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BackgroundGowing number of studies have demonstrated the association between gut microbiome and T2DM microvascular complications, however the causal relationship remains unclear. Therefore, we using the Mendelian randomization (MR) approach to investigate this causal relation.MethodsUsing gut microbiome data from the International MiBioGen Consortium genome-wide association study (GWAS) and T2DM microvascular complications data from the FinnGen Consortium GWAS to perform MR analyses. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs), the inverse variance weighting (IVW) method was used as the primary analysis method, and the results were tested for heterogeneity and horizontal pleiotropy.ResultsOur research identified that there are 5 known microbial species and 2 unknown microbial species in the gut microbiome that were causally related to T2DM retinopathy. Besides, three and seven known microbial species causal relationships between the gut microbiome and T2DM neuropathy and T2DM nephropathy, respectively.ConclusionsUsing MR methods, we demonstrated the causal relationship between gut microbiome and microvascular complications in T2DM, providing a new strategy for the prevention and treatment of it.

Abstract Cancer is a major cause of death globally, and traditional treatments often have limited efficacy and adverse effects. Immunotherapy has shown promise in various malignancies but is less effective in tumors with low immunogenicity or immunosuppressive microenvironment, especially sarcomas. Tertiary lymphoid structures (TLSs) have been associated with a favorable response to immunotherapy and improved survival in cancer patients. However, the immunological mechanisms and clinical significance of TLS in malignant tumors are not fully understood. In this review, we elucidate the composition, neogenesis, and immune characteristics of TLS in tumors, as well as the inflammatory response in cancer development. An in‐depth discussion of the unique immune characteristics of TLSs in lung cancer, breast cancer, melanoma, and soft tissue sarcomas will be presented. Additionally, the therapeutic implications of TLS, including its role as a marker of therapeutic response and prognosis, and strategies to promote TLS formation and maturation will be explored. Overall, we aim to provide a comprehensive understanding of the role of TLS in the tumor immune microenvironment and suggest potential interventions for cancer treatment.

The healing mechanism of traditional self-healing coatings can be divided into “extrinsic” and “intrinsic” types according to the reactants, among which intrinsic restorations can be recycled multiple times and have great potential for applications. But epoxy resin is difficult to achieve intrinsic healing process through secondary bonding and reaction between polymers owing to the high chain rigidity and cross-linking density. In this study, a composite coating combining both “extrinsic” and “intrinsic” healing methods has been fabricated by adding a novel polymer filler (MBT-PGMS), which was synthesized via grafting copolymerization of glycidyl-methacrylate, styrene, methyl-methacrylate and 2-mercaptobenzothiazole (MBT). Multiple analytical techniques have been used to characterize the structure and properties of fillers, and the effect on the anti-corrosion performance and self-healing efficiency of epoxy coatings in 3 wt.% NaCl solution has been studied by electrochemistry measurements and mechanical analysis. Results indicated that the intact coating containing MBT-PGMS (MBT-PGMS/EP) showed prominent corrosion resistance during the immersion of 90 days. Once the coating was scratched, the impedance of MBT-PGMS/EP increased gradually with increasing the immersion time, and reached the optimal performance as the filler amount at 5 wt.%, while the impedance modulus was about 2.8 × 108 Ω cm2 after immersion for 144 h. A dynamic crosslinking model in MBT-PGMS/EP has been proposed to explain the self-healing mechanism.

