tumor size and radiation therapy were confirmed to be predictors correlating with OS at initial diagnosis. In multivariate analysis, we found that younger age (P< 0.001), smaller tumor size (P< 0.001), white ethnicity (P< 0.001) and radiation therapy (P=0.004) were the factors that remained significantly associated with better survival. A nomogram was successfully constructed and validated by ROC, calibration plots and C-index of 0.773 (95% CI, 0.708– 0.838).Conclusion: The well-calibrated nomogram is the first clinical prediction model for predicting the prognosis for patients with craniopharyngiomas at initial diagnosis. Our study indicates that the surgical effect is not clear. Younger white patients with radiotherapy have a better prognosis, and the gross total resection (GTR) was not effective in prolonging the OS of a patient compared to no surgery and subtotal resection (STR).Keywords: craniopharyngioma, nomogram, overall survival, SEER

The ubiquitin-specific protease 8 (USP8) is a prototypic multidomain deubiquitinating enzyme with pleiotropic functions. We investigated the role of USP8 in hepatocellular carcinoma (HCC) by analyzing expression patterns of USP8 in HCC patients, and evaluating its functions and underlying signaling. Among 20 HCC patients investigated, we found that USP8 protein upregulation was a common phenomenon (17 out of 20) in HCC compared to normal liver tissue. Furthermore, the upregulation of USP8 was not associated with any clinicopathology. USP8 inhibition via genetic and pharmacological approaches resulted in growth inhibition and apoptosis induction in both sensitive and doxorubicin-resistant HCC cells. Of note, USP8 inhibition significantly enhanced doxorubicin or sorafenib's efficacy in HCC cells and mouse models. We further found that USP8 inhibition decreased levels of multiple receptor tyrosine kinases (RTKs) by ~90%, such as epidermal growth factor receptor (EGFR) and c-Met. Consistently, the downstream signaling regulated by RTKs was disrupted in HCC cells after USP8 inhibition, as shown by the decreased p-Akt, p-STAT3 and p-Raf. Our findings demonstrate that USP8 is a novel therapeutic target in HCC. Inhibiting USP8 has potential to overcome current drug resistance, particularly on HCC patients with high USP8 expression.

BACKGROUND AND STUDY AIMS Non-pedunculated lesions are easily missed on endoscopy, and histopathological examination shows that some of these lesions are adenomas. Adenoma is a precursor of colorectal cancer, a common tumor of the digestive tract. This study was conducted to compare the detection efficacy of non-pedunculated lesions in the same patient under different modes of blue laser endoscopy and to determine whether the surface pattern of the sample was consistent with its histopathological results. PATIENTS AND METHODS A total of 91 patients with non-pedunculated lesions diagnosed at our hospital between April 2018 and March 2019 were included in this study. White light imaging (WLI), linked color imaging (LCI), and blue laser imaging (BLI) modes were used to record the location, number, and Hiroshima classification of the surface patterns of the non-pedunculated lesions. The lesions were removed by different endoscopic excision methods for histopathological examination; the histopathological results were compared with the surface patterns. RESULTS A total of 105, 198, and 223 lesions were detected using the WLI, BLI, and LCI modes, respectively. The Wilcoxon signed rank test revealed a significant difference in the number of lesions detected using each observation mode (p

MiR-206 is abnormally expressed in infant hemangioma endothelial cells (HemECs), but the mechanism is not clear. We explored the intervention of miR-206 in HemECs in relation to extracellular matrix (ECM) metabolism. We selected 48 cases of infantile hemangioma (IH) from volunteer organizations. After the isolated and extracted HemECs were interfered with overexpressed or silenced miR-206, the effects of miR-206 on the proliferation, migration and invasion of HemECs were examined through basic cell function experiments. The expression differences of miR-206, DNA Methyltransferase 3A (DNMT3A) and ECM-related genes were analyzed as needed by qRT-PCR or Western blot. TargetScan and dual-luciferase experiments were applied to predict and confirm the binding relationship between miR-206 and DNMT3A. The correlation between miR-206 and DNMT3A was analyzed in IH tissues by Pearson correlation coefficient, and further confirmed in HemECs by conducting rescue experiments. A nude mouse model of xenograft tumor was constructed to verify the results of in vitro experiments. MiR-206, which was downregulated in proliferative hemangioma, suppressed the malignant development of HemECs by regulating ECM-related genes. As the target gene of miR-206, DNMT3A was high-expressed in IH tissues and was negatively correlated with miR-206. Overexpressed DNMT3A counteracted the inhibitory effect of miR-206 mimic on HemECs and its regulatory effect on ECM. The results of in vivo experiments were consistent with those from cell experiments. Thus, miR-206 could promote ECM accumulation through targeted inhibition of DNMT3A, further inhibiting the malignant development of HemECs and relieving IH.

Liu Zi,1,2,* Wencheng Zhou,1,3,* Jiake Xu,1,4 Junshu Li,5 Ning Li,2 Jianguo Xu,1,4,6 Chao You,1,4,6 Chengwei Wang,1,2 Meng Tian1,4,6 1Neurosurgery Research Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 5State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People’s Republic of China; 6West China Brain Research Centre, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chengwei Wang; Meng TianNeurosurgery Research Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaTel/Fax +86 28 85164168Email 21270526@qq.com; tianmong007@gmail.comBackground: Intracerebral hemorrhage (ICH), a devastating subtype of stroke, has a poor prognosis. However, there is no effective therapy currently available due to its complex pathological progression, in which neuroinflammation plays a pivotal role in secondary brain injury. In this work, the use of statin-loaded nanomicelles to target the neuroinflammation and improve the efficacy was studied in a mouse model of ICH.Methods: Rosuvastatin-loaded nanomicelles were prepared by a co-solvent evaporation method using polyethylene glycol-poly(ϵ-caprolactone) (PEG-PCL) copolymer as a carrier. The prepared nanomicelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), and then in vitro and in vivo studies were performed.Results: TEM shows that the nanomicelles are spherical with a diameter of about 19.41 nm, and DLS shows that the size, zeta potential, and polymer dispersity index of the nanomicelles were 23.37 nm, − 19.2 mV, and 0.221, respectively. The drug loading content is 8.28%. The in vivo study showed that the nanomicelles significantly reduced neuron degeneration, inhibited the inflammatory cell infiltration, reduced the brain edema, and improved neurological deficit. Furthermore, it was observed that the nanomicelles promoted the polarization of microglia/macrophages to M2 phenotype, and also the expression of the proinflammatory cytokines, such as IL-1β and TNF-α, was significantly down-regulated, while the expression of the anti-inflammatory cytokine IL-10 was significantly up-regulated. The related mechanism was proposed and discussed.Conclusion: The nanomicelles treatment suppressed the neuroinflammation that might contribute to the promoted nerve functional recovery of the ICH mouse, making it potential to be applied in clinic.Keywords: rosuvastatin, nanomicelles, neuroinflammation, intracerebral hemorrhage

