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The cGAS/STING signaling pathway is an important part of the cytoplasmic DNA sensor, which can trigger a type I interferon response to microbial infection when pathogenic DNA is detected. However, continuous inhibition of cGAS/STING signaling by viral infection may be an important cause of tumorigenesis. At the same time, recent studies have shown that although the cGAS/STING signaling pathway also plays a core role in anti-tumor immunity and cell senescence, the inflammatory response induced by cGAS/STING signaling will also promote tumorigenesis in different backgrounds. Here, we discuss the role of cGAS/STING in the context of infection, senescence, and tumors, especially with respect to progression, to facilitate a better understanding of the mechanism of the cGAS/STING pathway.

The ability of endoscopists to identify gastric lesions is uneven. Even experienced endoscopists may miss or misdiagnose lesions due to heavy workload or fatigue or subtle changes in lesions under white-light endoscopy (WLE). This study aimed to develop an artificial intelligence (AI) system that could diagnose six common gastric lesions under WLE and to explore its role in assisting endoscopists in diagnosis.Images of early gastric cancer, advanced gastric cancer, submucosal tumor, polyp, peptic ulcer, erosion, and lesion-free gastric mucosa were retrospectively collected to train and test the system. The performance of the system was compared with that of 12 endoscopists. The performance of endoscopists with or without referring to the system was also evaluated.A total of 29,809 images from 8947 patients and 1579 images from 496 patients were used to train and test the system, respectively. For per-lesion analysis, the overall accuracy of the system was 85.7%, which was comparable to that of senior endoscopists (85.1%, P = 0.729) and significantly higher than that of junior endoscopists (78.8%, P 0.001). With system assistance, the overall accuracies of senior and junior endoscopists increased to 89.3% (4.2%, P 0.001) and 86.2% (7.4%, P 0.001), respectively. Senior and junior endoscopists achieved varying degrees of improvement in the diagnostic performance of other types of lesions except for polyp. The diagnostic times of senior (3.8 vs 3.2 s per image, P = 0.500) and junior endoscopists (6.2 vs 4.6 s per image, P = 0.144) assisted by the system were both slightly shortened, despite no significant differences.The proposed AI system could be applied as an auxiliary tool to reduce the workload of endoscopists and improve the diagnostic accuracy of gastric lesions.

Bleeding is a severe complication of patients supported with extracorporeal membrane oxygenation (ECMO). This study aimed to analyze the occurrence, risk factors, and clinical outcomes of patients on ECMO with bleeding complications.ECMO cases reported to the multicenter ECMO registry database of the Chinese Society of Extracorporeal Life Support (CSECLS) from January 2017 to December 2020 were enrolled. General information, ECMO indications, application, complications, and patient outcomes were collected and analyzed.A total of 6541 ECMO patients from 112 centers were enrolled. Overall, 1185 patients (18.1%) presented with one of the following bleeding complications, including 82 cases (1.3%) with severe bleeding during ECMO catheterization, 462 cases (7.1%) with bleeding at the ECMO cannulation site, 200 cases (3.5%) with bleeding at the surgical site, 180 cases (2.8%) with cerebral hemorrhage, 99 cases (1.5%) with pulmonary hemorrhage, 200 cases (3.5%) with gastrointestinal hemorrhage, 82 cases (1.3%) with ECMO withdrawal, and 118 (1.8%) deaths due to severe bleeding. Extracorporeal cardiopulmonary resuscitation (ECPR) patients had the highest incidence of bleeding complications (22.4%), followed by those on circulatory support (18.7%) and respiratory support (15.4%) (p 0.001). Multivariate analysis showed that pediatric patients (odds ratio [OR] 1.509, p 0.001), patients receiving renal replacement therapy (OR 1.932, p 0.001), and patients receiving central ECMO cannulation (OR 3.023, p 0.001) were independent risk factors for all bleeding complications, while peripheral cannulation (OR 0.712, p 0.001) was an independent protective factor. Patients with any bleeding complication had significantly higher in-hospital mortality than patients without (61.9% vs. 46.3%, p 0.001).Up to 18.1% of ECMO patients in the CSECLS registry experienced bleeding complications, which was associated with higher in-hospital mortality, especially in patients who received ECPR, patients on circulatory support, and pediatric patients, which should arouse the attention of clinicians.

Sonic hedgehog subtype medulloblastoma is featured with overactivation of hedgehog pathway and can be targeted by SMO-specific inhibitors. However, the resistance is frequently developed leading to treatment failure of SMO inhibitors. W535L mutation of SMO (SMOIn this study, we profiled transcriptomes, methylomes, and interactomes of MB cells expression SMOWT or SMOW535L in the treatment of DMSO or SMO inhibitor, respectively.Analysis of transcriptomic data indicated that SMO inhibitor disrupted processes of endocytosis and cilium organization in MB cells with SMOTaken together, our work described SMO-related transcriptomes, metabolomes, and interactomes under different SMO status and treatment conditions, identifying CK2 and AKT as therapeutic targets for SHH-subtype MB cells with SMO inhibitor resistance.

Background Total hip arthroplasty (THA) is a successful treatment for many hip diseases. Length of stay (LOS) and hospital cost are crucial parameters to quantify the medical efficacy and quality of unilateral primary THA patients. Clinical variables associated with LOS and hospital costs haven’t been investigated thoroughly. Methods The present study retrospectively explored the contributors of LOS and hospital costs among a total of 452 unilateral primary THA patients from January 2019 to January 2020. All patients received conventional in-house rehabilitation services within our institute prior to discharge. Outcome parameters included LOS and hospital cost while clinical variables included patient characteristics and procedural variables. Multivariable linear regression analysis was performed to assess the association between outcome parameters and clinical variables by controlling confounding factors. Moreover, we analyzed patients in two groups according to their diagnosis with femur neck fracture (FNF) (confine THA) or non-FNF (elective THA) separately. Results Among all 452 eligible participants (266 females and 186 males; age 57.05 ± 15.99 year-old), 145 (32.08%) patients diagnosed with FNF and 307 (67.92%) diagnosed with non-FNF were analyzed separately. Multivariable linear regression analysis revealed that clinical variables including surgery duration, transfusion, and comorbidity (stroke) among the elective THA patients while the approach and comorbidities (stoke, diabetes mellitus, coronary heart disease) among the confine THA patients were associated with a prolonged LOS (P P Conclusions Specific clinical variables of the patient characteristics and procedural variables are associated the LOS and hospital cost, which may be different between the elective and confine THA patients. The findings may indicate that evaluation and identification of detailed perioperative factors are beneficial in managing perioperative preparation, adjusting patients’ anticipation, decreasing LOS, and reducing hospital cost.

Introduction: The objective of this study was to investigate changes in serum lipids among HIV-infected patients switching from non-nucleoside-reverse transcriptase inhibitors (NNRTI) to protease inhibitor (PI)-based highly active antiretroviral therapy (HAART), and to determine if changes of lipid profiles impacted the monocyte subsets recovery. Methodology: Fifty-seven subjects who switched from NNRTIs to PI-based HAART (NNRTIs to PI group) and fifty-five subjects who initially started with PI-based HAART (initial PI group) were recruited. According to their baseline triglyceride (TG) levels, the NNRTIs to PI and initial PI groups were further divided into non-hypertriglyceridemia and hypertriglyceridemia subgroups, respectively. The effects of PI-based HAART on lipid profiles and monocyte subsets were analyzed. Results: At 48 weeks, the TG changes in the NNRTIs to PI group was higher than that of the initial PI group. The increases of serum TG levels in the initial PI non-hypertriglyceridemia group was greater than that of the NNRTIs to PI non-hypertriglyceridemia group. For the hypertriglyceridemia group at baseline, significant increment in TG levels were observed in the NNRTIs to PI hypertriglyceridemia group. The percentages of circulating CD14highCD16+ and CD14lowCD16+ subsets were elevated in the two groups. At 48 weeks, the proportion of CD14highCD16+ monocytes declined gradually, and the proportion of CD14lowCD16+ monocytes decreased independently of the TG level. Conclusions: For non-hypertriglyceridemia individuals at baseline, PI-based regimens increased the TG level in the initial PI group. For the NNRTIs to PI hypertriglyceridemia group, PI-based regimens reinforced HAART-related hypertriglyceridemia.

