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Background: Medulloblastoma (MB) is a malignant pediatric central nervous system tumor that is prone to leptomeningeal metastasis. Currently, apart from magnetic resonance imaging and cerebrospinal fluid (CSF) cytology, there are no reliable biomarkers for MB progression. Cytokines are key proteins in signaling pathways in the tumor microenvironment and are closely related to tumor recurrence and progression. This study aimed to investigate the CSF cytokine profile in pediatric patients with MB to identify biomarkers of tumor progression and metastasis. Methods: In total, 10 patients were recruited for this study. Five patients had nonmetastatic MB and five had metastatic MB. A cytokine antibody array was used to detect the expression of 120 cytokines in the CSF, and differentially expressed cytokines were screened by integrated bioinformatics analysis. Results: Twenty-seven cytokines were upregulated in patients with MB compared to control individuals. Of these, eight were upregulated by > 1.5-fold (CCL2, BMP-4, beta-NGF, FGF-7, IL-12p40, eotaxin-2, M-CSF, and NT-4). Twelve cytokines were differentially expressed between patients with metastatic MB and nonmetastatic (nine cytokines were upregulated and three were downregulated). Among them, NAP-2, MIP-1α, MIP-1β, IGFBP-1, IGFBP-2 and IGFBP-3 were upregulated by more than two-fold. Gene Ontology analysis revealed that the upregulated cytokines were enriched mainly in “epithelial cell proliferation” and “chemotaxis,” and the Kyoto Encyclopedia of Genes and Genomes analysis indicated the enrichment of the “MAPK,” “PI3K-Akt,” and “Ras” signaling pathways. Conclusions: The present study investigated cytokine profiles in the CSF of pediatric patients with MB. Our results suggest that these differentially expressed cytokines may serve as novel markers for detecting MB, especially for assessing the risk of progression and metastasis.

Histological transformation is a phenomenon that is well described as one of the causes of tyrosine kinase inhibitor resistance in oncogene-driven non-small-cell lung cancer (NSCLC). The use of immune checkpoint inhibitors (ICIs) as a potential mechanism of acquired resistance to immunotherapy in NSCLC to small-cell lung cancer was also recently found. Here, we report the histological transformation of sarcomatoid carcinoma and metastasis in a lung adenocarcinoma patient without targetable genetic alterations who experienced long-term disease remission after nivolumab therapy. The patient subsequently developed rapid progression in the mediastinal and retroperitoneal lymph nodes, bones, and small intestine. Surgical resection of the small intestine lesion due to acute small intestine bleeding revealed the transformation of NSCLC to sarcomatoid carcinoma. The patient died 3 months after sarcomatoid carcinoma transformation and extensive disease progression, although he was rechallenged with immunotherapy. Genomic and immunohistochemical analyses revealed a comparable abundance of gene mutations and a limited number of immune cells in the tumor microenvironment, with low infiltration of CD8 + T cells, CD4 + T cells, regulatory T cells, and PD-L1 + macrophages in metastatic tumors, revealing a noninflamed immune microenvironment for ICI-resistant tumors.

Abstract Background The aim of this study was to analyze the effectiveness and safety of H101 in Chinese patients with malignant pleural effusion and ascites (MPE/MA) in the real world. Methods This multicenter, observational, real‐world study recruited patients with MPE/MA caused by malignant tumor receiving H101‐containing treatment between January 2020 and June 2022. Effectiveness was evaluated by overall remission rate (ORR), and safety was evaluated based on adverse events (AEs). Subgroup analysis was performed on patients grouped according to tumor type, the volume of MPE and MA, and dosage of H101. Results A total of 643 eligible patients were enrolled, and 467 received H101 monotherapy and 176 received H101 combined with chemotherapy. The ORR of total patients was60.3% with 388 case of PR. In the H101 monotherapy group, the decrease of MPE or MA was achieved in 282 (60.4%, PR) patients, 176 (37.7%, NC) patients showed no change in volume of MPE or MA, and nine (1.9%, PD) patients showed an increase, yielding an ORR of 60.4% (282/467). The ORR for the combination therapy group was 60.2% (106/176), with 106 cases of PR, 69 cases of NC and one case of PD. Subgroup analyses based on tumor type, volume of MPE and MA, and dosage of H101 all showed high ORR, approximately 60%. The main AEs associated with H101‐containing regimens were fever, nausea and vomiting. No serious AEs occurred in both groups. Conclusion Encouraging clinical benefits and manageable toxicity of H101 against MPE/MA were preliminarily observed in the real‐world clinical setting, indicating that the H101‐containing regimen is reliable, safe, and feasible, providing a novel and effective option for the treatment of this disease.

Ventilation may lead to a deterioration in indoor air quality in urban environments located close to roads. Understanding the differences in the chemical compositions of size-resolved particulate matter (PM) in indoor air and outdoor air could aid in assessing the health impacts of air in these settings and establishing relevant regulation policies. In this study, indoor and outdoor size-resolved PM was collected from an office in Beijing in summer (between 5 and 25 July 2020) and winter (between 5 and 31 January 2021). Its chemical components, including sulfate, nitrate, ammonium, chlorine, organic matter (OM), elemental carbon (EC), crustal materials (CM), and heavy metals (HM), were analyzed. The mean levels of indoor and outdoor PM2.1 and PM9 were found to be much higher than those in the guidelines for PM2.5 and PM10 outlined by the National Ambient Air Quality Standard. Moreover, the levels of PM2.1 and PM2.1–9 mass were higher outdoors than they were indoors. The size distributions of mass concentrations were shown to be bimodal, peaking at 0.43–0.65 μm and 4.7–5.8 μm, respectively. The most abundant chemicals were OM, nitrate, and sulfate for PM2.1 and OM, CM, and nitrate for PM2.1–9. We found higher percentages of sulfate, nitrate, ammonium, EC, and HM in smaller-size fractions of PM. Additionally, positive matrix factorization showed that biomass burning, secondary inorganic aerosol, coal combustion, dust, traffic, and industrial pollution were the main sources of PM during the study period. The greatest non-carcinogenic and carcinogenic hazards were found at 0.43–0.65 μm in summer and 2.1–3.3 μm in winter. Our results indicate that size-resolved PM of ambient origin may infiltrate buildings near roads to varying degrees, resulting in negative health effects.

Abstract Thromboelastography (TEG) remains a convenient and effective viscoelastic blood coagulation testing device for guiding blood component transfusion and assessing the risk of thrombosis. Here, a TEG enabled by a non‐contact triboelectric angle sensor (NTAS) with a small size (∼7 cm3) is developed for assessing the blood coagulation system. With the assistance of a superelastic torsion wire structure, the NTAS‐TEG realizes the detection of blood viscoelasticity. Benefiting from a grating and convex design, the NTAS holds a collection of compelling features, including accurate detection of rotation angles from −2.5° to 2.5°, high linearity (R2 = 0.999), and a resolution of 0.01°. Besides, the NTAS exhibits merits of low cost and simplified fabrication. Based on the NTAS‐TEG, a viscoelastic blood coagulation detection and analysis system is successfully constructed, which can provide a graph and parameters associated with clot initiation, formation, and stability for clinicians by using 0.36 mL of whole blood. The system not only validates the feasibility of the triboelectric coagulation testing sensor, but also further expands the application of triboelectric sensors in healthcare.