Background. Hepatocellular carcinoma (HCC), one of the most common primary malignancies, is theoretically an epitope candidate for immune checkpoint inhibitors, and therefore, the identification of HCC biomarkers is important. Structure-specific recognition protein 1 (SSRP1) is involved in almost all chromatin-related processes, including DNA replication, repair, and transcription. However, its role in HCC remains to be elucidated. Methods. This study investigated the expression of SSRP1 in HCCDB, Oncomine, HPA, and other databases. The prognostic value of SSRP1 in HCC and its relationship with clinical characteristics were then explored using Kaplan-Meier plotter. At the same time, SSRP1 coexpression genes were explored and functionally annotated in the LinkedOmics database. Finally, the correlation between the SSRP1 expression and HCC immune cell infiltration was explored in TIMER and online single-cell sequencing database. Results. Significantly elevated transcriptional and proteomic SSRP1 expressions were found in HCC. Increased SSRP1 mRNA expression was significantly correlated with relevant clinicopathological parameters such as immune cells. Notably, the SSRP1 expression was positively correlated with the infiltration levels of Treg and CD8+ T cells, especially exhausted CD8+ T cells. Interestingly, the SSRP1 expression was higher in both tumor Treg and exhausted CD8+ T cells than in adjacent tissues. Conclusion. SSRP1, as a new prognostic marker for HCC, promotes HCC development by influencing the infiltration of depleted CD8+ T cells and may influence the effect of immunotherapy.

More than 600,000 people are diagnosed with esophageal cancer (EC) every year globally, and the five-year survival rate of EC is less than 20%. Two common histological subtypes of EC, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), have great geographical variations in incidence rates. About half of the world’s EC was diagnosed in China and a majority of which belong to ESCC. Globally, the overall incidence rate of EC is decreasing. In some high-risk Asian regions, such as China, the incidence rate of ESCC has generally declined, potentially due to economic growth and improvement of diet habits. In some European high-income countries and the United States, the decline is mainly attributed to the decrease in smoking and drinking. The risk factors of EC are not well understood, and the importance of environmental and genetic factors in the pathogenesis is also unclear. The incidence and mortality of advanced EC can be reduced through early diagnosis and screening. White light endoscopy is still the gold standard in the current screening technology. This article reviews the epidemiology, risk factors, and screening strategies of EC in recent years to help researchers determine the most effective management strategies to reduce the risk of EC.

Objective To investigate the application of transposition flaps in the reconstruction of perianal skin defects after tumor resection. Methods From September 2018 to December 2019, 16 cases of perianal skin defects were repaired with unilateral or bilateral transposition flaps. The wound size before closure ranged from 4 cm × 8 cm to 7 cm × 10 cm. Fourteen patients achieved primary healing. Wound dehiscence occurred in one patient at the flap tip, whereas a slight infection occurred in another patient, which healed after a dressing change. During the follow-up period of 3–6 months, all patients were satisfied with the perianal area both aesthetically and functionally. Conclusion Transposition flaps are a promising option for the repair of perianal skin defects after tumor removal. Owing to the simplicity of the flap design, the wide popularity of this flap type among surgeons is anticipated.

To investigate differences between pituitary adenoma and craniopharyngioma on magnetic resonance imaging (MRI) with image features and three-dimensional texture features. A total of 126 patients diagnosed with pituitary adenoma (N = 63) or craniopharyngioma (N = 63) were enrolled. Qualitative magnetic resonance (MR) image features and texture features of tumors were extracted from preoperative MRI and evaluated using chi-square test or Mann–Whitney U test. Binary logistic regression analyses were performed to assess their abilities as independent diagnostic predictors, and ROC analyses were conducted to evaluate the diagnostic value of significant features. Mann–Whitney U test and ROC analyses were performed to explore the relationship between MR image features and texture features. Five MR image features were suggested to be significantly different between pituitary adenoma and craniopharyngioma. Three texture features from contrast-enhanced T1WI (HISTO-Skewness, GLCM-Contrast and GLCM-Energy), two texture features from T2WI (HISTO-Skewness and GLCM-Contrast) showed significant differences between two types of tumors. Logistic regression analyses suggested GLCM-Energy from contrast-enhanced T1WI, HISTO-Skewness and GLCM-Contrast from T2WI could be taken as independent predictors. Moreover, HISTO-Skewness and GLCM-Contrast from T2WI were found to be significantly related to cystic change. MR image features and texture features were associated with each other, and both types of features represented feasible diagnostic value in discrimination between pituitary adenoma and craniopharyngioma.

Therapeutic ex vivo T cell expansion is limited by low rates and poor functionality, especially for T cells from aged cancer patients. Here, we describe a novel method for T cell stimulation and expansion using a system named SunTag-based clustering of anti-CD3/CD28 scFv (SBCS). In this method, SunTag was used to recruit up to 13 copies of anti-CD3/CD28 scFv for T cell activation. Compared with the traditional method using immobilized CD3/CD28 antibodies, the SBCS system produced approximately 1.5-fold greater expansion of T cells from healthy donors, and more than 2-fold greater expansion of T cells from aged cancer patients after stimulation. The efficiency of expansion depended mainly on the concentration of the clustered polymers of anti-CD3 scFv rather than anti-CD28 scFv. We also demonstrated that the SBCS-expanded T cells could be used to prepare functional chimeric antigen receptor modified T cells for antitumor therapy.

Recently, B7-H3 was frequently reported to be overexpressed in various cancer types and has been suggested to be a promising target for cancer immunotherapy. In the present study, we analyzed the mRNA expression of B7-H3 in The Cancer Genome Atlas (TCGA) database and validated its expression across multiple cancer types. We then generated a novel B7-H3-targeted chimeric antigen receptor (CAR) and tested its antitumor activity both in vitro and in vivo. The B7-H3 expression heterogeneity and variation were frequent. Moderate or even high expression levels of B7-H3 were also observed in some tumor-adjacent tissues, but the staining intensity was weaker than that in tumor tissues. B7-H3 expression was absent or very low in normal tissues and organs. Flow cytometry indicated that the mean expression level of B7-H3 in eight bone marrow specimens from patients with acute myeloid leukemia (AML) was 57.2% (range 38.8–80.4). Furthermore, we showed that the B7-H3-targeted CAR-T cells exhibited significant antitumor activity against AML and melanoma in vitro and in xenograft mouse models. In conclusion, although B7-H3 represents a promising pan-cancer target, and B7-H3-redirected CAR-T cells can effectively control tumor growth, the expression heterogeneity and variation have to be carefully considered in translating B7-H3-targeted CAR-T cell therapy into clinical practice., Zhang et al. demonstrated that B7-H3 is highly expressed in multiple cancer types, and then they generated a B7-H3-targeted CAR and validated its antitumor effects both on hematologic and solid tumors. Their data also suggested that the expression heterogeneity and variation must be considered in translating B7-H3-targeted therapy into clinical practice.

Carbon dioxide is a common gas in the air which has been widely used in medical treatment. A carbon dioxide molecule consists of two oxygen atoms and one carbon atom through a covalent bond. In the body, carbon dioxide reacts with water to produce carbonic acid. In healthy people, carbon dioxide is maintained within a narrow range (35–45 mmHg) by physiological mechanisms. The role of hypocapnia (partial pressure of carbon dioxide < 35 mmHg) and hypercapnia (partial pressure of carbon dioxide > 45 mmHg) in the nervous system is intricate. Past researches mainly focus on the effect of hypocapnia to nerve protection. Nevertheless, Hypercapnia seems to play an important role in neuroprotection. The mechanisms of hypocapnia and hypercapnia in the nervous system deserve our attention. The purpose of this review is to summarize the effect of hypocapnia and hypercapnia in stroke and traumatic brain injury.