Transmitted drug resistance (TDR) is a critical ongoing public health challenge in HIV/AIDS therapy. We explore the prevalence of TDR, its patterns, its associated risk factors, and predicted drug sensitivity in Beijing between 2015 and 2018.Retrospective data on TDR from 3265 antiretroviral therapy (ART)-naïve patients were collected at Beijing Ditan Hospital from 1 August 2014 to 31 July 2018. TDR was defined according to the Stanford Drug Resistance Mutations Database. TDR prevalence, pattern, risk factors, and predicted drug sensitivity were analysed.The overall prevalence of HIV-1 TDR was 6.68% (218 of 3265), including 0.77%, 3.64%, and 2.36% resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors, respectively. The thymidine analogue mutations (TAMs) M41L/LM (4, 0.12%) and non-TAMs mutations M184V/MV/MI (8; 0.24%) were the primary NRTI-associated resistance mutations. K103N/KN (NNRTI associated) and M46L/I/IMV/IM/ML (protease inhibitor associated) were the other major resistance mutations. Patients 40-59 years old who had the CRF08_BC subtype were identified as having higher risk for drug resistance mutation.The prevalence of TDR among ART-naïve individuals with HIV-1 in Beijing was at a moderate level. Long-time and continuous surveillance of HIV TDR is necessary step in the therapy of ART-naive patients.

Image cropping aims to improve the composition as well as aesthetic quality of an image by removing extraneous content from it. Most of the existing image cropping databases provide only one or several human-annotated bounding boxes as the groundtruths, which can hardly reflect the non-uniqueness and flexibility of image cropping in practice. The employed evaluation metrics such as intersection-over-union cannot reliably reflect the real performance of a cropping model, either. This work revisits the problem of image cropping, and presents a grid anchor based formulation by considering the special properties and requirements (e.g., local redundancy, content preservation, aspect ratio) of image cropping. Our formulation reduces the searching space of candidate crops from millions to no more than ninety. Consequently, a grid anchor based cropping benchmark is constructed, where all crops of each image are annotated and more reliable evaluation metrics are defined. To meet the practical demands of robust performance and high efficiency, we also design an effective and lightweight cropping model. By simultaneously considering the region of interest and region of discard, and leveraging multi-scale information, our model can robustly output visually pleasing crops for images of different scenes. With less than 2.5M parameters, our model runs at a speed of 200 FPS on one single GTX 1080Ti GPU and 12 FPS on one i7-6800K CPU. The code is available at: \url{https://github.com/HuiZeng/Grid-Anchor-based-Image-Cropping-Pytorch}., Extension of a CVPR 2019 paper. Dataset and PyTorch Code are released. arXiv admin note: substantial text overlap with arXiv:1904.04441

The role of HOXA family genes in the occurrence and progression of a variety of human cancers has been scatteredly reported. However, there is no systematic study on the differential expression, prognostic significance and potential molecular mechanism of HOXA4 and HOXA5 in LUAD.In-house immunohistochemistry (IHC), multi-center microarrays, RT-qPCR and RNA-seq data were incorporated for comprehensively evaluating the expression and prognostic value of HOXA4 and HOXA5 in LUAD. The mechanism of HOXA4 and HOXA5 in the formation and development of LUAD was analyzed from multiple aspects of immune correlations, upstream transcriptional regulation, functional states of single cells and co-expressed gene network. The functional roles of HOXA4 and HOXA5 in LUAD were validated byAs a result, in 3201 LUAD samples and 2494 non-cancer lung samples, HOXA4 and HOXA5 were significantly downexpressed (P0.05). The aberrant expression of HOXA5 was significantly correlated with the clinical progression of LUAD (P0.05). HOXA5 showed remarkable prognostic value for LUAD patients (P0.05). The expression of HOXA4 and HOXA5 in LUAD were negatively correlated with tumor purity and positively correlated with the infiltration of various immune cells such as B cells, T cells and macrophages. HOXA4 and HOXA5 overexpression had notable inhibitory effect on the proliferation, migration and invasion of LUAD cells.In conclusion, the identified downexpressed HOXA4 and HOXA5 had significant distinguishing ability for LUAD samples and affected the cellular functions of LUAD cells. The low expression of HOXA5 indicated worse overall survival of LUAD patients. Therefore, the two HOXA family genes especially HOXA5 may serve as potential biomarkers for LUAD.

Nanomaterials show great potential for the treatment of bacterial infections, but their effects remain limited by low antibacterial efficiency and immune clearance. Facet-dependent nanozymes coated with pathogen receptor membranes were fabricated, providing an approach for producing superphotothermal antibacterial nanomaterials with high biocompatibility and low immune clearance. (100)- and (112)-Faceted CuFeSe2 presented excellent photothermal conversion efficiency (46%). However, the peroxidase-like activity of (100)-faceted CuFeSe2 enhanced the decomposition of H2O2 to hydroxyl radicals (•OH) and was markedly greater than that of (112)-faceted CuFeSe2, with nearly 100% of Staphylococcus aureus being killed under near-infrared (NIR) irradiation. Importantly, bacteria-pretreated immune membranes (i.e., pathogen receptor membranes) coated with CuFeSe2 exhibited superior S. aureus-binding ability, presented obvious immune-evading capability, and resulted in targeted delivery to infected sites. As a proof-of-principle demonstration, these findings hold promise for the use of pathogen receptor membrane-coated facet-dependent nanomaterials in clinical applications and the treatment of bacterial infections.

As a non-thermal ablation method, irreversible electroporation (IRE) has been widely investigated in the treatment of prostate cancer. However, no consensus has been achieved on the optimal parameters of IRE for prostate cancer. Since high voltage is known to carry risks of muscle contraction and patient discomfort, it is crucial to identify the minimum but effective and safer applied voltage to inhibit tumor growth. In this study, the effect of different applied voltages of IRE on prostate cancer was evaluated in BALB/c nude mice. Mathematical simulation and measurement of the actual ablation area revealed a larger ablation area at a higher voltage. In in vivo experiment, except for the three different voltages applied, all groups received identical electrical conditions: pulse number, 180 (20 groups × 9 pulses/group); pulse width, 100 µs; pulse interval, 2 ms; distance between the electrodes, 5 mm; and electrode exposure length, 15 mm. Whilst the tumor volume initially decreased in the 500 V (1000 V/cm) and 700 V (1400 V/cm) groups and subsequently increased, only a transient increase followed by a continuous decrease until the sacrifice was observed in the 900 V (1800 V/cm) group. This result demonstrated a lasting effect of a higher applied voltage on tumor growth inhibition. The histological, immunohistochemical, and western blot findings all confirmed IRE-induced apoptosis in the treatment groups. Taken together, 900 V seemed to be the minimum applied voltage required to reduce tumor growth, though subsequent studies are anticipated to further narrow the voltage intervals and lower the minimum voltage required for tumor inhibition.