BackgroundThe significant progress of immune therapy in non-central nervous system tumors has sparked interest in employing the same strategy for adult brain tumors. However, the advancement of immunotherapy in pediatric central nervous system (CNS) tumors is not yet on par. Currently, there is a lack of comprehensive comparative studies investigating the immune ecosystem in pediatric and adult CNS tumors at a high-resolution single-cell level.MethodsIn this study, we comprehensively analyzed over 0.3 million cells from 171 samples, encompassing adult gliomas (IDH wild type and IDH mutation) as well as four major types of pediatric brain tumors (medulloblastoma (MB), ependymoma (EPN), H3K27M-mutation (DIPG), and pediatric IDH-mutation glioma (P-IDH-M)). Our approach involved integrating publicly available and newly generated single-cell datasets. We compared the immune landscapes in different brain tumors, as well as the detailed functional phenotypes of T-cell and myeloid subpopulations. Through single-cell analysis, we identified gene sets associated with major cell types in the tumor microenvironment (gene features from single-cell data, scFes) and compared them with existing gene sets such as GSEA and xCell. The CBTTC and external GEO cohort was used to analyze and validate the immune-stromal-tumor patterns in pediatric brain tumors which might potentially respond to the immunotherapy.ResultsFrom the perspective of single-cell analysis, it was observed that major pediatric brain tumors (MB, EPN, P-IDH-M, DIPG) exhibited lower immune contents compared with adult gliomas. Additionally, these pediatric brain tumors displayed diverse immunophenotypes, particularly in regard to myeloid cells. Notably, the presence of HLA-enriched myeloid cells in MB was found to be independently associated with prognosis. Moreover, the scFes, when compared with commonly used gene features, demonstrated superior performance in independent single-cell datasets across various tumor types. Furthermore, our study revealed the existence of heterogeneous immune ecosystems at the bulk-RNA sequencing level among different brain tumor types. In addition, we identified several immune-stromal-tumor patterns that could potentially exhibit significant responses to conventional immune checkpoint inhibitors.ConclusionThe single-cell technique provides a rational path to deeply understand the unique immune ecosystem of pediatric brain tumors. In spite of the traditional attitudes of “cold” tumor towards pediatric brain tumor, the immune-stroma-tumor patterns identified in this study suggest the feasibility of immune checkpoint inhibitors and pave the way for the upcoming tide of immunotherapy in pediatric brain tumors.

Summary: Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1β from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte-associated antigen-4 have shown significantly durable clinical benefits and tolerable toxicities and have improved the survival of patients with various types of cancer. Since 2018, the National Medical Products Administration of China has approved 17 ICIs as the standard treatment for certain advanced or metastatic solid tumors. As ICIs represent a broad-spectrum antitumor strategy, the populations eligible for cancer immunotherapy are rapidly expanding. However, the clinical applications of ICIs in cancer patient populations with special issues, a term that refers to complex subgroups of patients with comorbidities, special clinical conditions, or concomitant medications who are routinely excluded from prospective clinical trials of ICIs or are underrepresented in these trials, represent a great real-world challenge. Although the Chinese Society of Clinical Oncology (CSCO) has provided recommendations for screening before the use of ICIs in special populations, the recommendations for full-course management remain insufficient. The CSCO Expert Committee on Immunotherapy organized leading medical oncology and multidisciplinary experts to develop a consensus that will serve as an important reference for clinicians to guide the proper application of ICIs in special patient populations. This article is a translation of a study first published in Chinese in The Chinese Clinical Oncology (ISSN 1009-0460, CN 32-1577/R) in May 2022 (27(5):442–454). The publisher of the original paper has provided written confirmation of permission to publish this translation in Therapeutic Advances in Medical Oncology .

BackgroundPrevious studies indicate that exogenous use of glucocorticoid (GC) affects immune checkpoint inhibitor (ICI) efficacy. However, there is a paucity of clinical data evaluating the direct impact of endogenous GC on the efficacy for cancer patients with immune checkpoint blockade.MethodsWe first compared the endogenous circulating GC levels in healthy individuals and patients with cancer. We next retrospectively reviewed patients with advanced cancer with PD-1/PD-L1 inhibitor alone or combination therapy in a single center. The effects of baseline circulating GC levels on objective response rate (ORR), durable clinical benefit (DCB), progression‐free survival (PFS), and overall survival (OS) were analyzed. The association of the endogenous GC levels with circulating lymphocytes, cytokines levels, and neutrophil to lymphocyte ratio, and tumor infiltrating immune cells, were systematically analyzed.ResultsThe endogenous GC levels in advanced cancer patients were higher than those in early-stage cancer patients as well as healthy people. In the advanced cancer cohort with immune checkpoint blockade (n=130), patients with high baseline endogenous GC levels (n=80) had a significantly reduced ORR (10.0% vs 40.0%; p

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized cancer therapy in the past decade and amplify T-cell-mediated immune responses by disrupting immunoinhibitory signals. The augmented T-cell immune response has led to a range of immune-related adverse effects (irAEs). Immune-related cardiotoxicity has been reported in case series but has been underappreciated due to difficulties in diagnosis. This article describes epidemiological, clinical presentation, subtype, and treatment data and a new systematic framework for the clinical management of cardiotoxicity.MethodsData were extracted for cancer patients who received ICIs in a single center between January 1, 2020, and February 28, 2022. ICI-associated cardiotoxicity was clinically diagnosed based on clinical presentations, biochemical biomarkers, and imaging features.ResultsWe identified a total of 12 (2.46%) cases of ICI-related cardiotoxicity from 487 patients who received PD-1 or PD-L1 inhibitors. All patients were diagnosed with advanced or metastatic solid tumors. The severity of ICI-related cardiotoxicity ranged from subclinical cardiac abnormalities (subclinical type) with only asymptomatic troponin-I (TnI) elevations (25.0%) to symptomatic cardiac abnormalities (clinical type) (75.0%). Patients with symptomatic cardiac abnormalities had several manifestations, including tachyarrhythmia (16.7%), bradyarrhythmia (41.7%), or cardiac failure (8.3%). The median immunotherapy exposure time was 1.5 doses (range: 1 to 5), and the median time from the initial immunotherapy to the onset of ICI-related cardiotoxicity was 33.5 days (IQR: 20.3 to 46.8). Most patients, including those with subclinical cardiac abnormalities, were administered systemic corticosteroids (58.3%). One (8.3%) patient was put on mechanical ventilation, one (8.3%) received plasma exchange therapy, one (8.3%) was implanted with a pacemaker, and one (8.3%) was admitted to the ICU. Three patients with symptomatic cardiac abnormalities (25.0%) died, and other patients presented with significant clinical improvement with good outcomes.ConclusionICI-related cardiotoxicity is uncommon but critical with a high mortality rate and poor prognosis, especially for a small group of patients with symptomatic cardiac abnormalities. More attention should be given to cardiotoxicity associated with ICIs, and these patients should be given baseline examinations and biochemical analyses before and after the initiation of immunotherapy, intensive cardiac assessments, an accurate and rapid diagnosis, and timely multidisciplinary management with immunosuppressive agents and other necessary clinical interventions.