The source of secondary lower respiratory tract bacterial infections in influenza patients is not fully understood. A case–control study was conducted during the 2017–2018 influenza epidemic period in Beijing, China. Nasopharyngeal swabs were collected from 52 virologically confirmed influenza patients and 24 healthy medical staff. The nasopharyngeal microbiota taxonomic composition was analysed using high-throughput sequencing of the 16S rRNA gene V3–V4 regions. The super-dominant pathobiontic bacterial genus (SDPG) was defined as that accounting for >50% of sequences in a nasopharyngeal swab. We attempted to isolate bacteria of this genus from both nasopharyngeal swabs and lower-respiratory tract samples and analyse their genetic similarities. We observed a significantly lower taxonomy richness in influenza cases compared with healthy controls. A SDPG was detected in 61% of severe cases but in only 24% of mild cases and 29% of healthy controls. In 10 cases, the species isolated from lower-respiratory tract infection sites were identified as belonging to the nasopharyngeal microbiota SDPG. Genetically identical strains were isolated from both nasopharyngeal swabs and lower-respiratory tract infection sites, including 23 Acinetobacter baumannii strains from six severe cases, six Klebsiella pneumoniae strains from two severe cases, five Pseudomonas aeruginosa strains from one severe and one mild case, and four Corynebacterium striatum strains from two severe cases. The SDPG in the nasopharyngeal microbiota are the likely cause of subsequent infection in influenza patients.

Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.

Background The prognosis of primary bile cholangitis (PBC) is linked to gut microbiota dysbiosis. This study investigated the association between the gut microbiome and elevated total bilirubin (TB) level in PBC patients treated with ursodeoxycholic acid (UCDA). Methods A total of 47 PBC patients with 12 months of UCDA treatment were enrolled. Patients were divided into the TB (+) (TB>1× upper limit of the normal range [ULN]; n=20) and TB(-) (TB≤1× ULN; n=27) groups. Stool and serum specimens were collected, and microbiota composition and functional characteristics in the 2 groups were evaluated by 16S RNA gene sequencing and bioinformatic analysis. Results Bacterial diversity was lower in the TB(+) group than in the TB(-) group, although there was no significant difference in bacterial community profile. The phylum Saccharibacteria showed differential abundance in the 2 groups. Meanwhile, the TB(-) group had lower abundance of the Gemmiger, Blautia, Anaerostipes, and Coprococcus genera than the TB(+) group, whereas Holdemania was absent. The abundance of Gemmiger formicillis and Coprococcus eutactus was positively correlated with that of Faecalibacterium prausnitzii, while Blautia, Anaerostipes, and Coprococcus were negatively correlated with total bile acid level. Conclusion TB level in PBC patients treated for 12 months with UCDA is associated with a distinct gut microbiome profile.

A case of Rickettsia sibirica subspecies sibirica BJ-90 infection in China was identified by metagenomic analysis of an eschar biopsy specimen and confirmed by nested PCR. Seroprevalence of spotted fever group Rickettsia was ≈17.4% among the local population. This report highlights the threat of rickettsioses to public health in the Qinghai-Tibet Plateau.

Background Acute kidney injury (AKI) has been occurs commonly in the clinical management of traumatic brain injury (TBI) patients and is correlated with outcomes in these patients. We designed this study to investigate the incidence, duration, stage, and burden of AKI among these patients. Methods A total of 419 TBI inpatients at our hospital were included in the study. We calculated the AKI burden, reflecting both stage and duration, and then analyzed associations among AKI occurrence, highest AKI stage, AKI duration, AKI burden, and outcomes with logistic regression analysis. Results Incidence of AKI among TBI patients was 19.8%. These patients’ AKIs occurred mainly on the first day from admission (10.74%), and mostly developed stage 1 AKI (9.79%). Modes of AKI duration and burden in those with AKI were both 1. Multivariate logistic regression showed AKI occurrence (OR 3.792, p=0.004) and the highest AKI stage (OR 3.122, p, Graphical Abstract

Background Community-acquired pneumonia (CAP) is a leading infectious cause of hospitalisation and death worldwide. The knowledge about the incidence and aetiology of CAP in China was fragmented. Methods A multicenter study performed at four hospitals in four regions in China and clinical samples from CAP patients were collected and used for pathogen identification from July 2016 to June 2019. Results A total of 1,674 patients were enrolled and the average annual incidence of hospitalized CAP was 18.7 cases per 10,000 people (95% confidence interval 18.5–19.0). The most common viral and bacterial agents found in patients were respiratory syncytial virus (19.2%) and Streptococcus pneumoniae (9.3%). The co-infections percentage was 13.8%. Pathogen distribution displayed variations within age groups, and seasonal and regional differences. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was not detected. Respiratory virus detection was significantly positively correlated with air pollutants, including PM2.5, PM10, NO2 and SO2; and significantly negatively correlated with ambient temperature and O3 content; bacteria detection was opposite. Conclusion The hospitalized CAP incidence in China was higher than previously known. CAP etiology showed differences in age, seasons, regions, and respiratory viruses were detected at a higher rate than bacterial infection overall. Air pollutants and temperature have influence on the detection of pathogens.

Preoperative prediction of visual recovery after pituitary adenoma surgery remains a challenge. We aimed to investigate the value of MRI-based radiomics of the optic chiasm in predicting postoperative visual field outcome using machine learning technology. A total of 131 pituitary adenoma patients were retrospectively enrolled and divided into the recovery group (N = 79) and the non-recovery group (N = 52) according to visual field outcome following surgical chiasmal decompression. Radiomic features were extracted from the optic chiasm on preoperative coronal T2-weighted imaging. Least absolute shrinkage and selection operator regression were first used to select optimal features. Then, three machine learning algorithms were employed to develop radiomic models to predict visual recovery, including support vector machine (SVM), random forest and linear discriminant analysis. The prognostic performances of models were evaluated via five-fold cross-validation. The results showed that radiomic models using different machine learning algorithms all achieved area under the curve (AUC) over 0.750. The SVM-based model represented the best predictive performance for visual field recovery, with the highest AUC of 0.824. In conclusion, machine learning-based radiomics of the optic chiasm on routine MR imaging could potentially serve as a novel approach to preoperatively predict visual recovery and allow personalized counseling for individual pituitary adenoma patients.

Background: Pigmented villonodular synovitis (PVNS) of the temporomandibular joint (TMJ) with skull base extension is a rare entity. Here, we summarize the clinical features, treatments, and outcomes of PVNS of the TMJ with skull base extension in a large case series. Methods: We reviewed the clinical information relating to patients diagnosed with PVNS of the TMJ with skull base extension information of patients in our center between 2011 and 2020. Results: We reviewed 10 patients (4 males and 6 females). All cases had presented with a unilateral lesion extending the middle skull base. PVNS of the TMJ with skull base extension occurred on the left side in 6 patients (60%) and on the right side in 4 patients (40%). Of the 10 patients, pain and mass were the most prevalent symptoms. All patients received surgery and no recurrence was seen after 35.90±25.35 months follow-up. Conclusion: Despite destructive biological behavior, surgery can achieve an excellent outcome for patients with PVNS of the TMJ with skull base extension. An en bloc resection may prevent recurrence and provide long-term relief. Radiotherapy may be reserved for subtotal excision and recurrent lesions but require further investigation.