Glioblastoma (GBM) is an aggressive primary brain tumor with unique immunity predominated by myeloid cells. GBM cells have been implicated to evade immune attack through hijacking myeloid-affiliated transcriptional programs to establish an immunosuppressive microenvironment. However, molecular features of immune-evading GBM cells in heterogeneous GBMs and their interactions with immune cells remain unclear. Herein, we employed single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to develop an in silico method for delineating GBM immune signature and identifying new molecular subsets for immunotherapy. We identified a new GBM cell subset, termed TC-6, that harbored immune-invading signature and actively interacted with tumor-associated macrophages (TAMs) to orchestrate an immune-suppressive niche. Proinflammatory transcriptional factors STAT1, STAT2, IRF1, IRF2, IRF3, and IRF7 were identified as the core regulons defining TC-6 subsets. Further immune transcriptome analyses revealed three immune subtypes (C1, C2, and C3). C3 subtype GBMs were enriched with TC-6 cells and immunosuppressive TAMs, and exhibited an immunomodulatory signature that associated with reduced efficacy of anti-PD-1 treatment. Interferon-related DNA damage resistance signaling was upregulated in C3 GBMs, predicting shortened survival of GBM patients who received chemo-radiation treatment. Treatment of OSI-930 as a molecular agent targeting c-kit and VEGFR2 tyrosine kinases may compromise the immunomodulatory signature of C3 GBMs and synergize with chemo-radiation therapy. We further developed a simplified 11-gene set for defining C3 GBMs. Our work identified TC-6 subset as an immune-evading hub that creates an immunomodulatory signature of C3 GBMs, gaining insights into the heterogeneity of GBM immune microenvironment and holding promise for optimized anti-GBM immunotherapy.

We aimed to determine prevalence and characteristics of anticardiolipin antibodies (ACLs) and its correlations with laboratory coagulation variables in patients with coronavirus disease 2019 (COVID-19). We retrospectively analyzed the prevalence of serum ACLs and its correlation with coagulative laboratory variables in 87 patients with COVID-19. ACLs were detected in 13/21 (61.91%) critically ill patients, and 21/66 (31.82%) in non-critically ill patients. For ACLs, IgA, and IgG were the most common types. The prevalence of IgG in critical ill patients was much higher than that in non-critical patients with odd ratio = 2.721. And the levels of all isotypes of ACLs in critically ill patients were much higher than those in non-critically ill patients. Correlation analysis showed that activated partial thromboplastin time and thrombin time had weak correlation with ACLs-IgG (R = 0.308, P = .031; R = 0.337, P = .018, respectively). Only the prevalence of ACLs-IgG shows a significant difference when compared critically ill patients with non-critically ill patients. ACLs do not seem to have a clear correlation with thrombosis occurred in COVID-19 patients.

Pancreatic cancer is one of the most common malignancies with very poor prognosis due to its broad resistance to chemotherapy. ARID1A, a subunit of SWI/SNF complex, is involved in pancreatic carcinogenesis through epigenetic silencing of oncogenes. In this study, we aimed to explore whether ARID1A was implicated in the gemcitabine resistance in pancreatic cancer patients via regulating RRM2. We examined the effect of ARID1A depletion on the gemcitabine sensitivity in pancreatic cancer cells and explored the role of RRM2 in ARID1A-mediated pancreatic cancer cells chemosensitivity to gemcitabine. We found that Knockout of ARID1A led to gemcitabine resistance in pancreatic cancer cells, effect of which could be reversed by RRM2, a gemcitabine resistance related gene. ARID1A decreased the transcription of RRM2, and directly bound to the promoter of RRM2. Moreover, expression of RRM2 was negatively correlated with ARID1A in pancreatic cancer tissues. Thus, ARID1A-mediated RRM2 epigenetic suppression is crucial for enhancement of pancreatic cancer chemosensitivity to gemcitabine, and ARID1A could be used as a biomarker to guide the gemcitabine chemotherapy of pancreatic cancer.

BACKGROUND: This study explored the effects of multi-component exercise training on the physical and cognitive function of the elderly with mild cognitive impairment (MCI). METHODS: A total of 90 older adults with MCI were chosen from screened volunteers and randomly assigned into 2 groups (n=45), and 84 completed the 6-month follow-up. Participants in the control group received general community health instruction, while the multi-component exercise training performed on the other group. The multi-component exercise training performed on these participants was designed to suit Chinese elderly based on advice from the nursing specialist and sports medicine specialist after the preliminary experiment. The Chinese version Mini-Physical Performance Test (CM-PPT), the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA) scores were examined by repeated measures analysis of variance to evaluate the physical and cognitive function of adults with MCI before and at 3 and 6 months after the intervention. The follow-up data collectors were blinded to group allocation. P

To explore the degradation, drug release, and mechanical properties of drug-incorporated films made of different ratios of poly(lactic-co-glycolic acid) (PLGA) and different amounts of paclitaxel (PTX), which may serve as the material platform for the manufacturing of biodegradable drug-eluting biliary stents. PLGA of different lactic acid/glycolic acid ratios (50/50, 70/30, and 80/20) and 0%, 10, 20, and 30% weight by weight (w/w) PTX was mixed to make PLGA films, which were then cut into small pieces for further testing. Films were immersed in phosphate-buffered saline (pH 7.4) for a maximum of 11 weeks. Samples were taken randomly at Day 2, 4, 6, 8, 10, 12, 14, and weekly thereafter until Week 11 to test tensile strength, weight loss, pH value of the soaking solution, and drug release. The morphology of films was observed using scanning electron microscope (SEM). At Week 10 of degradation, PLGA 80/20 still withstood a tensile strength of 9.7 newton (N), while PLGA 50/50 and 70/30 cracked spontaneously since Day 4. At Week 11, weight loss of PLGA 50/50, 70/30, and 80/20 was 95.15, 82.32, and 16.17%, respectively; and the lowest pH value of soaking solution was 1.87, 1.95, and 6.58, respectively. Drug release of 10, 20, and 30% PTX groups was 3.52–4.48%, 1.90–2.26%, and 1.44–2.06%, respectively. SEM proved smooth films before degradation; however, after the tensile strength was lost, cracks could be seen. The degradation rate of PLGA can be controlled by altering lactic acid/glycolic acid ratio. Overall, PLGA 50/50 and 70/30 degrade significantly faster than 80/20. PLGA can serve as an effective drug carrier for PTX while being the stent strut, and PTX can be slowly released as PLGA degrades.

Purpose To evaluate the current status of women interventional radiologists in China and discuss possible measures to boost their representation in this male-dominated field for a more diverse workplace environment in the future. Materials and Methods The list of Chinese interventional radiologists obtained from the Chinese College of Interventionalists was retrospectively reviewed. Key information was extracted from the database, including sex, chronologic trends of representation of women interventional radiologists, position, education level, geographic distribution, interventional radiology (IR) practice time, departmental affiliation, and hospital classification. Results Of the 13,855 entries, 7,324 (52.9%) were interventional radiologists having valid information. Among them, 684 (9.3%) were identified as women. The number of women interventional radiologists has continued to increase since the first woman registered in 1992. The average age of women interventional radiologists was 39.1 years ± 5.7 (range, 26–50). The majority of them were attending physicians (n = 280; 40.9%) with a bachelor’s degree (n = 363; 53.1%). Most women interventional radiologists (n = 215, 31.4%) joined this specialty 5–9 years after becoming physicians, whereas 128 (18.7%) started practicing IR from the very beginning. A total of 42.4% of women interventional radiologists were from the departments of IR and cardiology. Conclusions Although the total number shows an upward trend, women interventional radiologists are still underrepresented. Education level, geographic areas, and other socioeconomic factors may simultaneously influence the population size of women interventional radiologists in China.