ObjectivesTo investigate the potential factors affecting the clinical prognosis of intracranial sylvian arachnoid cysts(IAC) in children.MethodsAll patients with IAC admitted to our department from January, 1, 2015 to December, 31, 2016, were retrospectively reviewed. Patients were grouped based on surgical treatment (surgery cohort vs non-surgery cohort). The clinical and image outcome of the patients were followed routinely. The clinical characteristics and the prognosis of the patients were compared in different cohorts. Binary logistic regression analysis was applied to analyze the potential factors which may post an influence on the prognosis of the patients.ResultsOf 500 patients admitted to our department for IAC, 424 patients had good prognosis and 76 had poor prognosis, with no deaths occurred during the follow-ups. 68 patients had IAC related complications and 91 patients developed new symptoms during the follow-ups. There were significant differences (P

Abstract Background Indian Hedgehog (IHH), an important cell signaling protein, plays a key regulatory role in development of cartilage and chondrogenesis. Earlier studies have shown that heterozygous missense mutations in IHH gene may cause brachydactyly type A1 (BDA1), an autosomal dominant inheritance disease characterized by apparent shortness or absence of the middle phalanges of all digits. MicroRNAs (miRNAs) have been found to be significant post-transcriptional regulators of gene expression and significantly influence the process of bone-development. Therefore, it is possible that miRNAs are involved in the mechanism underlying the development of BDA1. However, the relationship between miRNAs and the pathogenesis of BDA1 remains unclear. Methods In this study, we used microarray-based miRNA profiling to investigate the role of miRNAs in BDA1 by characterization of differentially expressed miRNAs in C3H10T1/2 cell line induced by wild type (WT) and p.E95K mutant (MT) IHH signaling. Results Our results identified 6 differentially expressed miRNAs between WT and control (CT) group and 5 differentially expressed miRNAs between MT and CT groups. In particular, miR-135a-1-3p was found to be a significantly differentially expressed miRNA between WT and CT group. Results of dual-luciferase reporter gene experiment successfully discovered Hoxd10 was one of the target gene of miR-135a-1-3p. Additionally, our pathway analysis revealed that the targets of these miRNAs of interest were highly involved with Runx1/2, Notch and collagen-related pathways. Conclusions Taken together, our findings provided important clue for future study of the process of miRNA-regulation in IHH signaling and novel insights into the regulatory role of miRNA in pathogenesis of BDA1.

Background: Nivolumab has been approved in China as second-line treatment for advanced non-small-cell lung cancer (NSCLC) via weight-based infusion, based on the CheckMate 078 study. We investigated the safety and efficacy of 240 mg flat-dose nivolumab in patients with advanced NSCLC, including those with hepatitis B virus (HBV) and epidermal growth factor receptor ( EGFR ) mutation/ALK receptor tyrosine kinase ( ALK ) translocation due to high prevalence in China. Methods: CheckMate 870 was a single-arm, open-label, phase IIIb trial in Asian (primarily Chinese) patients with previously treated advanced NSCLC. Patients received flat-dose nivolumab 240 mg every 2 weeks (Q2W) for up to 2 years. The primary endpoint was the incidence and severity of treatment-related select adverse events (TRsAEs) in non-HBV patients; secondary and exploratory endpoints included severity of high-grade TRsAEs in HBV-infected patients, and safety, efficacy and patient-reported outcomes (PROs) in the whole population. Results: Out of 404 patients enrolled, 400 received treatment. Median (standard deviation) age was 60.5 (8.68) years and the majority were male (78.5%). At a median follow-up of 37.6 months, no Grade 5 TRsAEs were reported, and the frequency of Grade 3–4 TRsAEs was low (0.0–5.9%) in non-HBV and HBV NSCLC patients. Median overall survival (OS) and progression-free survival (PFS) in all treated patients were 14.7 (12.3–18.1) and 3.6 (2.3–3.8) months, respectively. Median OS was 14.2 (12.3–18.1) and 22.3 (10.0–NA) months for non-HBV and HBV-infected patients, 19.3 (11.2–31.7) and 13.7 (11.5–18.1) months for EGFR -positive and wild-type subgroups, and 19.3 (12.9–23.5) and 13.3 (10.9–17.7) months for those with programmed death-ligand 1 (PD-L1) expression ⩾1% and

BackgroundChildren are more susceptible to the higher rate of massive blood transfusion because of the less allowable blood loss and lower intraoperative tolerance to blood loss during the resection of brain tumors. The surgical concept of en bloc resection, which is widely used in other tumors, may contribute to the improvement of brain tumor resection. However, there is still a lack of comprehensive research on its application in pediatric brain tumors.ObjectiveThe aim of this study is to investigate the outcomes of the en bloc concept and the factors associated with the application of the en bloc concept in pediatric brain tumors.MethodsAccording to the surgical concept involved, the patients were divided into three subgroups: complete en bloc concept, partial en bloc concept, and piecemeal concept. The matching comparison (complete and partial en bloc concept groups vs. piecemeal concept group) was conducted to investigate the effect of the en bloc concept on the outcomes. Then, the patient data from January 2018, when the en bloc concept was routinely integrated into the brain tumor surgery in our medical center, were reviewed and analyzed to find out the predictors associated with the application of en bloc concept.ResultsIn the en bloc group, the perioperative parameters, such as hospital stay (p = 0.001), pediatric intensive care unit (PICU) stay (p = 0.003), total blood loss (p = 0.015), transfusion rate (p = 0.005), and complication rate (p = 0.039), were all significantly improved. The multinomial logistic regression analysis showed that tumor volume, bottom vessel, and imaging features, such as encasing nerve or pass-by vessel, finger-like attachment, ratio of “limited line”, and ratio of “clear line”, were independent predictors for the application of the en bloc concept in our medical center.ConclusionThis study supports the application of complete and partial en bloc concept in the pediatric brain tumor surgery based on the preoperative evaluation of imaging features, and compared with the piecemeal concept, the en bloc concept can improve the short outcomes without significant increases in the neurological complications. Large-series and additional supportive pieces of evidence are still warranted.