Background: Although many studies have shown that erythropoietin plays an important role in the prognosis of traumatic brain injury (TBI) patients, the effective dose of erythropoietin has not been clearly defined. Our aim was to systematically elucidate the safety and efficacy of erythropoietin administration regimens in TBI patients.Methods: Data search included PubMed, the Cochrane Library, EMBASE and ClinicalTrials.gov for articles published before December, 2020, updated to June 2021. Network meta-analysis was performed when sufficient comparable evidence was available, and CINeMA tool was used to evaluated the quality of our evidence.Results: A total of 6 RCTs involving 981 patients were included in the network meta-analysis. All studies assessed the effect of erythropoietin on mortality. Erythropoietin reduced the mortality rate in patients with TBI, and the risk of death decreased with increasing dose, but the difference was not statistically significant (odd ratio of 12,000u vs Placebo=0.98, 95%CI, 0.03-40.34; odd ratio of group 30,000u vs Placebo=0.56, 95%CI, 0.06-5.88; odd ratio of 40,000u vs Placebo=0.35, 95%CI, 0.01-9.43; odd ratio of 70,000u vs Placebo=0.29, 95%CI, 0.01-9.26; odd ratio of group 80,000u vs Placebo=0.22, 95%CI, 0.00-7.45). Three studies involving 739 patients showed that erythropoietin did not increase the incidence of deep vein thrombosis in patients with TBI. However, the risk tended to rise as the dose increases. Two studies demonstrated that erythropoietin did not increase the incidence of pulmonary embolism. The evidential quality of all the results of the evidence ranged from low to medium.Conclusion: Although the efficacy of erythropoietin was not statistically demonstrated, we found a trend in the association of erythropoietin dose with reduced mortality and increased embolic events in TBI patients. We are looking forward to more high-quality original studies focusing on the dose and timing of erythropoietin for the treatment of TBI, in order to obtain stronger evidence on the optimal erythropoietin dose.Study Registration: PROSPERO (CRD42021272500).

BACKGROUND Vestibular schwannoma (VS) and meningioma are the most two common tumors in the cerebellopontine angle (CPA). Accurate preoperative differentiation of the two lesions is important due to their different surgical approaches and outcomes for the preservation of hearing and facial nerve function. Magnetic resonance (MR) scan is commonly performed to preoperatively evaluate CPA tumors and to differentiate VS from meningioma in clinical routine. However, in some cases, overlaps of conventional MR imaging patterns between the two lesions could make preoperative diagnosis challenging. The purpose of this study is to investigate the ability of radiomics, a novel method providing objective and quantitative information beyond visual assessment, in differentiation between VS and meningioma located at CPA using machine learning technology. MATERIAL AND METHODS This retrospective study enrolled eligible patients who were diagnosed with VS (N = 50) or meningioma (N = 41) in the CPA. A set of mineable three-dimensional radiomic parameters were extracted from preoperative contrast-enhanced T1-weighted images. Optimal features were selected first with three selection methods including distance correlation, least absolute shrinkage and selection operator (LASSO) and gradient boosting decision tree (GBDT). Then three machine learning classification algorithms, namely linear discriminant analysis (LDA), support vector machine (SVM) and random forest were employed to build discriminative models. Area under the curve (AUC), accuracy, sensitivity and specificity were calculated to assess the performance of each model. RESULTS Nine models were established with different combinations of selection methods and machine learning classifiers. Three classifiers with the suitable selection method all represented feasible ability in differentiation with AUC more than 0.86 in the validation set, and LDA-based models seemed to show better diagnostic performance than those based on the other two classifiers. The combination of LASSO and LDA classifier was found to show the highest AUC of 0.942 in the validation set. CONCLUSION Radiomics-based models via machine learning approaches could potentially be utilized to assist in preoperative differentiation between VS and meningioma in the CPA.

Background The cardiac dysfunction has been confirmed as a common non-neurological complication and associated with increased mortality in traumatic brain injury (TBI) patients. As a biological marker of cardiac injury, the cardiac troponin T (TnT) has been verified correlated with outcome of some non-traumatic brain injury patients. However, the prognostic value of TnT in TBI patients has not been clearly illustrated. We designed this study to explore the association between TnT and outcome of TBI patients in different age subgroups. Methods Patients diagnosed with TBI in a prospective critical care database were eligible for this study. Univariate logistic regression analysis was firstly performed to explore the relationship between included variables and mortality. Then, the real effect of TnT on outcome of different age subgroups was analyzed by multivariate logistic regression analysis adjusting the confounding effects of other significant risk factors. Finally, we draw receiver operating characteristic (ROC) curves to evaluate the prognostic value of TnT in different age groups of TBI patients. Results 520 patients were included in this study with mortality rate of 20.2%. There were 112 (21.5%) non-elderly patients (age

PurposeTo investigate the diagnostic ability of radiomics-based machine learning in differentiating atypical low-grade astrocytoma (LGA) from anaplastic astrocytoma (AA).MethodsThe current study involved 175 patients diagnosed with LGA (n = 95) or AA (n = 80) and treated in the Neurosurgery Department of West China Hospital from April 2010 to December 2019. Radiomics features were extracted from pre-treatment contrast-enhanced T1 weighted imaging (T1C). Nine diagnostic models were established with three selection methods [Distance Correlation, least absolute shrinkage, and selection operator (LASSO), and Gradient Boosting Decision Tree (GBDT)] and three classification algorithms [Linear Discriminant Analysis (LDA), Support Vector Machine (SVM), and random forest (RF)]. The sensitivity, specificity, accuracy, and areas under receiver operating characteristic curve (AUC) of each model were calculated. Diagnostic ability of each model was evaluated based on these indexes.ResultsNine radiomics-based machine learning models with promising diagnostic performances were established. For LDA-based models, the optimal one was the combination of LASSO + LDA with AUC of 0.825. For SVM-based modes, Distance Correlation + SVM represented the most promising diagnostic performance with AUC of 0.808. And for RF-based models, Distance Correlation + RF were observed to be the optimal model with AUC of 0.821.ConclusionRadiomic-based machine-learning has the potential to be utilized in differentiating atypical LGA from AA with reliable diagnostic performance.