Brucellosis is a severe zoonotic infectious disease caused by the infection of the

The large-scale production and frequent use of endocrine-disrupting chemicals (EDCs) have led to the continuous release and wide distribution of these pollutions in the natural environment. At low levels, EDC exposure may cause metabolic disorders, sexual development, and reproductive disorders in aquatic animals and humans. Adsorption treatment, particularly using nanocomposites, may represent a promising and sustainable method for EDC removal from wastewater. EDCs could be effectively removed from wastewater using various carbon-based nanomaterials, such as carbon nanofiber, carbon nanotubes, graphene, magnetic carbon nanomaterials, carbon membranes, carbon dots, carbon sponges, etc. Important applications of carbon nanocomposites for the removal of different kinds of EDCs and the theory of adsorption are discussed, as well as recent advances in carbon nanocomposite synthesis technology and characterization technology. Furthermore, the factors affecting the use of carbon nanocomposites and comparisons with other adsorbents for EDC removal are reviewed. This review is significant because it helps to promote the development of nanocomposites for the decontamination of wastewater.

Purpose Our aim is to analyze the clinical characteristics and prognostic factors of Epstein-Barr (EB) virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in children. Methods Children with newly diagnosed HLH were retrospectively analyzed. Results Finally, a total of 95 children with HLH were enrolled in this study, including 43 (45.3%) with EBV-HLH and 52 (54.7%) with non-EBV-HLH. Laboratory tests showed that the levels of absolute neutrophil count (ANC) decrease (P = 0.031) and triglycerides (TG) increase (P = 0.036) in the EBV-HLH group were statistically significant compared with those in the non-EBV-HLH group, respectively. We found that the remission rate during induction period in the EBV-HLH group and non-EBV-HLH group was 75.8% and 89.3%, respectively. The correlation analysis showed that the elevated degree of total bilirubin (TBIL) (P = 0.042), triglyceride (TG) (P = 0.009), serum ferritin (SF) (P = 0.008) and interleukin-8 (IL-8) (P = 0.004) were related with the remission rate during induction in the EBV-HLH group. Further univariate analysis showed that the elevated degree of TBIL (P = 0.048) and TG (P = 0.019) were significant risk factors for the remission rate during induction in the EBV-HLH group. In the multivariate analysis, we observed that there was statistical significance for the degree of TG elevation (P = 0.015) between the two groups. The correlation analysis showed that the elevated degree of TBIL (P = 0.030), the elevated degree of SF (P = 0.020) and the elevated degree of interleukin-6 (P = 0.010) were related to the induction mortality of children with EBV-HLH. Conclusion TBIL and TG are valid indicators to assess the efficacy and prognosis of EVBHLH among children in induction period.

Background Vascular endothelial growth factor D (VEGFD), a member of the VEGF family, is implicated in angiogenesis and lymphangiogenesis, and is deemed to be expressed at a low level in cancers. S-nitrosylation, a NO (nitric oxide)-mediated post-translational modification has a critical role in angiogenesis. Here, we attempt to dissect the role and underlying mechanism of S-nitrosylation-mediated VEGFD suppression in lung adenocarcinoma (LUAD). Methods Messenger RNA and protein expression of VEGFD in LUAD were analyzed by TCGA and CPTAC database, respectively, and Assistant for Clinical Bioinformatics was performed for complex analysis. Mouse models with urethane (Ure)–induced LUAD or LUAD xenograft were established to investigate the role of S-nitrosylation in VEGFD expression and of VEGFD mutants in the oncogenesis of LUAD. Molecular, cellular, and biochemical approaches were applied to explore the underlying mechanism of S-nitrosylation-mediated VEGFD suppression. Tube formation and wound healing assays were used to examine the role of VEGFD on the angiogenesis and migration of LUAD cells, and the molecular modeling was applied to predict the protein stability of VEGFD mutant. Results VEGFD mRNA and protein levels were decreased to a different extent in multiple primary malignancies, especially in LUAD. Low VEGFD protein expression was closely related to the oncogenesis of LUAD and resultant from excessive NO-induced VEGFD S-nitrosylation at Cys277. Moreover, inhibition of S-nitrosoglutathione reductase consistently decreased the VEGFD denitrosylation at Cys277 and consequently promoted angiogenesis of LUAD. Finally, the VEGFDC277S mutant decreased the secretion of mature VEGFD by attenuating the PC7-dependent proteolysis and VEGFDC277S mutant thus reversed the effect of VEGFD on angiogenesis of LUAD. Conclusion Low-expression of VEGFD positively correlates with LUAD development. Aberrant S-nitrosylation of VEGFD negates itself to induce the tumorigenesis of LUAD, whereas normal S-nitrosylation of VEGFD is indispensable for its secretion and repression of angiogenesis of LUAD.

Introduction: We aimed to explore the abnormal expression of dual-specificity protein phosphatase 1 (DUSP1) and its latent molecular mechanisms in ovarian carcinoma (OVCA).Materials and Methods: Two clinical cohorts collected from two different hospitals were used to evaluate the expression of DUSP1 protein in OVCA tissues. RNA-sequencing and microarray datasets were utilised to verify DUSP1 expression at mRNA levels in both OVCA tissues and in the peripheral blood of OVCA patients. Furthermore, an integrated calculation was performed to pool the standard mean difference (SMD) from each cohort in order to comprehensively assess the expression of DUSP1 in OVCA. Furthermore, we examined the relationship among DUSP1, tumour microenvironment (TME), and chemotherapy resistance in OVCA. Moreover, we used pathway enrichment analysis to explore the underlying mechanisms of DUSP1 in OVCA.Results: A pooled SMD of −1.19 (95% CI [−2.00, −0.38], p = 0.004) with 1,240 samples revealed that DUSP1 was downregulated in OVCA at both mRNA and protein levels. The area under the receiver operating characteristic curve of 0.9235 indicated the downregulated DUSP1 in peripheral blood may have a non-invasive diagnostic value in OVCA. Through six algorithms, we identified that DUSP1 may related to tumour-infiltrating T cells and cancer associated fibroblasts (CAFs) in OVCA. Pathway enrichment demonstrated that DUSP1 might participate in the mitogen-activated protein kinase (MAPK) signalling pathway. Furthermore, DUSP1 may have relations with chemotherapy resistance, and a favourable combining affinity was observed in the paclitaxel-DUSP1 docking model.Conclusion: DUSP1 was downregulated in OVCA, and this decreasing trend may affect the infiltration of CAFs. Finally, DUSP1 may have a targeting relation with paclitaxel and participate in MAPK signaling pathways.

To investigate the molecular pathogenesis of two coagulation factor Ⅺ (FⅪ) deficiency patients.Coagulant assays: activated partial thromboplastin time (APTT), normal pooled-plasma corrected APTT test, PT, PT-INR and one-stage assay of coagulation factors activities were validated to diagnose coagulation factor Ⅺ deficiency. The patients' DNA samples were extracted and all exons and flanking sequences of F11 gene were amplified using PCR. After purified, the products of PCR were sequenced directly, the mutations were detected by comparing with wild sequences and analyzed using some bio-informatics softwares.The two patients were diagnosed with coagulation factor Ⅺ deficiency due to prolonged APTT, corrected APTT and low activities of coagulation factor FⅪ. The results of APTT, FⅪ: C were 88.1s, 1.1% and 107.1s, 3.8%, and the prolonged APTT could be corrected to normal range 32.9 s and 31.5 s, respectively. Through genetic analysis, we discovered compound heterozygous mutations g.1305-1GA and g.1325delT in patient 1 and the sequencing results of TA plasmid clones showed that the two mutations were located on different strands of chromosomes. Compound heterozygous mutations g.1124AG and g.1550CG were detected in patient 2 resulting in Lys357Arg and Cys482Trp. Software analysis indicated the mutations probably brought amino acid sequence changed, protein features affected and splice site changed.Compound heterozygous mutations g.1305-1GA, g.1325delT and g.1124AG, g.1550CG had been identified in two coagulation factor Ⅺ deficiency patients which might be responsible for their prolonged APTT and low FⅪ: C. To the best of our knowledge, g.1325delT and g.1550CG have been reported, while g.1124AG and g.1305-1GA are reported for the first time in the literature.