Minichromosome maintenance proteins are DNA-dependent ATPases that bind to replication origins and allow a single round of DNA replication. One member of this family, MCM3, is reportedly active in most cancers. To systematically elucidate the mechanisms affected by aberrant MCM3 expression and evaluate its clinical significance, we analyzed multi-omics data from the GEO database and validated them in cell lines and tumor samples. First, we showed the upregulation of MCM3 in medulloblastoma (MB) at bulk and single-cell RNA sequence levels and revealed the potential role of MCM3 via DNA replication. Then we found the dysregulation of MCM3 might result from abnormal methylation of MCM3. Moreover, we discovered that MCM3 might affect varied biological processes such as apoptosis, autophagy, and ferroptosis and that MCM3 was correlated with immune components such as fibroblast and neutrophils, which were associated with overall survival in different medulloblastoma subtypes. Furthermore, we found that MCM3 expression was correlated with the IC50 values of cisplatin and etoposide. The nomogram of MCM3-related genes showed the reliable and better prediction of 1- and 5-year survival compared to current histological and molecular classifications. Overall, the results of our study demonstrated that MCM3 might serve as a potential biomarker with clinical significance and better guidance than current histological and molecular classifications for clinical decision-making.

Abstract The promulgation and implementation of the national and Beijing municipal standards for air pollutants emitted from crematoriums has effectively alleviated the problem of “black smoke” in crematoriums, but noticeable odor in crematoriums remains. We determined the level of odor emissions in crematoriums by monitoring the odor concentrations of cremators, incinerators, and cremation workshops in five crematoriums in Beijing. Subsequently, we analyzed the major contributing factors to the odor level and proposed control measures. A high odor concentration in crematoriums was observed; two different mechanisms were proposed to explain this finding. First, poor ventilation conditions in workshops and inadequate airtightness of equipment resulted in dimensionless concentrations of unorganized odor emissions in the workshops ranging from 97 to 732, with an average of 504, which is much higher than the standard level of 20. Second, the postprocessing facilities used in cremation sites produce poor odor removal, which, coupled with fuel usage and unregulated operations, led to high concentrations of organized odor emissions ranging from 231 to 1303 (910 on average) for cremators and incinerators. The odor emissions of cremators and incinerators meet the Integrated Emission Standards of Air Pollutants (DB11-501-2017), which are suitable for industries containing industrial kilns but not for crematoriums. The odor emissions in crematoriums are lower than those emitted from industries, such as fiber manufacturing and activated carbon processing. However, the unique geographical locations of crematoriums, high population density, and high exposure risk to local residents necessitate strengthening the management and control of odor emissions from crematoriums. To further address the problem of odor emissions from crematoriums in Beijing, further clarification and tightening of industry standards for the concentration limits of organized and unorganized odor emissions is recommended. Crematoriums will thus be prompted to increase odor control in workshops and adopt and improve deodorization facilities, including the installation and application of treatment facilities, such as adsorption and biological control.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts’ discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs.

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety data from the Chinese subpopulation are reported. Methods: IMbrave150, a global, randomized, open-label, phase 3 study in patients with systemic treatment-naive unresectable HCC, included an extension phase that enrolled additional patients from mainland China. Patients were randomized (2:1) to receive intravenous atezolizumab 1,200 mg plus bevacizumab 15 mg/kg once every 3 weeks or sorafenib 400 mg twice a day until unacceptable toxicity or loss of clinical benefit. Co-primary endpoints were OS and independent review facility-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population. Results: Of 194 Chinese patients enrolled from April 16, 2018, to April 8, 2019 (137 in the global study and 57 in the China extension phase), 133 received atezolizumab plus bevacizumab and 61 received sorafenib. At the data cutoff (August 29, 2019), the stratified hazard ratio for OS was 0.44 (95% CI, 0.25–0.76) and for PFS was 0.60 (95% CI, 0.40–0.90). The respective median OS and PFS with atezolizumab plus bevacizumab were not reached (NR; 95% CI, 13.5 months to NR) and 5.7 months (95% CI, 4.2–8.3) versus 11.4 months (95% CI, 6.7 to NR) and 3.2 months (95% CI, 2.6–4.8) with sorafenib. Grade 3–4 adverse events (AEs) occurred in 78 of 132 (59.1%) atezolizumab plus bevacizumab-treated and 27 of 58 (46.6%) sorafenib-treated patients. The most common grade 3–4 AE with atezolizumab plus bevacizumab was hypertension, occurring in 15.2% of patients; however, other high-grade AEs were infrequent. Conclusion: Clinically meaningful improvements in OS and PFS observed with atezolizumab plus bevacizumab versus sorafenib suggest that atezolizumab plus bevacizumab may become a practice-changing treatment for Chinese patients with unresectable HCC.

Acceleration sensors have a wide variety of applications for industrial engineering, biology and navigation. However, passive sensing, narrow detection range, large size, and high manufacturing cost curb their further development. Here, we present a miniaturized acceleration sensor (MAS) with rationally patterned electrodes, based on the single electrode triboelectric mechanism, featuring small size, high accuracy, large detection scale, and environmental friendliness. A stainless-steel ball, as the moving part of the MAS, experiences physical movement that is converted into an electrical signal. Equipped with rationally patterned electrodes, the MAS retains the smallest size and lowest weight compared with the currently reported self-powered acceleration sensors. Benefiting from the voltage-relationship-based direction detection mechanism, eight directions can be identified by one TENG module. Consequently, rotated 22.5° relatively, two TENG modules enable the MAS to detect 16 directions. Moreover, accelerations ranging from 0.1 m/s2 to 50 m/s2 can be identified according to the relationship of response time and accelerations in the horizontal direction. The relationship is obtained through the measurements of the sum of output voltages (VSOC) for the four bottom electrodes with varying accelerations. In addition, no distinct decrease of VSOC is observed after continuously operating for 2000 circles, presenting excellent robustness. Hence, this cost-effective and rationally patterned MAS reveals great potential for human machine interaction, VR/AR (virtual/augmented reality), sports training, and smart city.