BackgroundSoft tissue sarcoma (STS) is a highly heterogeneous musculoskeletal tumor with a significant impact on human health due to its high incidence and malignancy. Long non-coding RNA (lncRNA) and Neutrophil Extracellular Traps (NETs) have crucial roles in tumors. Herein, we aimed to develop a novel NETsLnc-related signature using machine learning algorithms for clinical decision-making in STS.MethodsWe applied 96 combined frameworks based on 10 different machine learning algorithms to develop a consensus signature for prognosis and therapy response prediction. Clinical characteristics, univariate and multivariate analysis, and receiver operating characteristic curve (ROC) analysis were used to evaluate the predictive performance of our models. Additionally, we explored the biological behavior, genomic patterns, and immune landscape of distinct NETsLnc groups. For patients with different NETsLnc scores, we provided information on immunotherapy responses, chemotherapy, and potential therapeutic agents to enhance the precision medicine of STS. Finally, the gene expression was validated through real-time quantitative PCR (RT-qPCR).ResultsUsing the weighted gene co-expression network analysis (WGCNA) algorithm, we identified NETsLncs. Subsequently, we constructed a prognostic NETsLnc signature with the highest mean c-index by combining machine learning algorithms. The NETsLnc-related features showed excellent and stable performance for survival prediction in STS. Patients in the low NETsLnc group, associated with improved prognosis, exhibited enhanced immune activity, immune infiltration, and tended toward an immunothermal phenotype with a potential immunotherapy response. Conversely, patients with a high NETsLnc score showed more frequent genomic alterations and demonstrated a better response to vincristine treatment. Furthermore, RT-qPCR confirmed abnormal expression of several signature lncRNAs in STS.ConclusionIn conclusion, the NETsLnc signature shows promise as a powerful approach for predicting the prognosis of STS. which not only deepens our understanding of STS but also opens avenues for more targeted and effective treatment strategies.

Introduction: Widespread intra-peritoneal metastases is a main feature of high grade serous ovarian carcinoma (HGSOC). Recently, the extent of tumour heterogeneity was used to evaluate the cancer genomes among multi-regions in HGSOC. However, there is no consensus on the effect of tumour heterogeneity on the evolution of the tumour metastasis process in HGSOC. Objectives: We performed whole-exome sequencing in multiple regions of matched primary and metastatic HGSOC specimens to reveal the genetic mechanisms of ovarian tumourigenesis and malignant progression. Methods: 63 samples (including ovarian carcinoma, omentum metastasis, and normal tissues) were used. We analyzed the genomic heterogeneity, traced the subclone dissemination and establishment history and compared the different genetic characters of cancer evolutionary models in HGSOC. Results: We found that HGSOC had substantial intra-tumour heterogeneity (median 54.2, range 0 ∼ 106.7), high inter-patient heterogeneity (P

Abstract Soft tissue sarcoma (STS) is an uncommon malignancy that often carries a grim prognosis. Trophinin‐associated protein (TROAP) is augmented in a variety of tumors and can affect tumor proliferation. Nevertheless, the prognostic value and specific functions of TROAP in STS are still vague. Herein, we display that TROAP exhibits an augmented trend in STS, and its elevation correlates with a poor prognosis of STS. Furthermore, its reduction is related to increased immune cell infiltration, enhanced stroma, and elevation of immune activation. Meanwhile, the TROAP‐derived genomic signature is validated to predict patient prognosis, immunotherapy, and drug response reliably. A nomogram constructed based on age, metastatic status, and a TROAP‐derived risk score of an STS individual could be used to quantify the survival probability of STS. In addition, in vitro experiments have demonstrated that TROAP is overexpressed in STS, and the downregulation of TROAP could affect the proliferation, migration, metastasis, and cell cycle of STS cells. In summary, the TROAP expression is elevated in STS tissues and cells, which is related to the poor prognosis and malignant biological behaviors of STS. It could act as a potential prognostic biomarker for diagnosis and treatment of STS.

Abstract Objectives To explore the efficacy of induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) in stage II nasopharyngeal carcinoma (NPC) treated with intensity‐modulated radiotherapy (IMRT). Methods Totally, 450 eligible patients with staged II NPC on the basis of the 8th edition of the AJCC/UICC TNM staging system were eventually included from January 2010 to September 2020. The one‐to‐one propensity score‐matched (1:1 PSM) analysis was employed to balance variables. We conducted univariate and multivariate analysis of survival to identify prognostic factors and demonstrated the findings in the matching cohort. Results In total, 141 pairs were selected by 1:1 PSM. IC + CCRT group in the matched data decreased 5‐year progression‐free survival (PFS, 75.5% vs. 88.0%, p = 0.032) and distant metastasis‐free survival (DMFS, 86.0% vs. 96.5%, p = 0.009). There was no significant difference in 5‐year overall survival (OS, 93.8% vs. 95.6%, p = 0.192) and locoregional relapse‐free survival (LRRFS, 87.1% vs. 94.3%, p = 0.169) compared with RT/CCRT. Multivariate analysis indicated that IC + CCRT was associated with significantly poor PFS (p = 0.024) and DMFS (p = 0.010). High neutrophil‐to‐lymphocyte ratio (>4.1) was negatively associated with OS (p = 0.034), PFS (p = 0.017) and DMFS (p = 0.001). Conclusion Adding IC to CCRT or IMRT alone has decreased PFS and DMFS, therefore, IC should not be recommended in stage II NPC patients. No significant differences in OS and LRRFS were observed in stage II disease.