Ectopic salivary glands have been found in both extracranial and intracranial locations, however, intrasellar symptomatic salivary gland is extremely rare and its clinical manifestation, radiological characteristics and outcome have not been systematically studied. Here we present a case series of intrasellar symptomatic salivary gland and perform a literature review to better characterize this disease. We retrospectively reviewed the data of three patients with intrasellar symptomatic salivary gland from our institutional and other cases available in literatures. Information for sex, age at diagnosis, clinical symptoms, radiological features, treatment strategy and prognosis were recorded. A total of 11 cases (including our own) were identified. There were three men and eight women, with an average age at diagnosis of 28.3 years. The peak incidence was in the second and the third decade (72.7% of all cases). The most common symptom was headache (81.8% of all patients). About 63.6% patients had one or more abnormal hormone levels, and prolactin was likely the most vulnerable hormone. The radiological appearances of intrasellar salivary gland were various, and four cases mimicked pituitary adenoma radiologically. All patients underwent transsphenoidal surgery with no mortality. Although intrasellar symptomatic salivary gland is rare, it should be considered in the differential diagnosis of intrasellar lesions. Preoperative diagnosis is challenging since it mimics pituitary neoplasm in clinical and radiological manifestations, and confirmation for this disease could only be conducted through pathological examination. Transsphenoidal surgical resection is the preferred therapy and the patient prognosis is usually good.

The purpose of this study is to explore the inhibition or activation effects of microRNA-146 B on the expression of PTP1B in gastric cancer cells. The expressions of PTP1B and miR-146b in gastric cancer were detected by RT-qPCR. The effects of miR-146b on cell apoptosis and proliferation of gastric cancer were detected. The methods used in the detection process included Annexin V/PI dying method, colony formation assay, and MTT assay. The downstream target gene miR-146b was predicted and screened by bioinformatics and luciferase reporter assay. The mRNA and protein expressions of the target gene PTP1B miR-146b were determined using RT-qPCR and western blot. The expression of miR-146 B in mice was detected by the cells transfected with microRNA-146 B in vivo. Compared with normal tissues, PTP1B was higher and miR-146b was lower in cancer cells. Over-expression of miR-146b can inhibit cell viability and increase the apoptosis rate. According to the luciferase reporter assay, PTP1B was the downstream target gene of miR-146b. The re-introduction of PTP1B reversed the growth inhibition and apoptosis of gastric cancer cells induced by miR-146b. From the mouse xenograft model, the over-expression of miR-146b inhibited the tumor growth and reduced the expression level of PTP1B. miR-146b directly inhibits the expression of PTP1B and suppressed the growth and development of gastric cancer.

OBJECTIVERupture of arteriovenous malformations (AVMs) would result in high mortality and prevalence of disability in pediatric patients. Decisions regarding the treatment of AVMs need to weigh the risk of rupture over the course of their natural history against the possibility of creating a lesion during treatment. Multiple factors have been proposed to predict hemorrhagic presentation of pediatric patients with AVMs. The aim of this meta-analysis was to evaluate the predictors of hemorrhagic presentation in pediatric patients with AVMs.METHODSThe authors searched the PubMed and EMBASE databases. Studies reporting the predictors of hemorrhagic presentation in children with untreated brain AVMs were included. The predictive ability of identified predictors was assessed by odds ratios (ORs) and 95% confidence intervals (CIs).RESULTSA higher risk of hemorrhagic presentation was found in AVMs with smaller size (< 3 cm, OR 2.97, 95% CI 1.94–4.54, p < 0.00001), deep venous drainage (OR 2.28, 95% CI 1.55–3.36, p < 0.0001), a single draining vein (OR 2.23, 95% CI 1.27–3.92, p = 0.005), a single feeder (OR 3.72, 95% CI 1.31–10.62, p = 0.01), a deep location (OR 1.82, 95% CI 1.22–2.72, p = 0.004), an infratentorial location (OR 2.25, 95% CI 1.19–4.26, p = 0.01), and diffuse morphology (OR 8.94, 95% CI 3.01–26.55, p < 0.0001). In addition, the AVMs with draining vein ectasia (OR 0.35, 95% CI 0.13–0.97, p = 0.04) and high Spetzler-Martin (SM) grade (OR 0.53, 95% CI 0.36–0.78, p = 0.001) had a lower risk of hemorrhagic presentation in pediatric patients.CONCLUSIONSSmaller AVMs, deep venous drainage, a single draining vein, a single feeder, deep/infratentorial location, diffuse morphology, and high SM grade were identified as positive predictors for hemorrhagic presentation. Particularly, patients with diffuse AVMs have a higher risk of hemorrhagic presentation than other factors and may need active treatments. However, factors such as age, sex, draining vein stenosis, and associated aneurysms were not associated with hemorrhagic presentation.

BACKGROUNDThe novel coronavirus disease-2019 (COVID-19 Pandemic) has brought difficulties to the management of patients undergoing transcatheter aortic valve replacement (TAVR).OBJECTIVESThis prospective, observational cohort study sought to evaluate the feasibility of a novel, virtual, and remote health care strategy for TAVR patients with smart wearable devices.METHODSA total of 100 consecutive severe aortic stenosis patients who underwent elective transfemoral TAVR were enrolled and each received a HUAWEI smartwatch at least one day before TAVR. Vital signs were continuously tracked and recorded. Single lead electrocardiogram (ECG) was recorded periodically after TAVR. A designated heart team member was to provide remote data-assisted health care to address the medical demand.RESULTSThirty-eight cardiac events were reported in 34 patients after discharge, with most of the events (76.0%) were detected and confirmed by the smartwatch. Six patients were advised and readmitted to the hospital for arrhythmia events, among whom, four received pacemaker implantations. The remaining 28 (82.4%) patients received telemedicine monitoring instead of face-to-face clinical visits, and three of them received new medication treatment under a doctor’s online guidance of doctors. New-onset LBBB was found in 48 patients with transient and recovered spontaneously in 30 patients, while new-onset atrial fibrillation in 4 patients. There were no significant differences in the average weekly heart rates, the ratio of abnormal or low oxygen saturation when compared with the baseline. The average daily steps increased over time significantly (baseline, 870±1353 steps; first week, 1986±2406 steps; second week, 2707±2716 steps; third week, 3059±3036 steps; fourth week, 3678±3485 steps, p < 0.001).CONCLUSIONSSmartwatch can facilitate remote health care for patients undergoing TAVR during COVID-19 and enables a novel remote follow-up strategy. The majority of cardiac clinical events that occurred within 30-day follow-up were detected by the smartwatch, mainly due to the record of conduction abnormality. (SMART Watch Facilitated Early Discharge in Patients undergoing Transcatheter Aortic Valve Replacement, NCT04454177).

Background Portal hypertension induced esophageal and gastric variceal bleeding is the main cause of death among patients of decompensated liver cirrhosis. Therefore, a standardized, biomarker-based test, to make an early-stage non-invasive risk assessment of portal hypertension, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified. Methods We conducted a pilot study consisting of 5 portal hypertensive gastropathy (PHG) patients and 5 normal controls, sampling the gastric mucosa of normal controls and PHG patients before and after endoscopic cyanoacrylate injection, using label-free quantitative (LFQ) mass spectrometry, to identify potential biomarker candidates in gastric mucosa from PHG patients and normal controls. Then we further used parallel reaction monitoring (PRM) to verify the abundance of the targeted protein. Results LFQ analyses identified 423 significantly differentially expressed proteins. 17 proteins that significantly elevated in the gastric mucosa of PHG patients were further validated using PRM. Conclusions This is the first application of an LFQ-PRM workflow to identify and validate PHG–specific biomarkers in patient gastric mucosa samples. Our findings lay the foundation for comprehending the molecular mechanisms of PHG pathogenesis, and provide potential applications for useful biomarkers in early diagnosis and treatment. Trial registration and ethics approval: Trial registration was completed (ChiCTR2000029840) on February 25, 2020. Ethics Approvals were completed on July 17, 2017 (NYSZYYEC20180003) and February 15, 2020 (NYSZYYEC20200005).