BackgroundPublished findings suggest sex differences in lung cancer risk and a potential role for sex steroid hormones. Our aim was to perform a meta-analysis to investigate the effects of sex steroid hormone exposure specifically on the risk of lung cancer in women.MethodsThe PubMed, MEDLINE, Web of Science, and EMBASE databases were searched. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for female lung cancer risk associated with sex steroid hormones were calculated overall and by study design, publication year, population, and smoking status. Sensitivity analysis, publication bias, and subgroup analysis were performed.ResultsForty-eight studies published between 1987 and 2019 were included in the study with a total of 31,592 female lung cancer cases and 1,416,320 subjects without lung cancer. Overall, higher levels of sex steroid hormones, both endogenous (OR: 0.92, 95% CI: 0.87–0.98) and exogenous (OR: 0.86, 95% CI: 0.80–0.93), significantly decreased the risk of female lung cancer by 10% (OR: 0.90, 95% CI: 0.86–0.95). The risk of lung cancer decreased more significantly with a higher level of sex steroid hormones in non-smoking women (OR: 0.88, 95% CI: 0.78–0.99) than in smoking women (OR: 0.98, 95% CI: 0.77–1.03), especially in Asia women (OR: 0.84, 95% CI: 0.74–0.96).ConclusionsOur meta-analysis reveals an association between higher levels of sex steroid hormone exposure and the decreased risk of female lung cancer. Surveillance of sex steroid hormones might be used for identifying populations at high risk for lung cancer, especially among non-smoking women.

Anti-double-stranded DNA (anti-dsDNA) is closely associated with the inflammatory burden in the brain after ischemic stroke. Here, we studied the inflammatory cascade and investigated the mechanisms behind the pro-inflammatory role of dsDNA in systemic lupus erythematosus (SLE). The serum levels of interleukin-1beta (IL-1β) and IL-6 in SLE patients and the corresponding controls were evaluated using ELISA, and the expression level of caspase-1 was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). We found that the serum levels of IL-1β and IL-6 were increased in the SLE patients. The expression of caspase-1 was upregulated and positively correlated with the levels of pro-inflammatory factors. The level of anti-dsDNA was also elevated and positively correlated with the results for the mean fluorescence intensity (MFI) of caspase-1. Additionally, we evaluated the functions of PRKCD encoding protein kinase c delta (PKCδ) and NLRC4, in vivo, in MRL/Faslpr mice. We found that renal injury was aggravated, and the levels of pro-inflammatory factors were increased in the MRL/Faslpr mice. We also found that increased levels of NLRC4 in the mice exacerbated renal injury and increased the levels of pro-inflammatory factors, whereas inhibition of PKCδ had the opposite results. These findings provide unique perspectives on pathogenesis of SLE and indicate that inhibition of anti-dsDNA could attenuate renal inflammatory burden, representing a promising therapeutic opportunity for SLE.

Adenosine-to-inosine (A-to-I) RNA editing is a widespread posttranscriptional modification that has been shown to play an important role in tumorigenesis. Here, we evaluated a total of 19,316 RNA editing sites in the tissues of 80 lung adenocarcinoma (LUAD) patients from our Nanjing Lung Cancer Cohort (NJLCC) and 486 LUAD patients from the TCGA database. The global RNA editing level was significantly increased in tumor tissues and was highly heterogeneous across patients. The high RNA editing level in tumors was attributed to both RNA (ADAR1 expression) and DNA alterations (mutation load). Consensus clustering on RNA editing sites revealed a new molecular subtype (EC3) that was associated with the poorest prognosis of LUAD patients. Importantly, the new classification was independent of classic molecular subtypes based on gene expression or DNA methylation. We further proposed a simplified model including eight RNA editing sites to accurately distinguish the EC3 subtype in our patients. The model was further validated in the TCGA dataset and had an area under the curve (AUC) of the receiver operating characteristic curve of 0.93 (95%CI: 0.91-0.95). In addition, we found that LUAD cell lines with the EC3 subtype were sensitive to four chemotherapy drugs. These findings highlighted the importance of RNA editing events in the tumorigenesis of LUAD and provided insight into the application of RNA editing in the molecular subtyping and clinical treatment of cancer.

Limited value is achieved in systemic chemotherapy for oral squamous cell carcinoma (OSCC), due to cancer cell resistance against cytotoxic agents. Tumor suppressor activities of selenium-binding protein 1 (SELENBP1) have been shown in multiple human cancers except for OSCC. The aim of this study is to clarify the biological functions and potential mechanism of SELENBP1 in OSCC. SELENBP1 expression and its clinical significance in OSCC were analyzed from The Cancer Genome Atlas (TCGA) database. Quantitative polymerase chain reaction (qPCR) or western blot was applied to determine SELENBP1, NRF2 and KEAP1 mRNA or protein levels. Sulforhodamine B assay (SRB) was performed to examine the cytotoxic effects of 5-fluorouracil (5-FU) and cisplatin on OSCC cells. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to investigate the role of SELENBP1 in KEAP1 transcription. SELENBP1 downregulation is positively correlated with a poor prognosis for OSCC patients. SELENBP1 knockdown enhances resistance of OSCC cells to 5-FU and cisplatin, while SENENBP1 overexpression displays the opposite effects. Mechanistically, SELENBP1 reduces NRF2 protein levels by promoting its polyubiquitination and degradation. SELENBP1 induces KEAP1 transcription by binding to KEAP1 promoter. Downregulation of SELENBP1 is induced by miR-4786-3p binding to the 3′ untranslated region (UTR) of SELENBP1. SENENBP1 is identified as a novel protective biomarker for OSCC patients. Targeting at the miR-4786-3p–SELENBP1–KEAP1–NRF2 signaling axis may enhance the efficacy of chemotherapy for OSCC.

A chain-shattering polymeric SO2 prodrug micelle system was fabricated for effective SO2 delivery and redox-triggered SO2 based gas therapy of osteosarcoma.

Although a highHealthy subjects who underwent hospital health examinations in the hospital health management department from September 2020 to September 2021 were consecutively enrolled. Anthropometric and biochemical characteristics were measured, and all subjects underwent 13C UBT. Univariate and multivariate analyses were used to evaluate the factors associated withOf the 5007 participants included, the overall prevalence ofThese findings suggest that detailed and strict weight and glucose management is crucial to reduce the prevalence of H. pylori infection. Management strategies should be identified and implemented with regard to these identified factors to reduce the notable economic and healthcare burden in China.