Abstract Ovarian cancer has the highest mortality rate among gynecologic tumors, with a 5-year survival rate of less than 25%. There is an urgent need for early diagnosis and new drugs to reduce the disease burden of ovarian cancer. The aim of this study was to investigate the effectiveness of SLC11A2 as a therapeutic target and marker for ovarian cancer. Expression data of SLC11A2 were obtained from public databases. Then, the biological functions of SLC11A2 were validated in four ovarian cancer cell lines. Finally, we collected ovarian cancer clinical tissues, serum, and plasma exosomes and used immunohistochemistry, Elisa, and liquid chromatography-mass spectrometry (LC–MS) to validate the test efficacy of SLC11A2. The results showed that ovarian cancers with high SLC11A2 mRNA expression had shorter 5-year PFS and MST. Knockdown of SLC11A2 reduced ovarian cancer migration and increased cisplatin-induced apoptosis. Serum SLC11A2 may help improve the detection rate of ovarian cancer.

Brassinosteroids (BRs) play pivotal roles in improving plant stress tolerance. To investigate the mechanism of BR regulation of salt tolerance in kiwifruit, we used ‘Hongyang’ kiwifruit as the test material. We exposed the plants to 150 mmol/L NaCl stress and irrigated them with exogenous BR (2,4-epibrassinolide). The phenotypic analysis showed that salt stress significantly inhibited photosynthesis in kiwifruit, leading to a significant increase in the H2O2 content of leaves and roots and a significant increase in Na+/K+, resulting in oxidative damage and an ion imbalance. BR treatment resulted in enhanced photosynthesis, reduced H2O2 content, and reduced Na+/K+ in leaves, alleviating the salt stress injury. Furthermore, transcriptome enrichment analysis showed that the differentially expressed genes (DEGs) related to BR treatment are involved in pathways such as starch and sucrose metabolism, pentose and glucuronate interconversions, and plant hormone signal transduction, among others. Among the DEGs involved in plant hormone signal transduction, those with the highest expression were involved in abscisic acid signal transduction. Moreover, there was a significant increase in the expression of the AcHKT1 gene, which regulates ion transduction, and the antioxidant enzyme AcFSD2 gene, which is a key gene for improving salt tolerance. The data suggest that BRs can improve salt tolerance by regulating ion homeostasis and reducing oxidative stress.

Abstract Although great advances have been made over the past decades, therapeutics for osteosarcoma are quite limited. We performed long‐read RNA sequencing and tandem mass tag (TMT)‐based quantitative proteome on osteosarcoma and the adjacent normal tissues, next‐generation sequencing (NGS) on paired osteosarcoma samples before and after neoadjuvant chemotherapy (NACT), and high‐throughput drug combination screen on osteosarcoma cell lines. Single‐cell RNA sequencing data were analyzed to reveal the heterogeneity of potential therapeutic target genes. Additionally, we clarified the synergistic mechanisms of doxorubicin (DOX) and HDACs inhibitors for osteosarcoma treatment. Consequently, we identified 2535 osteosarcoma‐specific genes and several alternative splicing (AS) events with osteosarcoma specificity and/or patient heterogeneity. Hundreds of potential therapeutic targets were identified among them, which showed the core regulatory roles in osteosarcoma. We also identified 215 inhibitory drugs and 236 synergistic drug combinations for osteosarcoma treatment. More interestingly, the multiomic analysis pointed out the pivotal role of HDAC1 and TOP2A in osteosarcoma. HDAC inhibitors synergized with DOX to suppress osteosarcoma both in vitro and in vivo. Mechanistically, HDAC inhibitors synergized with DOX by downregulating SP1 to transcriptionally modulate TOP2A expression. This study provided a comprehensive view of molecular features, therapeutic targets, and synergistic drug combinations for osteosarcoma.