Abstract Background It is very important to develop a highly efficient cerebrospinal fluid (CSF) detection system with diagnosis and prediction function, for which the detection of circulating tumor cells (CTCs) in CSF is a good choice. In contrast to the past use of epithelial EpCAM as CTCs separation target, a cytoplasm protein of GFAP antibody was first selected to construct highly-sensitive immunomagnetic liposome beads (IMLs). The validation and efficiency of this system in capturing CTCs for brain tumors were measured both in vitro and in vivo. The associations between the numbers of CTCs in patients with their clinical characteristics were further analyzed. Results Our data show that CTCs can be successfully isolated from CSF and blood samples from 32 children with brain tumors. The numbers of CTCs in CSF were significantly higher than those in blood. The level of CTCs in CSF was related to the type and location of the tumor rather than its stage. The higher the CTCs number is, the more possibly the patient will suffer from poor prognosis. Genetic testing in GFAP CTC-DNA by sanger sequencing, q-PCR and NGS methods indicated that the isolated CTCs (GFAP+/EGFR+) are the related tumor cell. For example, the high expression of NPR3 gene in CSF CTCs was consistent with that of tumor tissue. Conclusions The results indicated that GFAP-IML CTCs isolation system, combined with an EGFR immunofluorescence assay of antitumor marker, can serve as a brand-new method for the identification of CTCs for brain tumors. Via lumbar puncture, a minimally invasive procedure, this technique may play a significant role in the clinical diagnosis and drug evaluation of brain tumors.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, most NSCLC patients are at advanced stage at the time of diagnosis. For patients without sensitive driven-oncogene mutations, chemotherapy is still the main treatment at present, the overall prognosis is poor. Improving outcomes and obtaining long-term survival are the most urgent needs of patients with advanced NSCLC. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs), especially targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), have made a breakthrough in the treatment of NSCLC, beneficial to patients’ survival and changed the treatment pattern for NSCLC. It shows more and more important role in the treatment of NSCLC. Led by NSCLC expert committee of Chinese society of clinical oncology (CSCO), relevant experts in this field were organized. On the basis of referring to domestic and foreign literature, systematically evaluating the results of Chinese and foreign clinical trials, and combining the experiences of the experts, the experts group reached an agreement to develop this consensus. It will guide domestic counterparts for better application of ICIs to treat NSCLC.

Abstract Background The purpose of the present study was to obtain information on the use of PD-1/PD-L1 inhibitors by oncologists in China through a national questionnaire survey. Methods Between the 7th and 25th of July in 2019, a questionnaire designed by the Chinese Society of Clinical Oncology Immuno-Oncology (CSCO IO) Committee on the current status of the use of PD-1/PD-L1 inhibitors was distributed online and offline to cancer-related medical departments in thirty different provinces and autonomous regions of China. The national questionnaire consisted of three sections as follows: general information, current status of the application of PD-1/PD-L1 inhibitors in the clinic, and oncologists’ concerns regarding utilization. Results The valid response rate of the current status survey was 76.3%. The proportion of senior doctors (physician-in-charge or a more superior position for more than 3 years) among the respondents was relatively high (67.0% in 588). Of the respondents, 59.2% had prescribed PD-1/PD-L1 inhibitors during clinical treatment, and the most frequent reason for not prescribing these inhibitors was the choice “do not understand the mechanism and the efficacy of PD-1/PD-L1 inhibitors”. In addition, 77.9% of the prescribers used the medications in an off-label situation, and the most important motivation for this use was the fact that “there were indications abroad but not domestically”. In addition, 77.9% of the prescribers believed that “immunotherapy-related adverse effects could be controlled or intervened through follow-up management”. The prescribers were mostly concerned about “how to identify pseudoprogression and hyperprogression” and “immunity-related adverse effects management”. Conclusion The present study highlights the current status of PD-1/PD-L1 inhibitors in China. Increasing numbers of medical oncologists are interested in PD-1/PD-L1 inhibitors, and they are in need of immunotherapy education.

Background: Tumor purity is defined as the proportion of cancer cells in the tumor tissue, and its effects on molecular genetics, the immune microenvironment, and the prognosis of children’s central nervous system (CNS) tumors are under-researched.Methods: We applied random forest machine learning, the InfiniumPurify algorithm, and the ESTIMATE algorithm to estimate the tumor purity of every child’s CNS tumor sample in several published pediatric CNS tumor sample datasets from Gene Expression Omnibus (GEO), aiming to perform an integrated analysis on the tumor purity of children’s CNS tumors.Results: Only the purity of CNS tumors in children based on the random forest (RF) machine learning method was normally distributed. In addition, the children’s CNS tumor purity was associated with primary clinical pathological and molecular indicators. Enrichment analysis of biological pathways related to the purity of medulloblastoma (MB) revealed some classical signaling pathways associated with MB biology and development-related pathways. According to the correlation analysis between MB purity and the immune microenvironment, three immune-related genes, namely, CD8A, CXCR2, and TNFRSF14, were negatively related to MB purity. In contrast, no significant correlation was detected between immunotherapy-associated markers, such as PD-1, PD-L1, and CTLA4; most infiltrating immune cells; and MB purity. In the tumor purity–related survival analysis of MB, ependymoma (EPN), and children’s high-grade glioma, we discovered a minor effect of tumor purity on the survival of the aforementioned pediatric patients with CNS tumors.Conclusion: Our purity pediatric pan-CNS tumor analysis provides a deeper understanding and helps with the clinical management of pediatric CNS tumors.

Glioblastoma is a rare yet lethal type of tumor that poses a crucible for the medical profession, owing to its rapid proliferation and invasion resulting in poor prognosis. Circular RNAs (circRNAs), a subclass of regulatory RNAs, are implicated in the regulation of cancerous progression. This study aims to investigate the roles and underlying mechanism of circPIK3C2A in regulating proliferation and invasion of glioblastoma. qRT-PCR assays showed that the expression level of circPIK3C2A was aberrantly higher in glioblastoma cell lines, in comparison with that in normal glia cells. The ectopic expression of circPIK3C2A promoted the proliferation, invasion and clonal formation of glioblastoma cells, while circPIK3C2A loss-of-function exerted exactly the opposite biological effects on the cells. The construction of subcutaneous xenograft tumor model in nude mice indicated that circPIK3C2A loss-of-function effectively diminished tumor load in vivo and prolonged the survival time of tumor-bearing animals. Luciferase reporter assay confirmed the interaction among circPIK3C2A/miR-877-5p and FOXM1. CircPIK3C2A function as competitive endogenous RNA via sponging miR-877-5p through certain binding sites, thereby modulating the expression of FOXM1. Our results collectively indicate that circPIK3C2A functions as ceRNA by mediating miR-877-5p/FOXM1 axis, providing a novel perspective of applying CircPIK3C2A in the clinical intervention of glioblastoma in the future.

The authors wish to make the following corrections to this paper [...]

Abstract Introduction Glioblastoma (GBM), the primary malignant tumor in the central nervous system, features high aggressiveness and mortality. Long noncoding RNAs (lncRNAs) can exert the crucial function in regulating various human diseases, including GBM. However, the function and mechanism of lncRNA DLGAP1 antisense RNA 1 (DLGAP1‐AS1) in GBM remain still unknown. Methods DLGAP1‐AS1 expression in GBM cells was detected by RT‐qPCR. Functional assays were conducted to determine GBM cell proliferation and apoptosis. RIP, RNA pull down, and luciferase reporter assay were applied for measuring the interplay of DLGAP1‐AS1 with other RNAs. Results DLGAP1‐AS1 was distinctly upregulated in GBM cells. DLGAP1‐AS1 depletion inhibited cell proliferation, but induced apoptosis. MiR‐515‐5p could be sponged by DLGAP1‐AS1 in GBM cells and to repress cell proliferation in GBM. Further, Rho‐associated coiled‐coil containing protein kinase 1 (ROCK1) and Nuclear factor erythroid‐2 like 1 (NFE2L1) were confirmed as the target gene of miR‐515‐5p. Wnt signaling pathway could be activated by DLGAP1‐AS1 via regulating ROCK1 and NFE2L1 expression. Rescue assays proved that overexpression of both ROCK1 and NFE2L1 could totally reverse the inhibitory effect of silencing DLGAP1‐AS1 on GBM cell proliferation. Conclusion LncRNA DLGAP1‐AS1 accelerated cell proliferation in GBM via targeting miR‐515‐5p/ROCK1/NFE2L1 axis and activating Wnt signaling pathway.