Gastric cancer (GC) remains a major world-wide challenge, especially in Asian countries. Chemotherapy with 5-fluorouracil (5-FU) and cisplatin is used as the first-line treatment and development of chemoresistance is a major cause of progression. UMP/CMP kinase is responsible for the phosphorylation of the ribonucleotide metabolite 5-fluoro-5′-monophosphate (FUMP) in 5-FU metabolic process, and recognized as a key step in the conversion of 5-FU to cytotoxic metabolites. Our bioinformatics analysis and molecular experiments demonstrated that high expression of CMPK1 was associated with prolonged survival and response to 5-FU treatment in GC samples. Further analysis demonstrated that miR-130b as a key epigenetic regulator of CMPK1, and miR-130b-mediated attenuation of CMPK1 resulted in resistance of gastric cancer cells to DNA damage and cell death after treatment with 5-FU. Rescue experiments with augmented CMPK1 expression abolished the effect of miR-130b demonstrating the key function of this miRNA in this pathway. Thus, this newly identified miR-130b-CMPK1 axis suggests a potentially new chemotherapeutic strategy for improved response to 5-FU therapy.

The mechanism of liver hepatocellular carcinoma (LIHC) development in correlation with tumor microenvironments and somatic mutations is still being elucidated. This study aims to identify the potential molecular mechanisms and candidate biomarkers in response to tumor microenvironments and somatic mutations. Multiple bioinformatics analysis methods were applied to assess the tumor immunological microenvironment, differentially expressed genes, genetic function enrichment, immunocyte infiltration, regulatory network construction, and tumor mutational burden, and to identify DNA methylation sites. The immunological microenvironment features of ESTIMATE score (OS: p = 0.017, HR = 0.64; RFS: HR = 0.43, p < 0.001) have an important impact on the prognosis of LIHC patients. Cut-off by ESTIMATE score and prognostic information identified 666 DEGs (45 downregulated and 621 upregulated) that were linked with leukocyte migration and lymphocyte activation. In immunocyte infiltration analysis, NK cells (resting), M1 macrophages, CD8+ T cells, and regulatory T cells (Tregs), which are considered core immunoregulatory cells, exhibited significant differences between higher and lower ESTIMATE scores (overall survival and recurrence-free survival p-values < 0.01). Subsequently, further analysis of immunocyte-hub gene identification illustrated that the expression levels of CXCL12 and IL7R significantly correlated with core immunoregulatory cells and somatic mutations (CXCL12: p = 2.1E-06; IL7R: p = 0.001). This study provides new insight into our understanding of the mechanisms of immunocyte regulation and microenvironment involved in LIHC development as well as the effective biomarkers of CXCL12 and IL7R and core immunoregulatory cells, which may emerge as novel therapies for LIHC patients.

Ischemic stroke is a devastating disease exhibiting a dismal prognosis due to overactive inflammation in the early stage and poor endogenous angiogenesis capacity in the late stage. To treat ischemic stroke, it is highly desirable to suppress the inflammatory response and combine it with sequential regulation of angiogenesis in the ischemic area. Here, we developed an engineered hyaluronic acid hydrogel for sequentially targeted dual drug delivery with different release kinetics to realize optimized combinatorial therapy. In this system, 6-bromoindirubin-3′-oxime (BIO), a glycogen synthase kinase 3 beta (GSK3β) inhibitor, was loaded in Pluronic F127 (PF127) nanoparticles for initial release to alleviate the inflammatory response and reduce cell apoptosis, while vascular endothelial growth factor (VEGF) was loaded in poly (lactic-co-glycolic acid) (PLGA) porous microspheres that enabled sustained release for continuous angiogenesis induction. As expected, hydrogels loaded with BIO/PF127 nanoparticles and VEGF/PLGA microspheres exerted a distinct therapeutic effect in two stages of ischemic stroke; they reduced the levels of early inflammatory factors IL-1β, IL-6 and TNF-α, promoted the polarization of microglia and astrocytes toward an anti-inflammatory phenotype, and improved late angiogenesis and behavioral performance. Hence, sequential delivery of anti-inflammatory and pro-angiogenic agents, corresponding to the spatiotemporal course of pathology development of ischemic stroke, provides a novel option to treat ischemic stroke via phased regulation of pathophysiological processes.

Streptomycin is considered to be one of the effective antibiotics for the treatment of plague. In order to investigate the streptomycin resistance of Y. pestis in China, we evaluated streptomycin susceptibility of 536 Y. pestis strains in China in vitro using the minimal inhibitory concentration (MIC) and screened streptomycin resistance-associated genes (strA and strB) by PCR method. A clinical Y. pestis isolate (S19960127) exhibited high-level resistance to streptomycin (the MIC was 4,096 mg/L). The strain (biovar antiqua) was isolated from a pneumonic plague outbreak in 1996 in Tibet Autonomous Region, China, belonging to the Marmota himalayana Qinghai–Tibet Plateau plague focus. In contrast to previously reported streptomycin resistance mediated by conjugative plasmids, the genome sequencing and allelic replacement experiments demonstrated that an rpsL gene (ribosomal protein S12) mutation with substitution of amino-acid 43 (K43R) was responsible for the high-level resistance to streptomycin in strain S19960127, which is consistent with the mutation reported in some streptomycin-resistant Mycobacterium tuberculosis strains. Streptomycin is used as the first-line treatment against plague in many countries. The emergence of streptomycin resistance in Y. pestis represents a critical public health problem. So streptomycin susceptibility monitoring of Y. pestis isolates should not only include plasmid-mediated resistance but also include the ribosomal protein S12 gene (rpsL) mutation, especially when treatment failure is suspected due to antibiotic resistance., Author summary The plague natural foci are widely distributed in the world, and correspondingly, the plague still poses a significant threat to human health in some countries with endemic plague foci. Streptomycin is used as the first-line treatment against plague in many countries for the antibiotic is considered to be one of the effective antibiotics, particularly for the treatment of pneumonic plague. The resistance to streptomycin had been reported in Y. pestis strains from Madagascar in previous studies. In this study, we reported the high-level resistance to streptomycin in a clinical isolate of Y. pestis from a pneumonic patient in Tibet Autonomous Region, China, and a novel mechanism of streptomycin resistance, i.e. mutation in the rpsL gene were identified. The knowledge acquired about streptomycin resistance in Y. pestis will remain of great practical value. For the emergence of resistance to streptomycin in Y. pestis would render the treatment failure, thus corresponding antibiotic monitoring should be routinely carried out in countries threatened by plague. In addition, based on our further understanding about streptomycin resistance of Y. pestis isolates, such monitoring should not only include plasmid-mediated resistance but also include the ribosomal protein S12 gene (rpsL) mutation in Y. pestis isolates.