Objective: To conduct a bibliometric analysis of literature on hemorrhagic shock published between 2000 and 2021 with the help of Citespace to explore the current status, hotspots and research trends in this regard, with the results presented in a visualized manner. Methods: The data over the past 22 years were retrieved from the Web of Science (WOS) Core Collection database and downloaded as the “Full Record and Cited References”. Cooperative analysis, cluster analysis, co-citation analysis, and burst analysis were performed based on the data on countries/regions, institutions, journals, authors, and keywords through Citespace. Results: A total of 2027 articles were retrieved. The number of annual publications fluctuated but was generally on an upward trend. The United States stands out as the most productive country (989 articles), the University of Pittsburgh the most productive publishing institution (109 articles), SHOCK the most cited journal (1486 articles), TAO LI the most productive author (40 articles), DEITCH EA the most cited author (261 times of citation), hemorrhagic shock the most frequent keyword (725 times of occurrence), and “traumatic brain injury” the most covered article in keyword clustering (29 articles). The burst analysis revealed Harvard University as the institution with the highest strength value and the Journal of Trauma and Acute Care Surgery the most important journal. It was also concluded that HASAN B ALAM, AARON M WILLIAMS, and LIMIN ZHANG may continue to publish high-quality articles in the future. In the meanwhile, both “protect” and “transfusion” were considered the hotspots and trends in current research. Conclusions: The United States has been a major contributor to the publication of the articles over the past 22 years, with the most productive publishing institution, the most cited journal, and the most cited author all coming from the US. Hemorrhagic shock, injury, resuscitation, trauma, models, activation, expression, fluid resuscitation, rats, and nitric oxide are hot topics in relevant research. According to the keyword burst analysis, the areas related to “protect” and “transfusion” may rise as the research directions in the future. However, since the hotspots in the research of hemorrhagic shock are short-lived and fast-changing, the researchers should pay more attention to the development trend in this field.

Low-grade myofibroblastic sarcoma (LGMS) characterized by the increased proliferation of myofibroblasts is a rare type of malignant myofibroblastic tumor that frequently occurs in the head and neck region. Presently, there is no consensus regarding the treatment of LGMS. Here, we report a rare case of LGMS of the pharynx in a 40-year-old male admitted to our hospital. The patient underwent resection for a right metastatic lesion and parapharyngeal mass. However, he had recurrence and multiple metastases without a surgical indication. Then the patient received the treatment of anlotinib plus pembrolizumab for 4 cycles, and there was a partial response (PR) to the treatment. Due to the adverse reaction of anlotinib, the patient subsequently received monotherapy of pembrolizumab for 22 cycles and achieved a complete response (CR). As the first case report of the immunotherapy for LGMS, our study highlights that this strategy may be of great significance to the treatment of LGMS.

Abstract Regulated pyroptosis is critical for pathogen elimination by inducing infected cell rupture and pro‐inflammatory cytokines secretion, while overwhelmed pyroptosis contributes to organ dysfunction and pathological inflammatory response. Caffeic acid (CA) and ferulic acid (FA) are both well‐known antioxidant and anti‐inflammatory phenolic acids, which resemble in chemical structure. Here we found that CA, but not FA, protects macrophages from both Nigericin‐induced canonical and cytosolic lipopolysaccharide (LPS)‐induced non‐canonical pyroptosis and alleviates LPS‐induced mice sepsis. It significantly improved the survival of pyroptotic cells and LPS‐challenged mice and blocked proinflammatory cytokine secretion. The anti‐pyroptotic effect of CA is independent of its regulations in cellular lipid peroxidation, mitochondrial function, or pyroptosis‐associated gene transcription. Instead, CA arrests pyroptosis by directly associating with gasdermin D (GSDMD) and blocking its processing, resulting in reduced N‐GSDMD pore construction and less cellular content release. In LPS‐induced septic mice, CA inhibits GSDMD activation in peritoneal macrophages and reduces the serum levels of interleukin‐1β and tumor necrosis factor‐α as the known pyroptosis inhibitors, disulfiram and dimethyl fumarate. Collectively, these findings suggest that CA inhibits pyroptosis by targeting GSDMD and is a potential candidate for curbing the pyroptosis‐associated disease.