Abstract Acute inflammation is a central component in the progression of spinal cord injury (SCI). Anti-inflammatory drugs used in the clinic are often administered systemically at high doses, which can paradoxically increase inflammation and result in drug toxicity. A cluster-like mesoporous silica/arctigenin/CAQK composite (MSN-FC@ARC-G) drug delivery system was designed to avoid systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord. In this nanosystem, mesoporous silica was modified with the FITC fluorescent molecule and CAQK peptides that target brain injury and SCI sites. The size of the nanocarrier was kept at approximately 100 nm to enable penetration of the blood–brain barrier. Arctigenin, a Chinese herbal medicine, was loaded into the nanosystem to reduce inflammation. The in vivo results showed that MSN-FC@ARC-G could attenuate inflammation at the injury site. Behavior and morphology experiments suggested that MSN-FC@ARC-G could diminish local microenvironment damage, especially reducing the expression of interleukin-17 (IL-17) and IL-17-related inflammatory factors, inhibiting the activation of astrocytes, thus protecting neurons and accelerating the recovery of SCI. Our study demonstrated that this novel, silica-based drug delivery system has promising potential for clinical application in SCI therapy.

High-frequency common mode voltage elimination is one of the most important issues for transformerless PV grid-connected inverters. Many interesting single-phase inverter topologies have been reported to reduce the common mode voltage. However, most of them are voltage-source inverters, which suffer from a limited lifetime and reliability. In order to solve the problem, a new single-phase six-switch current source inverter is proposed. A one-dimensional space vector modulation strategy is also presented so as to eliminate the high-frequency common mode voltage. The proposed topology yields lower total harmonic distortion (THD). The experimental results reveal that the maximum value of leakage current can be significantly reduced from 1.3A to 0.14 A with the proposed solution. And, the RMS value of leakage current for the proposed solution is 28.1 mA, which complies with VDE-0126-1-1 standard. In this paper, the theoretical analysis and experimental evaluation tests are carried out to verify the effectiveness of the proposed solution.

For the grid-connected system, the unbalanced and harmonic components of three-phase grid voltage have a significant impact on the accuracy of grid synchronization. And the positive, negative sequences, harmonics, as well as dc component of the three-phase grid voltage are difficult to separate and extract in a fast and precise way. In this paper, a new fully digital phase-locked loop (FDPLL) is proposed. Compared with the existing continuous-domain methods, it is simple to implement, and able to quickly and accurately extract the positive and negative sequence components for grid synchronization. In order to verify the effectiveness and feasibility of the proposed method, the time-domain simulation is carried out. Finally, the feasibility of the proposed method is experimentally verified with a 32-bit floating-point TMS320F28335 DSP. The experimentally results verify the effectiveness of the proposed solution.

The conventional single-phase multilevel current source inverters suffer from the high count of switches for increasing the levels. Therefore, how to generate more levels with reduced-count of switches is attractive. In this paper, a programmable single-phase current source inverter is presented. It can achieve the programmable level output with only five switches. Different from the existing single-phase reduced-count multilevel inverters, it has the advantages of a simple structure and programmable level output. Finally, the simulation and experimental tests are carried out. And, the experimental results verify the effectiveness of the proposed programmable multilevel inverter.

Immune-checkpoint inhibitors (ICIs) are revolutionizing the field of immuno-oncology. Side effects and tumor microenvironment currently represent the most significant obstacles to using ICIs. In this study, we conducted an extensive cross-sectional survey to investigate the concept and practices regarding the use of ICIs in cancer patients in China. The results provide real-world data on the adverse events (AEs) of ICIs and the factors influencing the use of ICIs. This survey was developed by the Expert Committee on Immuno-Oncology of the Chinese Society of Clinical Oncology (CSCO-IO) and the Expert Committee on Patient Education of the Chinese Society of Clinical Oncology (CSCO-PE). The surveys were distributed using a web-based platform between November 29, 2019 and December 21, 2019. A total of 1,575 patients were included. High costs (43.9%), uncertainty about drug efficacy (41.2%), and no reimbursement from medical insurance (32.4%) were the factors that prevented the patients from using ICIs. The patients were most concerned about the onset time or effective duration of ICIs (40.3%), followed by the indications of ICIs and pre-use evaluation (33.4%). Moreover, 9.0, 57.1, 21.0, and 12.9% of the patients reported tumor disappearance, tumor volume reduction, no change in tumor volume, and increased tumor volume. Among the patients who received ICIs, 65.7% reported immune-related AEs (irAEs); 96.1% reported mild-to-moderate irAEs. Cancer patients in China had a preliminary understanding of ICIs. Yet, the number of patients treated with ICIs was small.

Abstract Background Glioblastoma (GBM) is the most common and most malignant primary brain cancer in adults. Despite multimodality treatment, the prognosis is still poor. Therefore, further work is urgently required to discover novel therapeutic strategies for GBM treatment. Methods The synergistic effects of cotreatment with the histone deacetylase (HDAC) inhibitor panobinostat and bromodomain inhibitor JQ1 or OTX015 were validated using cell viability assays in GBM cell lines. Furthermore, the inhibitory mechanisms were investigated via an EdU proliferation assay, an apoptosis assay, qPCR, Western blot and RNAseq analyses. Results We found that the cotreatment with panobinostat and JQ1 or OTX015 synergistically inhibited cell viability in GBM cells. The cotreatment with panobinostat and JQ1 or OTX015 markedly inhibited cell proliferation and induced apoptosis in GBM cells. Compared with treatment with each drug alone, the cotreatment with panobinostat and JQ1 induced more profound caspase 3/7 activation and cytotoxicity. Mechanistic investigation showed that combination of panobinostat with JQ1 or OTX015 results in stronger repression of GBM-associated oncogenic genes or pathways as well as higher induction of GBM-associated tumor-suppressive genes. Conclusion Our study demonstrated that HDAC inhibitor and bromodomain inhibitor had synergistical efficacy against GBM cells. The cotreatment with HDAC inhibitor and bromodomain inhibitor warrants further attention in GBM therapy.