Background. Several studies have focused on the prognostic role of microRNA 222 in glioma. But different conclusions were drawn by these studies. We aimed to systematically evaluate the role of microRNA 222 in glioma by conducting a meta-analysis. Methods. A systematic literature search until January 2020 was conducted in Web of Science, EMBASE, Cochrane Library, PubMed, and China National Knowledge Infrastructure. The general characteristics and relevant data of nine articles were extracted. Hazard ratios (HRs) with 95% confidence intervals (CIs) were applied to evaluate the prognostic role of microRNA 222 in glioma. The primary outcomes were overall survival (OS) and disease-free survival (DFS). Results. Nine articles (11 data sets) with 1564 patients were included. We systematically evaluated the role of microRNA 222 for OS and DFS in glioma patients (HR for OS=1.72; 95% CI, 1.31-2.26; p=0.001; HR for DFS=1.02; 95% CI, 0.86-1.22; p=0.032). Subgroup analyses were performed according to the sources of patients, the types of the samples, the stages of the tumors, the methods for detecting the microRNA 222, and the sample size. No significant publication bias was found. Conclusion. In conclusion, our study provided evidence that a high expression of microRNA 222 was related to worse overall survival in glioma patients. However, given the limited study number, more high-quality studies are warranted in the future.

Background Targeting cancer antigens by T cell-engaging bispecific antibody (BiAb) or chimeric antigen receptor T cell therapy has achieved successes in haematological cancers, but attempts to use them to fight solid cancers have been disappointing, in part due to antigen escape. MEK inhibitor had limited activity as a single agent, but enhanced antitumor activity when combined with other therapies, such as targeted drugs or immunotherapy agents. This study aimed to analyze the expression of B7-H3 in non-small-cell lung cancer (NSCLC) and bladder cancer (BC) and to evaluate the combinatorial antitumor effect of a B7-H3 × CD3 BiAb with MEK inhibitor trametinib. Methods We analyzed the mRNA expression of B7-H3 in NCSLC and BC using Oncomine database and validated its expression by immunohistochemistry staining of clinical samples. B7-H3 expression and the effects of trametinib on RAS-mutated NSCLC and BC cell lines were determined by flow cytometry. Antitumor efficacy of B7-H3 × CD3 BiAb alone and its combination with trametinib were evaluated both in vitro and in vivo. Results B7-H3 was highly expressed in NSCLC and BC compared with normal samples and its increased expression was associated with poor prognosis. Treatment with trametinib alone could induce apoptosis in tumor cell, while has no effect on T cell proliferation, and a noticeable elevation of B7-H3 expression in tumor cells was also observed following treatment. B7-H3 × CD3 BiAb specifically and efficiently redirected their cytotoxicity against B7-H3-overexpressing tumor cells both in vitro and in xenograft mouse models, which was synergized by trametinib. While trametinib treatment alone affected tumor growth, the combined therapy increased T cell infiltration and significantly suppressed tumor growth. Conclusion Together, these data suggest that combination therapy with B7-H3 × CD3 BiAb and MEK inhibitor may serve as a new therapeutic strategy in the future clinical practice for the treatment of NSCLC and BC.

The purpose of our study was to investigate the inhibitory effect of carboplatin injection on human neuroblastoma human neuroblastoma cell (SK-N-SH) cells and to clarify its action mechanism. In this study, human neuroblastoma SK-N-SH cells were divided into two groups. The treatment group was intervened by carboplatin injection (25 μM), while the control group was intervened by drug solvent. After treating separately for 24 and 72 h, the cells were collected, and western blot (WB) and real-time PCR were used to detect the expression of the proliferation marker protein (Ki67); cells grown on cover slips were prepared and immunocytochemistry (ICC) and hematoxylin–eosin (HE) staining were adopted to observe the protein expression of Ki67 and the morphological changes of the cells; clone formation assay was used to detect the clonality of each cell group. The cytotoxicity of carboplatin on SK-N-SH cell was checked by AlamarBlue viability test. Both WB and PCR results showed that after cells were injected with carboplatin for 24 and 72 h, the expression levels of both Ki67 gene and protein were decreased, and they had a significant difference from those of the control group. Carboplatin injection inhibited the expression of Ki67, and the inhibitory effect was particularly significant as the action time prolonged. ICC results showed that the protein expression of Ki67 in the treatment group was lower than that in the control group, and there was a significant difference in expression between them. As shown by HE results, the number of cell necrosis and apoptosis in the treatment group was significantly higher than that in the control group, while the results of clone formation assay showed that in the treatment group, after being injected with carboplatin, the proliferation ability of cells was inhibited, so the number of cells was significantly reduced compared with that of the control group. Carboplatin at the tested concentration displayed no cytotoxicity on SK-N-SH cell. The conclusions are that carboplatin injection can inhibit human neuroblastoma SK-N-SH cells, and the longer it acts on SK-N-SH cells, the more obvious the inhibitory effect would be.

On 12 November 2019, one couple from the Sonid Left Qi (County) in the Inner Mongolia Autonomous Region was diagnosed with pneumonic plague in Beijing. The wife acquired the infection from her husband. Thereafter, two bubonic plague cases were identified in Inner Mongolia on November 16th and 24th. In this study, genome-wide single nucleotide polymorphism (SNP) analysis was used to identify the phylogenetic relationship of Yersinia pestis strains isolated in Inner Mongolia. Strains isolated from reservoirs in 2018 and 2019 in Inner Mongolia, together with the strain isolated from Patient C, were further clustered into 2.MED3m, and two novel lineages (2.MED3q, 2.MED3r) in the 2.MED3 population. According to the analysis of PCR-based molecular subtyping methods, such as the MLVA 14 scheme and seven SNP allele sequencing, Patients A/B and D were classified as 2.MED3m. In addition, strains from rodents living near the patients’ residences were clustered into the same lineage as patients. Such observations indicated that human plague cases originated from local reservoirs. Corresponding phylogenetic analysis also indicated that rodent plague strains in different areas in Inner Mongolia belong to different epizootics rather than being caused by spreading from the same epizootic in Meriones unguiculatus in 2019., Author summary The plague still poses a significant threat to human health, such as in Madagascar, which experienced a large pneumonic plague outbreak in 2017. The pneumonic plague always arouses great concern for its pathogenicity and propagation, especially in densely populated cities. In November 2019, one couple in the Inner Mongolia Autonomous Region suffered pneumonic plague and was transferred to Beijing. Subsequently, another two bubonic plague cases were identified in Inner Mongolia. Genome-wide SNP analysis, together with two PCR-based molecular subtying methods, was used for source-tracking purposes. Corresponding results indicated that human plague cases originated from local rodent plague epizootics. Because there were no obvious geographic barriers between the plague foci area in Inner Mongolia and its counterpart area in Mongolia, early warning and risk communication is necessary.