Purpose: Our purpose was to systematically appraise the clinicopathological significance and explore the molecular bases of CKS2 in endometrial carcinoma.Patients and Methods: We measured the clinicopathological significance of CKS2 using diverse methods of public RNA-seq, microarrays, and in-house tissue microarrays to investigate the molecular basis of CKS2 in endometrial carcinoma through upstream transcriptional analysis, immune infiltration correlation analysis, and co-expression analysis.Results: Both the analysis for public RNA-seq plus the microarray data and in-house tissue microarray confirmed the significant overexpression of CKS2 in a total of 1,021 endometrial carcinoma samples compared with 279 non-cancer endometrium samples (SMD = 2.10, 95% CI = 0.72–3.48). The upregulated CKS2 was significantly related to the lymph node metastasis and advanced clinical grade of endometrial carcinoma patients (p < 0.001). Mutation types such as amplification and mRNA occurred with high frequency in the CKS2 gene in endometrial carcinoma patients. A series of miRNAs and transcription factors, such as hsa-miR-26a, hsa-miR-130a, hsa-miR-30, E2F4, MAX, and GABPA, were predicted to regulate the transcription and expression of CKS2. Significant links were found between CKS2 expression and the infiltration level of B cells, CD4+ T cells, and neutrophils in endometrial carcinoma. CKS2-coexpressed genes were actively involved in pathways such as the mitotic cell cycle process, PID aurora B pathway, and prolactin signaling pathway.Conclusion: The overexpressed CKS2 showed positive correlations with the clinical progression of endometrial carcinoma and was associated with various cancer-related biological processes and pathways, showing potential as a promising clinical biomarker for endometrial carcinoma.

Current industrial development has led to an increase in sulfate-rich industrial sewage, threatening industrial ecology and the environment. Incorrectly treating high-concentration sulfate wastewater can cause serious environmental problems and even harm human health. Water with high sulfate levels can be treated as a resource and treated harmlessly to meet the needs of the circular economy. Today, governments worldwide are working hard to encourage the safe disposal and reuse of industrial salt-rich wastewater by recycling sulfate-rich wastewater (SRW) resources. However, the conflict of interests between the SRW production department, the SRW recycling department, and the governments often make it challenging to effectively manage sulfate-rich wastewater resources. This study aims to use the mechanism of evolutionary game theory (EGT) to conduct theoretical modelling and simulation analysis on the interaction of the behaviour of the above three participants. This paper focuses on the impact of government intervention and the ecological behaviour of wastewater producers on the behavioural decisions of recyclers. The results suggest that the government should play a leading role in developing the SRW resource recovery industry. SRW producers protect the environment in the mature stage, and recyclers actively collect and recover compliant sulfate wastewater resources. Governments should gradually deregulate and eventually withdraw from the market. Qualified recyclers and environmentally friendly wastewater producers can benefit from a mature SRW resources recovery industry.

Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.

Individuals with metabolic dysregulation of cellular glycosylation often experience severe influenza disease, with a poor immune response to the virus and low vaccine efficacy. Here, we investigate the consequences of aberrant cellular glycosylation for the glycome and the biology of influenza virus. We transiently induced aberrant N-linked glycosylation in cultured cells with an oligosaccharyltransferase inhibitor, NGI-1. Cells treated with NGI-1 produced morphologically unaltered viable influenza virus with sequence-neutral glycosylation changes (primarily reduced site occupancy) in the hemagglutinin and neuraminidase proteins. Hemagglutinin with reduced glycan occupancy required a higher concentration of surfactant protein D (an important innate immunity respiratory tract collectin) for inhibition compared to that with normal glycan occupancy. Immunization of mice with NGI-1-treated virus significantly reduced antihemagglutinin and antineuraminidase titers of total serum antibody and reduced hemagglutinin protective antibody responses. Our data suggest that aberrant cellular glycosylation may increase the risk of severe influenza as a result of the increased ability of glycome-modified influenza viruses to evade the immune response.

As extremely active sites processing terrestrially derived dissolved organic matter (DOM), lakes deserve sufficient attention. Because of high-complexity interactions between DOM and the surrounding environment, the natural and anthropogenic drivers controlling the composition and chemodiversity of DOM molecules in lakes remain unclear. Here, 13,952 DOM molecules were identified and assessed in 45 lakes across China via ultrahigh-resolution mass spectrometry. Furthermore, the effects of both natural and anthropogenic factors on the DOM composition, DOM chemodiversity, and greenhouse gas emissions were investigated. The majority of the variations in DOM chemical composition could be attributed to the differences in the hydrology and nutrient concentrations of the lakes, and human activities also played a role, mainly through atmospheric pollution. Environmental factors mainly influenced DOM chemodiversity in the form of S-containing compounds. N-containing compounds exhibited a positive correlation with CO

The development of the embryonic lung demands complex endodermal–mesodermal interactions, which are regulated by a variety of signaling proteins. Hedgehog (Hh) signaling is vital for lung development. It plays a key regulatory role during several morphogenic mechanisms, such as cell growth, differentiation, migration, and persistence of cells. On the other hand, abnormal expression or loss of regulation of Hh signaling leads to airway asthmatic remodeling, which is characterized by cellular matrix modification in the respiratory system, goblet cell hyperplasia, deposition of collagen, epithelial cell apoptosis, proliferation, and activation of fibroblasts. Hh also targets some of the pathogens and seems to have a significant function in tissue repairment and immune-related disorders. Similarly, aberrant Hh signaling expression is critically associated with the etiology of a variety of other airway lung diseases, mainly, bronchial or tissue fibrosis, lung cancer, and pulmonary arterial hypertension, suggesting that controlled regulation of Hh signaling is crucial to retain healthy lung functioning. Moreover, shreds of evidence imply that the Hh signaling pathway links to lung organogenesis and asthmatic airway remodeling. Here, we compiled all up-to-date investigations linked with the role of Hh signaling in the development of lungs as well as the attribution of Hh signaling in impairment of lung expansion, airway remodeling, and immune response. In addition, we included all current investigational and therapeutic approaches to treat airway asthmatic remodeling and immune system pathway diseases.

The endogenous hydrogen sulfide (H

Acute myeloid leukemia (AML) is a hematological malignancy with high incidence and recurrence rates. Gene expression profiling has revealed that transcriptional overexpression of glioma‐associated oncogene 1 (GLI1), a vital gene in the Hedgehog (Hh) signaling pathway, occurs in poor-prognosis AML, and high levels of phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1) and AKT3 predict shorter overall survival in AML patients. In this study, we discovered that GLI1 overexpression promotes cell proliferation and reduces chemotherapy sensitivity in AML cells while knocking down GLI1 has the opposite effect. Moreover, GLI1 promoted cell cycle progression and led to elevated protein levels of cyclins and cyclin-dependent kinases (CDKs) in AML cells. By luciferase assays and co-immunoprecipitation, we demonstrated that the PI3K/AKT pathway is directly activated by GLI1. GLI1 overexpression significantly accelerates tumor growth and upregulated p-AKT, CDK4, and cyclinD3 in vivo. Notably, the GLI1 inhibitor GANT61 and the CDK4/6 inhibitor PD 0332991 had synergistic effects in promoting Ara-c sensitivity in AML cell lines and patient samples. Collectively, our data demonstrate that GLI1 reduces drug sensitivity by regulating cell cycle through the PI3K/AKT/GSK3/CDK pathway, providing a new perspective for involving GLI1 and CDK4/6 inhibitors in relapsed/refractory (RR) patient treatment.

Background introduction Nail injuries are important causes of penetrating craniocerebral injuries. Theirs incidence is very low, but the injuries can be fatal. Since the nail gun was gradually popularized in 1959, the incidence of nail injuries has been increasing. Here we report a case of nail gun injury to superior sagittal sinus and review the literature of the past 60 years to find out what are the possible factors of nail gun injury and what are their respective ratios? Clinical report An 18-year-old male patient was accidentally injured in the head by the worker's nail gun, accompanied by scalp pain, no physical sensation disorder, and consciousness disorder. A computed tomography scan of his skull showed the penetrating site at the right frontal area, near the superior sagittal sinus. Seven days later, the patient underwent a successful surgery without neurological sequelae. Discussion Nail injuries are rare, but can be potentially fatal. We found that nail guns were the main cause of nail injuries, and other causes include occupational injury, violence, lack of supervision of young children (potential for domestic violence, and child abuse), mental illness, and suicide attempts. While paying attention to the anatomical location of trauma, clinicians should also think more about the possibility of injury so as to provide better help to patients in time.