Objective: Combination therapy with programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors might be viewed as a promising therapeutic strategy for resistant lung cancer, and it is becoming common that a second PD-1/PD-L1 inhibitor might be used following progression on previous PD-1/PD-L1 inhibitor. However, a subgroup of patients will experience various autoimmune toxicities, termed as immune-related adverse events (irAEs), that occur as a result of on-target and off-tumor inflammation.Materials and Methods: In this report, we presented a patient with small cell lung cancer who received different PD-1/PD-L1 inhibitors during the course of disease progression. This patient experienced radiation-related pneumonitis, immune-related pneumonitis, as well as concomitant bacterial pneumonia.Results: In particular, this patient developed immune-related pneumonitis with a second PD-1 inhibitor when she had a progressive disease on previous PD-L1 inhibitor. This patient was initially responsive to steroid treatment, but rapidly develop more severe pneumonitis and concomitant bacterial pneumonia with no response to antibiotics and steroid treatment. Finally, this patient got a good clinical response when receiving additional immunosuppressive medications infliximab and mycophenolate mofetil.Conclusions: Patients with a history of radiation-induced pneumonitis and treated with sequential different PD-1/PD-L1 inhibitors have a relative high risk to develop high-grade or steroid-resistant pneumonitis, and additional immunosuppressive medications should be used earlier when severe pulmonary toxicity occurs.

Abstract For the problem that the linear scale of intrusion signals in the optical fiber pre-warning system (OFPS) is inconsistent, this paper presents a method to correct the scale. Firstly, the intrusion signals are intercepted, and an aggregate of the segments with equal length is obtained. Then, the Mellin transform (MT) is applied to convert them into the same scale. The spectral characteristics are obtained by the Fourier transform. Finally, we adopt back-propagation (BP) neural network to identify intrusion types, which takes the spectral characteristics as input. We carried out the field experiments and collected the optical fiber intrusion signals which contain the picking signal, shoveling signal, and running signal. The experimental results show that the proposed algorithm can effectively improve the recognition accuracy of the intrusion signals.

Recently, with the great development of e-health, more and more countries have made certain achievements in the field of electronic medical treatment. The digitization of medical equipment and the structuralization of electronic medical records are the general trends. While bringing convenience to people, the explosive growth of medical data will further promote the value of mining medical data. Obviously, finding out how to safely store such a large amount of data is a problem that urgently needs to be solved. Additionally, the particularity of medical data makes it necessarily subject to great privacy protection needs. This reinforces the importance of designing a safe solution to ensure data privacy. Many existing schemes are based on single-server architecture, which have some natural defects (such as single-point faults). Although blockchain can help solve such problems, there are still some deficiencies in privacy protection. To solve these problems, this paper designs a medical data privacy protection system, which integrates blockchain, group signature, and asymmetric encryption to realize reliable medical data sharing between medical institutions and protect the data privacy of patients. This paper proves theoretically that it meets our security and privacy requirements, and proves its practicability through system implementation.

Session-based recommendation, which aims to match user needs with rich resources based on anonymous sessions, nowadays plays a critical role in various online platforms (e.g., media streaming sites, search and e-commerce). Existing recommendation algorithms usually model a session as a sequence or a session graph to model transitions between items. Despite their effectiveness, we would argue that the performance of these methods is still flawed: (1) Using only fixed session item embedding without considering the diversity of users’ interests and target items. (2) For user’s long-term interest, the difficulty of capturing the different priorities for different items accurately. To tackle these defects, we propose a novel model which leverages both the target attentive network and self-attention network to improve the graph-neural-network (GNN)-based recommender. In our model, we first model user’s interaction sequences as session graphs which serves as the input of the GNN, and each node vector involved in session graph can be obtained via the GNN. Next, target attentive network can activates different user interests corresponding to varied target items (i.e., the session embedding learned varies with different target items), which can reveal the relevance between users’ interests and target items. At last, after applying the self-attention mechanism, the different priorities for different items can be captured to improve the precision of the long-term session representation. By using a hybrid of long-term and short-term session representation, we can capture users’ comprehensive interests at multiple levels. Extensive experiments demonstrate the effectiveness of our algorithm on two real-world datasets for session-based recommendation.

With the rapid increase in the popularity of big data and internet technology, sequential recommendation has become an important method to help people find items they are potentially interested in. Traditional recommendation methods use only recurrent neural networks (RNNs) to process sequential data. Although effective, the results may be unable to capture both the semantic-based preference and the complex transitions between items adequately. In this paper, we model separated session sequences into session graphs and capture complex transitions using graph neural networks (GNNs). We further link items in interaction sequences with existing external knowledge base (KB) entities and integrate the GNN-based recommender with key-value memory networks (KV-MNs) to incorporate KB knowledge. Specifically, we set a key matrix to many relation embeddings that learned from KB, corresponding to many entity attributes, and set up a set of value matrices storing the semantic-based preferences of different users for the corresponding attribute. By using a hybrid of a GNN and KV-MN, each session is represented as the combination of the current interest (i.e., sequential preference) and the global preference (i.e., semantic-based preference) of that session. Extensive experiments on three public real-world datasets show that our method performs better than baseline algorithms consistently.

As the core of blockchain technology, the consensus algorithm plays an important role in determining the security, data consistency, and efficiency of blockchain systems. The existing mainstream consensus algorithm is experiencing difficulties satisfying the needs of efficiency, security, and decentralization in real-world scenarios. This paper proposes a hybrid consensus algorithm based on modified Proof-of-Probability and Delegated Proof-of-Stake. In this method, the work of block generation and validation is, respectively, completed by the nodes using the modified Proof-of-Probability consensus algorithm and Delegated Proof-of-Stake consensus algorithm. When a transaction occurs, the system sends several target hash values to the whole network. Each modified Proof-of-Probability node has a different sorting algorithm, so they have different mining priorities. Every time a hash is decrypted by a modified Proof-of-Probability node, the modulo operation is done to the value of nonce, which is then compared with the expected value given by the supernode selected by the Delegated Proof-of-Stake nodes. If they are not the same, the Proof-of-Probability node enters the waiting time and the other Proof-of-Probability nodes continue to mine. By adopting two consensus algorithms, the malicious nodes must control more than 51% of the nodes that adopt the two consensus algorithms, at the same time, to effectively attack the system, that is, they must have more than 51% of the computing power and more than 51% of the tokens. This not only increases the cost of malicious attacks, but also reduces waste of computing power. In addition, the efficiency of the DPoS algorithm makes up for the deficiency of the PoP algorithm in system efficiency, and the mining behavior based on probability in the PoP algorithm also significantly weakens the ability of supernodes in the DPoS algorithm to conduct monopoly behavior or other malicious behaviors. In a word, the combination of the two algorithms makes the system perform better in terms of security, system efficiency, and decentralization.