Purpose: The aim of this study was to investigate the diagnostic value of machine-learning models with radiomic features and clinical features in preoperative differentiation of common lesions located in the anterior skull base. Methods: A total of 235 patients diagnosed with pituitary adenoma, meningioma, craniopharyngioma, or Rathke cleft cyst were enrolled in the current study. The discrimination was divided into three groups: pituitary adenoma vs. craniopharyngioma, meningioma vs. craniopharyngioma, and pituitary adenoma vs. Rathke cleft cyst. In each group, five selection methods were adopted to select suitable features for the classifier, and nine machine-learning classifiers were employed to build discriminative models. The diagnostic performance of each combination was evaluated with area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity calculated for both the training group and the testing group. Results: In each group, several classifiers combined with suitable selection methods represented feasible diagnostic performance with AUC of more than 0.80. Moreover, the combination of least absolute shrinkage and selection operator as the feature-selection method and linear discriminant analysis as the classification algorithm represented the best comprehensive discriminative ability. Conclusion: Radiomics-based machine learning could potentially serve as a novel method to assist in discriminating common lesions in the anterior skull base prior to operation.

Recent work suggested that methylene blue (MB) has beneficial effects in a variety of neurological disorders, while its role in neonatal hypoxic-ischemic (HI) encephalopathy is still unclear. The current study was designed to investigate the effects of MB on HI-induced brain damage and its underlying mechanisms. The results showed that MB treatment can strongly attenuate HI-induced brain loss and neuronal damage in the cortex and hippocampus of neonatal rats. Further mechanistic analysis suggested that MB treatment was able to significantly reduce blood-brain barrier disruption after HI insult. In addition, MB profoundly inhibited microglia and astrocyte activation and the pro-inflammatory cytokines production in neonatal cortex and hippocampus after HI. Further, MB treatment resulted in dramatic suppression of oxidative damage, as evidenced by robustly decreased DHE and protein carbonyls levels in HI brain. Moreover, MB strongly preserved mitochondrial function by repressing HI-induced mitochondrial fragmentation, and the following neuronal death in cortex and hippocampus. Finally, behavioral tests revealed that MB significantly improved the spatial reference memory and motor coordination of neonatal HI rats. Taken together, these findings demonstrate that the mechanisms behind neuroprotective actions of methylene blue are multifactorial, including suppression of oxidative stress and neuroinflammation, restoration of mitochondrial function, as well as attenuation of blood-brain barrier disruption. Our study might provide further directions for MB as a promising option in neonatal HI encephalopathy therapy.

Modulating the surface properties of nanoparticles (NPs) is an important approach to accomplish immune escape, prolonged the blood retention time, and enhance the ability of targeted drug delivery. The camouflage of cancer cell membrane onto nanoparticles has been proved to be an ideal approach to enhance active targeting ability of NPs. Herein, we isolated the membrane of melanoma cells to coat doxorubicin (DOX) and indocyanine green (ICG)-loaded hollow copper sulfide NPs (ID-HCuSNP@B16F10) for targeted photothermal therapy, photoacoustic imaging, and chemotherapy. A remarkable in vitro anticancer effect after irradiation and homologous targeting can be observed in B16F10 cells after the treatment of ID-HCuSNP@B16F10. Moreover, ID-HCuSNP@B16F10 exhibits excellent photothermal effect in melanoma animal models and achieves a high tumor ablation rate. This biomimetic system can realize high drug loading efficiency, enhanced targeting ability, and ideal antitumor efficiency.

Central nervous system (CNS) maintains a high level of metabolism, which leads to the generation of large amounts of free radicals, and it is also one of the most vulnerable organs to oxidative stress. Emerging evidences have shown that, as the key homeostatic cells in CNS, astrocytes are deeply involved in multiple aspects of CNS function including oxidative stress regulation. Besides, the redox level in CNS can in turn affect astrocytes in morphology and function. The complex and multiple roles of astrocytes indicate that their correct performance is crucial for the normal functioning of the CNS, and its dysfunction may result in the occurrence and progression of various neurological disorders. To date, the influence of astrocytes in CNS oxidative stress is rarely reviewed. Therefore, in this review we sum up the roles of astrocytes in redox regulation and the corresponding mechanisms under both normal and different pathological conditions.

Cancer immunotherapy using checkpoint blockade has brought about a paradigm shift in the treatment of advanced-stage cancers. Unfortunately, not all patients benefit from these therapies, paving the way for other immune checkpoints to be targeted. CD47, a 'marker-of-self' protein that is overexpressed broadly across tumor types, is emerging as a novel potent macrophage immune checkpoint for cancer immunotherapy. Recently, CD47 blockade by Hu5F9-G4 has shown promise combined with Rituximab in non-Hodgkin's lymphoma. Here we review the complex structure and various physiological functions of CD47 and their implications in cancer biology. Further, this review considers future directions and challenges in advancing this promising target platform to widespread therapeutic use.

Toxicity to central nervous system tissues is the common side effects for radiotherapy of brain tumor. The radiation toxicity has been thought to be related to the damage of cerebral endothelium. However, because of lacking a suitable high-resolution vivo model, cellular response of cerebral capillaries to radiation remained unclear. Here, we present the flk:eGFP transgenic zebrafish larvae as a feasible model to study the radiation toxicity to cerebral capillary. We showed that, in living zebrafish larvae, radiation could induce acute cerebral capillary shrinkage and blood-flow obstruction, resulting brain hypoxia and glycolysis retardant. Although in vivo neuron damage was also observed after the radiation exposure, further investigation found that they didn’t response to the same dosage of radiation in vitro, indicating that radiation induced neuron damage was a secondary-effect of cerebral vascular function damage. In addition, transgenic labeling and qPCR results showed that the radiation-induced acute cerebral endothelial damage was correlated with intensive endothelial autophagy. Different autophagy inhibitors could significantly alleviate the radiation-induced cerebral capillary damage and prolong the survival of zebrafish larvae. Therefore, we showed that radiation could directly damage cerebral capillary, resulting to blood flow deficiency and neuron death, which suggested endothelial autophagy as a potential target for radiation-induced brain toxicity.

Purpose: Given that heterogeneous expression and variants of antigens on solid tumors are responsible for relapse after chimeric antigen receptor (CAR)-T cell therapy, we hypothesized that combinatorial targeting two tumor-associated antigens would lessen this problem and enhance the antitumor activity of T cells. Methods: The co-expression level of CD70 and B7-H3 was analyzed in multiple tumor tissue samples. Further, two putative antigens were identified in The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis database. Two CD70 targeted CARs with different antigen binding domain, truncated CD27 and CD70 specific single-chain antibody fragment (scFv), were designed to screen a more suitable target-antigen binding moiety. Accordingly, we designed a bivalent tandem CAR (TanCAR) and further assessed the anti-tumor efficacy of TanCAR-T cells in vitro and in vivo. Results: Our results indicated that co-expression of CD70 and B7-H3 was observed on multiple tumor types including kidney, breast, esophageal, liver, colon cancer, glioma as well as melanoma. The CD70 targeted CAR-T cells with binding moiety of CD70 specific scFv exhibit a higher affinity and antitumor effect against CD70+ tumor cells. TanCAR-T cells induced enhanced ability of cytolysis and cytokine release over unispecific CAR-T cells when encountering tumor cells expressing two target-antigens. Further, low doses of TanCAR-T cells could also effectively control the lung cancer and melanoma xenografts and improved overall survival of the treated animals. Conclusion: TanCAR-T cells targeting CD70 and B7-H3 exhibit enhanced antitumor functionality and improve the problem of antigenic heterogeneity and variant in the treatment against solid tumor and melanoma.