Triptolide, a component of the Chinese herb Tripterygium wilfordii Hook F, has been proved to be effective in the treatment of rheumatoid arthritis (RA). However, its underlying mechanisms on RA have not yet been well established. We observed the inhibitory effect of triptolide on the expression of inflammatory cytokines and proliferation of fibroblast-like synoviocytes (FLS) induced by the complex of interleukin-6 (IL-6) and the soluble form of the IL-6 receptor (sIL-6R). Furthermore, to clarify the underlying mechanisms, we treated FLS with the Janus-activated kinase 2 (JAK2) inhibitor/signal transducer and activator of transcription 3 (STAT3) activation blocker AZD1480. In this study, immunohistochemical staining was used to identify vimentin (+) and CD68 (-) in FLS. The FLS proliferation was measured by cell proliferation assay, and the cell cycles were analyzed by flow cytometry. Furthermore, ELISA was used to detect the expression of the inflammatory factors in culture solution. The expression levels of p-JAK2, JAK2, p-STAT3 and STAT3 were investigated through Western blotting analysis. The results showed that IL-6/sIL-6R significantly increased the cell proliferation and expression of inflammatory cytokines, including IL-6, interleukin-1β (IL-1β) and vascular endothelial growth factor (VEGF). Triptolide or AZD1480 inhibited the cell proliferation and inflammatory cytokine expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3. The study suggested that the physiological effects of triptolide on RA were due to its contribution to the inhibition of the inflammatory cytokine expression and FLS proliferation by suppressing the JAK2/STAT3 signaling pathway. It may provide an innovative insight into the effect of triptolide in preventing RA pathogenesis.

Targeted therapy has stepped into the perioperative treatment arena and launched a radical revolution in the treatment of early-stage oncogene-driven non-small-cell lung cancer (NSCLC). A series of practice-changing clinical trials has enriched the therapeutic perspectives of potentially curable NSCLC. While the CTONG1104 trial took the first step in investigating the adjuvant gefitinib - a first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), for the treatment of resected EGFR-mutated NSCLC - the subsequent ADAURA study marked adjuvant osimertinib as the standard of care for resected EGFR-mutant NSCLC. Other targeted agents matched for ALK, ROS1, NTRK, BRAF V600, and RET molecular alterations are also currently being evaluated in the adjuvant and neoadjuvant settings, and there is an urgent need to study biomarker selection, optimal duration, and paradigm making. All these efforts are intended to hit the same target, which is to treat patients on a more personalized level. We review herein the recent major breakthroughs in perioperative targeted therapy for oncogene-driven NSCLC, focusing especially on data from published clinical trials. We discuss challenges from surgical, pathological, and oncological perspectives, and provide recommended strategies for the clinical management of early-stage NSCLC patients.

Background. Currently, the benefits of nasopharyngeal carcinoma (NPC) therapy are limited, and it is necessary to further explore possible therapeutic targets. Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) has been extensively studied in other cancer species, but little has been explored in NPC. The aim of this study was to verify the expression level of ARNT2 and its underlying mechanism in NPC. Methods. Datasets containing ARNT2 mRNA expression levels were retrieved and collected from various databases to explore the expression status of ARNT2 in NPC. ARNT2-related coexpressed genes, differential expressed genes, and target genes were obtained for functional enrichment analysis. The potential target gene of ARNT2 and their regulatory relationship were studied through ChIP-seq data. CIBERSORTx was used to assess the immune infiltration of NPC, and the association with ARNT2 expression was calculated through correlation analysis. Results. ARNT2 was upregulated and possessed an excellent discriminatory capability in NPC samples. ARNT2 positively correlated target genes were clustered in pathways in cancer, while negatively correlated target genes were enriched in immune-related pathway. The ChIP-seq information of ARNT2 and histone showed that prostaglandin-endoperoxide synthase 2 (PTGS2) was a potential target gene of ARNT2. CIBERSORTx revealed the immunity status in NPC, and ARNT2 expression was correlated with infiltration of five immune cells. Conclusions. ARNT2 is overexpressed in NPC and may regulate PTGS2 to participate in the cancer process. ARNT2 serves as a key oncogenic target in NPC patients.

Background With the improved knowledge of disease biology and the introduction of immune checkpoints, there has been significant progress in treating renal cell carcinoma (RCC) patients. Individual treatment will differ according to risk stratification. As the clinical course varies in RCC, it has developed different predictive models for assessing patient’s individual risk. However, among other prognostic scores, no transparent preference model was given. MicroRNA as a putative marker shown to have prognostic relevance in RCC, molecular analysis may provide an innovative benefit in the prophetic prediction and individual risk assessment. Therefore, this study aimed to establish a prognostic-related microRNA risk score model of RCC and further explore the relationship between the model and the immune microenvironment, immune infiltration, and immune checkpoints. This practical model has the potential to guide individualized surveillance protocols, patient counseling, and individualized treatment decision for RCC patients and facilitate to find more immunotherapy targets. Methods Downloaded data of RCC from the TCGA database for difference analysis and divided it into a training set and validation set. Then the prognostic genes were screened out by Cox and Lasso regression analysis. Multivariate Cox regression analysis was used to establish a predictive model that divided patients into high-risk and low-risk groups. The ENCORI online website and the results of the RCC difference analysis were used to search for hub genes of miRNA. Estimate package and TIMER database were used to evaluate the relationship between risk score and tumor immune microenvironment (TME) and immune infiltration. Based on Kaplan-Meier survival analysis, search for immune checkpoints related to the prognosis of RCC. Results There were nine miRNAs in the established model, with a concordance index of 0.702 and an area under the ROC curve of 0.701. Nine miRNAs were strongly correlated with the prognosis (P Conclusions The established nine-miRNAs prognostic model has the potential to facilitate prognostic prediction. Moreover, this model was closely related to the immune microenvironment, immune infiltration, and immune checkpoint genes of RCC.

Background The role of pyroptosis-related genes (PRGs) in esophageal adenocarcinoma (EAC) remains unknown. Methods In this study, the first PRGs prognostic signature (PPS) of EAC was constructed based on the results of multivariate stepwise Cox regression analysis. Based on 1,047 samples of EAC and normal esophagus (NE), differentially expressed PRGs were selected for the establishment of the PPS. The discrimination effect of this PPS was detected by receiver operating characteristic curves, and the prognosis value of this PPS was determined through Cox regression analysis and Kaplan-Meier curves. Net benefits of the EAC patients from the nomogram (constructed based on the PPS and some clinical parameters) were assessed via decision curve analysis. The potential molecular mechanism of the PPS in EAC was explored via gene set enrichment analysis. The ability of PPS to distinguish EAC and NE was evaluated based on the results of summary receiver operating characteristic curves. Results The significant prognostic value of PPS can be observed at all of the training cohort, test cohort, and validation cohort, such as its independent risk role in the prognosis of the EAC patients (hazard ratio > 0; 95% CI not including 0). The positive net benefits of the nomogram for the EAC patients can be detected via decision curve analysis, and the potential molecular mechanism of the PPS in EAC is likely related to cell pyroptosis. Last, some of the PRGs (particularly CASP5) included in this PPS specifically support its feasibility for identifying EAC (area under the curves > 0.7). Conclusions The construction of this PPS in EAC enhances the present understanding of the relationship between PRGs and EAC, thus representing a novel approach to the clinical identification and management of EAC based on PRGs.