The innate immune response is the first line defense against viral infections. Novel genes involved in this system are continuing to emerge. SLC15A3, a proton-coupled histidine and di-tripeptide transporter that was previously found in lysosomes, has been reported to inhibit chikungunya viral replication in host cells. In this study, we found that SLC15A3 was significantly induced by DNA virus herpes simplex virus-1(HSV-1) in monocytes from human peripheral blood mononuclear cells. Aside from monocytes, it can also be induced by HSV-1 in 293T, HeLa cells, and HaCaT cells. Overexpression of SLC15A3 in 293T cells inhibits HSV-1 replication and enhances type I and type III interferon (IFN) responses, while silencing SLC15A3 leads to enhanced HSV-1 replication with reduced IFN production. Moreover, we found that SLC15A3 interacted with MAVS and STING and potentiated MAVS- and STING-mediated IFN production. These results demonstrate that SLC15A3 participates in anti-HSV-1 innate immune responses by regulating MAVS- and STING-mediated signaling pathways.

Bulk metallic glasses (BMGs) deform irreversibly through shear banding manifested as serrated-flow behavior during compressive tests. The strain-rate-dependent plasticity under uniaxial compression at the strain rates of 2 × 10−2, 2 × 10−3, and 2 × 10−4·s−1 in a Pd-based BMG is investigated. The serrated flow behavior is not observed in the stress-strain curve at the strain rate of 2 × 10−2·s−1. However, the medial state occurs at the strain rates of 2 × 10−3·s−1, and eventually the self-organized critical (SOC) behavior appears at the strain rate of 2 × 10−4·s−1. The distribution of the elastic energy density shows a power-law distribution with the power-law exponent of −2.76, suggesting that the SOC behavior appears. In addition, the cumulative probability is well approximated by a power-law distribution function with the power-law exponent of 0.22 at the strain rate of 2 × 10−4·s−1. The values of the goodness of fit are 0.95 and 0.99 at the strain rates of 2 × 10−3 and 2 × 10−4·s−1, respectively. The transition of the dynamic serrated flows of BMGs is from non-serrated flow to an intermediate state and finally to the SOC state with decreasing the strain rates.

3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-isopropoxymethyl benzyl)benzene-1,2-diol (HPN) is a bromophenol derivative from the marine red alga Rhodomela confervoides. We have previously found that HPN exerted an anti-hyperglycemic property in db/db mouse model. In the present study, we found that HPN could protect HepG2 cells against palmitate (PA)-induced cell death. Data also showed that HPN inhibited cell death mainly by blocking the cell apoptosis. Further studies demonstrated that HPN (especially at 1.0 μM) significantly restored insulin-stimulated tyrosine phosphorylation of IR and IRS1/2, and inhibited the PTP1B expression level in HepG2 cells. Furthermore, the expression of Akt was activated by HPN, and glucose uptake was significantly increased in PA-treated HepG2 cells. Our results suggest that HPN could protect hepatocytes from lipid-induced cell damage and insulin resistance via PTP1B inhibition. Thus, HPN can be considered to have potential for the development of anti-diabetic agent that could protect both hepatic cell mass and function.

An interesting inverter topology is proposed in this paper. It is similar to the typical three-phase full bridge inverter from the topology point of view, but smartly designed for the ground current reduction in single-phase photovoltaic (PV) inverter applications. Theoretical analysis is conducted to clarify the operation mechanism of the proposed topology. Performance evaluation is carried out to verify the effectiveness of the proposed topology for the ground current suppression.

The authors wish to make the following corrections to this paper [...]

BACKGROUND:Neutrophil-to-lymphocyte ratio (NLR) has been shown to be a prognostic indicator in several types of cancer. We aimed to investigate the association between NLR and survival in surgery-treated non-small cell lung cancer (NSCLC) patients. STUDY DESIGN:This large retrospective study included 1,245 patients who underwent initial surgery for stage I-III NSCLC at The University of Texas MD Anderson Cancer Center between December 2002 and November 2010. We analyzed the relationship of NLR with clinicopathological variables, local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), recurrence-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) in patients with high or low NLR using Kaplan-Meier method. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the prognostic strength of NLR. RESULTS:There was a statistically significant association between the pretreatment NLR and histology type (P = 0.003) and tumor grade (P = 0.028). At a median follow-up time of 50.6 months, high NLR was associated with reduced DRFS (P = 0.011), OS (P < 0.0001) and DSS (P = 0.004); it was not associated with LRFS and RFS. Multivariable Cox analysis further revealed that NLR (P = 0.027), pathologic stage (P < 0.0001) and lymphovascular invasion (P < 0.0001) were strong independent predictors for DRFS. NLR was also an independent marker predicting poor OS (P = 0.002) and DSS (P = 0.017). CONCLUSION:The pretreatment NLR can serve as a biomarker to predict distant recurrence and death in stage I-III NSCLC patients. Combination of NLR and pathologic stage can better predict the OS and DSS in stage I-II NSCLC patients.

Many accidents happen under shunting mode when the speed of a train is below 45 km/h. In this mode, train attendants observe the railway condition ahead using the traditional manual method and tell the observation results to the driver in order to avoid danger. To address this problem, an automatic object detection system based on convolutional neural network (CNN) is proposed to detect objects ahead in shunting mode, which is called Feature Fusion Refine neural network (FR-Net). It consists of three connected modules, i.e., the depthwise-pointwise convolution, the coarse detection module, and the object detection module. Depth-wise-pointwise convolutions are used to improve the detection in real time. The coarse detection module coarsely refine the locations and sizes of prior anchors to provide better initialization for the subsequent module and also reduces search space for the classification, whereas the object detection module aims to regress accurate object locations and predict the class labels for the prior anchors. The experimental results on the railway traffic dataset show that FR-Net achieves 0.8953 mAP with 72.3 FPS performance on a machine with a GeForce GTX1080Ti with the input size of 320 × 320 pixels. The results imply that FR-Net takes a good tradeoff both on effectiveness and real time performance. The proposed method can meet the needs of practical application in shunting mode.

A new single-phase transformerless current source inverter is proposed in this paper. The proposed inverter can achieve leakage current reduction, which is crucial for the conventional current source inverter. The basic concept of the proposed solution is to develop the new inverter by the duality principle from the voltage source inverter. The theoretical analysis is carried out to determine the switching states of the proposed inverter for the leakage current reduction. Also, a new modulation strategy is presented to achieve the optimized switching states. Finally, the experimental results are presented. Comparing with conventional single-phase current source inverter, the leakage current can be significantly reduced by the proposed inverter, which verifies the effectiveness of the proposed solution.

Scheduling EV user’s charging behavior based on charging price and applying renewable energy resources are the effective methods to release the load pressure of power grids brought about by the large-scale popularity of electric vehicles (EVs). This paper presents a novel approach for EV charging scheduling based on price negotiation. Firstly, the EV charging system framework based on price negotiation and renewable energy resources is discussed. Secondly, the price negotiation model is presented, including the initial price models and the conditions of transactions. Finally, an EV charging scheduling mechanism based on price negotiation (CSM-PN), including the price adjustment strategies of both the operator and EV users is proposed to seek a final transaction during multi-round price negotiation. Simulation results show that this novel approach can effectively improve the charging station operator’s income, reduce the EV users’ costs, and balance the load of the power grid while improving the efficiency of the EV charging system.