The current study was conducted to analyze the functions of blood neutrophils in transition cows and their association with postpartum mastitis risk as indicated by somatic cell counts (SCCs) in milk. Seventy-six healthy Holstein dairy cows were monitored from Week 4 prepartum to Week 4 postpartum. Five dairy cows with low SCCs (38 ± 6.0 × 103/mL) and five with high SCCs (3,753 ± 570.0 × 103/mL) were selected based on milk SCCs during the first three weeks of lactation. At Week 1 pre- and postpartum, serum samples were obtained from each cow to measure neutrophil extracellular trap (NET)-related variables, and blood neutrophils were collected for transcriptome analysis by RNA sequencing. The serum concentration of NETs was significantly higher (P < 0.05) in cows with high SCCs than in cows with low SCCs (36.5 ± 2.92 vs. 18.4 ± 1.73 ng/mL). The transcriptomic analysis revealed that the transcriptome differences in neutrophils between high- and low-SCC cows were mainly in cell cycle-related pathways (42.6%), including the cell cycle, DNA damage, and chromosomal conformation, at Week 1 prepartum. The hub genes of these pathways were mainly involved in both the cell cycle and NETosis. These results indicated that the formation of NETs in the blood of transition dairy cows was different between cows with low and high SCCs, which may be used as a potential indicator for the prognosis of postpartum mastitis risk and management strategies of perinatal dairy cows.

To investigate the efficacy and safety of dicycloplatin as chemotherapeutic regimen in transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).In this randomized, open-label, phase II trial, patients with unresectable HCC who were TACE treatment-naïve or experienced recurrence after surgical resection or ablation were enrolled at 7 centers in China from March 2019 to November 2019. Participants were randomly assigned (1:1:1) to receive TACE with chemotherapeutic regimen of dicycloplatin alone (group A1), dicycloplatin plus epirubicin (group A2), or epirubicin alone (group B). The primary endpoint was objective response rate (ORR). The secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety.The ORR at 6 months in group A1 (n = 22) was significantly better than that in group B (p = 0.093; 90% confidence interval [CI], 1.03-9.45). The DCR in group A1 was significantly higher than that in group B (p = 0.045; 90% CI, 1.29-12.88). There was no significant difference in DOR among the groups (p = 0.271). The median PFS were 6.00 and 3.05 months in groups A2 (n = 25) and B (n = 24), respectively (p = 0.061). Grade 3 or worse adverse events were similar among groups in the safety population (p = 0.173).TACE with dicycloplatin was comparably safe and well tolerable as epirubicin alone in patients with unresectable HCC. Compared with epirubicin alone, significant improvement in ORR and DCR when dicycloplatin was applied, as well as prolonged PFS when dicycloplatin plus epirubicin was applied, was generated.• To our knowledge, this is the first multicenter randomized trial to assess the efficacy and safety of TACE with dicycloplatin in patients with unresectable HCC. • This phase II trial showed that TACE with dicycloplatin alone or plus epirubicin was comparably safe and well tolerable as epirubicin alone. • Significant improvements in ORR, DCR when dicycloplatin was applied, and prolonged PFS when dicycloplatin plus epirubicin was applied were recorded compared with epirubicin alone.

Purpose. Skin cutaneous melanoma (SKCM) is one of the most malignant and aggressive cancers with poor prognosis due to its rapid progression towards metastasis. Thus, finding clinically relevant biomarkers for early diagnosis, prognosis, and therapy prediction is essential. This study focused on the identification of SLC25A13 as a novel biomarker for SKCM and is aimed at investigating the biological functions of solute carrier family 25 member 13 (SLC25A13) in the development of SKCM. Methods. GEPIA was used to analyze the diagnostic and prognostic values of SLC25A13 in SKCM using the TCGA dataset. PrognoScan was used to validate the prognostic value of SLC25A13 and its coexpressed genes in SKCM. TISIDB was established to reveal the relationship between the expression of SLC25A13 and immune infiltration in SKCM. The protein expression of SLC25A13 in SKCM was evaluated by the Human Protein Atlas. The signaling pathways and biological functions of SLC25A13 in SKCM were analyzed by LinkOmics. Metascape was applied to analyze the functional enrichment analysis of SLC25A13. Protein-protein interaction analysis of SLC25A13 was performed by GeneMANIA. Results. The mRNA and protein levels of SLC25A13 in the SKCM were much higher than those in the normal tissue. Furthermore, the overexpression of SLC25A13 predicts worse outcomes of SKCM patients. Moreover, the SLC25A13 expression was negatively correlated with the immune infiltration level of SKCM. The overexpression of SLC25A13 coexpressed genes, such as ACLY and AFG3L2, and SCL25A13 interacting genes also predicted the unfavorable prognosis of SKCM patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of SLC25A13 coexpressed genes showed that these genes are enriched in ATPase activity, cell cycle, mTOR, and VEGFA-VEGFR2 signaling pathways, which were relevant to tumor development and angiogenesis. Gene set enrichment analysis (GSEA) demonstrated that the SLC25A13 expression was related to infiltrating immune cells in SKCM. Conclusion. Our findings revealed that SLC25A13 might be a potential prognostic and therapeutic biomarker for SKCM.

The interaction of SIRPα with CD47 represents a major mechanism for preventing macrophage phagocytosis. However, CD47-independent mechanisms are poorly defined. Here, we report a critical role of SLAM family receptors (SFRs), ubiquitously expressed on hematopoietic cells and forming homotypic interactions, in constraining macrophage phagocytosis. We found that SFR deficiency triggered macrophage phagocytosis of hematopoietic cells, leading to severe rejection of donor hematopoietic graft in recipient mice. Specific SFR members, mainly SLAMF3 and SLAMF4, were identified as "don't eat me" receptors on macrophages. These receptors inhibited "eat me" signals, such as LRP1-mediated activation of mTOR and Syk, through SH2 domain-containing phosphatases. SFRs combined with, but were independent of, CD47 to mitigate macrophage phagocytosis, and the combined deletion of SFRs and CD47 resulted in hematopoietic cytopenia in mice. This SFR-mediated tolerance was compromised in patients with hemophagocytic lymphohistiocytosis, a syndrome characterized by inappropriate phagocytosis toward hematopoietic cells. Loss of SFRs potently elicited macrophage rejection of hematopoietic tumors. Deletion of SFRs also significantly enhanced the phagocytosis of CD19-positive hematopoietic targets by the macrophages expressing the chimeric CD19 antigen receptor. Therefore, SFR-mediated inhibition of macrophage phagocytosis is critical to hematopoietic homeostasis, and SFRs may represent previously unknown targets for tumor immunotherapy.

The lncRNA MIR4435-2 host gene (MIR4435-2HG) is located on human chromosome 2q13, and its expression is up-regulated in 18 tumors. MIR4435-2HG participates in 6 signaling pathways to promote tumorigenesis, including the TGF-β signaling pathway, Wnt/β-catenin signaling pathway, MDM2/p53 signaling pathway, PI3K/AKT signaling pathway, Hippo signaling pathway, and MAPK/ERK signaling pathway. MIR4435-2HG competitively binds with 20 miRNAs to form a complex ceRNA network, thereby regulating the expression of downstream target genes. The high expression of MIR4435-2HG is also closely related to the clinicopathological characteristics and poor prognosis of a variety of tumors. Also, the high expression of MIR4435-2HG in peripheral blood or serum has the value of predicting the risk of 9 tumors. In addition, MIR4435-2HG participates in the mechanism of action of three cancer drugs, including resveratrol for the treatment of lung cancer, cisplatin for non-small cell lung cancer and colon cancer, and carboplatin for triple-negative breast cancer. This article systematically summarizes the diagnostic and prognostic value of MIR4435-2HG in a variety of tumors and outlines the ceRNA network and signaling pathways related to MIR4435-2HG, which will provide potential directions for future MIR4435-2HG research.