BackgroundSoft tissue sarcoma (STS) is a class of malignant tumors originating from mesenchymal stroma with a poor prognosis. Accumulating evidence has proved that angiogenesis is an essential hallmark of tumors. Nevertheless, there is a paucity of comprehensive research exploring the association of angiogenesis-related genes (ARGs) with STS.MethodsThe ARGs were extracted from previous literature, and the differentially expressed ARGs were screened for subsequent analysis. Next, the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were conducted to establish the angiogenesis-related signature (ARSig). The predictive performance of the novel ARSig was confirmed using internal and external validation, subgroup survival, and independent analysis. Additionally, the association of the ARSig with the tumor immune microenvironment, tumor mutational burden (TMB), and therapeutic response in STS were further investigated. Notably, we finally conducted in vitro experiments to verify the findings from the bioinformatics analysis.ResultsA novel ARSig is successfully constructed and validated. The STS with a lower ARSig risk score in the training cohort has an improved prognosis. Also, consistent results were observed in the internal and external cohorts. The receiver operating characteristic (ROC) curve, subgroup survival, and independent analysis further indicate that the novel ARSig is a promising independent prognostic predictor for STS. Furthermore, it is proved that the novel ARSig is relevant to the immune landscape, TMB, immunotherapy, and chemotherapy sensitivity in STS. Encouragingly, we also validate that the signature ARGs are significantly dysregulated in STS, and ARDB2 and SRPK1 are closely connected with the malignant progress of STS cells.ConclusionIn sum, we construct a novel ARSig for STS, which could act as a promising prognostic factor for STS and give a strategy for future clinical decisions, immune landscape, and personalized treatment of STS.

The use of radiotherapy for hypopharyngeal cancer (HC) treatment is increasing, and it is currently the primary treatment option for this cancer. However, radioresistance occurs in a proportion of patients. Here, we found that radiation increased proteasomal gene expression and that proteasome assembly was dependent on the induction of transcription factor NRF1 in HC. Through screening assays, we identified a mechanism by which proteasome-mediated degradation of DEP domain-containing mTOR-interacting protein (DEPTOR) contributes to the elevation of mTORC1 signaling after radiation. Therefore, after treatment with proteasome inhibitors (PIs), stabilization of DEPTOR inhibited mTORC1 signaling elevated by radiation and ultimately sensitized HC to radiotherapy. Mechanically, PIs not only interrupted the deubiquitination and degradation of DEPTOR but also suppressed the ubiquitination of DEPTOR mediated by β-TrCP. Clinically, the high levels of DEPTOR in HC cells were associated with sensitivity to radiotherapy and favorable prognosis. Stabilizing DEPTOR through targeting proteasome-mediated degradation is a potential strategy for sensitizing HC to radiotherapy.

Ultrasound-based therapies in combination with immune checkpoint blockade have been shown to improve the efficacy of cancer immunotherapy. Here the authors report the design of a pH-responsive and sono-irradiation activatable nanosystem functionalized with anti-PD-L1 and adenosine deaminase for sono-metabolic cancer immunotherapy.

Background: Soft tissue sarcoma (STS) is a highly malignant tumor with a dismal prognosis. Presently, the dysregulation of fatty acid metabolism has received increasing attention in tumor research, but fewer reports are relevant to STS.Methods: Based on fatty acid metabolism-related genes (FRGs), a novel risk score for STS was developed utilizing univariate analysis and least absolute shrinkage selection operator (LASSO) Cox regression analyses in the STS cohort, which were further validated using the external validation cohort from other databases. Furthermore, independent prognostic analysis, C-index, ROC curves, and nomogram were carried out to investigate the predictive performance of fatty acid-related risk scores. We also analysed the differences in enrichment pathways, the immune microenvironment, gene mutations, and immunotherapy response between the two distinct fatty acid score groups. Moreover, the real-time quantitative polymerase chain reaction (RT-qPCR) was used to further verify the expression of FRGs in STS.Results: A total of 153 FRGs were retrieved in our study. Next, a novel fatty acid metabolism-related risk score (FAS) was constructed based on 18 FRGs. The predictive performance of FAS was also verified in external cohorts. In addition, the independent analysis, C-index, ROC curve, and nomograph also revealed that FAS could serve as an independent prognostic factor for the STS patients. Meanwhile, our results demonstrated that the STS cohort in two distinct FAS groups had different copy number variations, immune cell infiltration, and immunotherapy responses. Finally, the in vitro validation results demonstrated that several FRGs included in the FAS exhibited abnormal expression in STS.Conclusion: Altogether, our work comprehensively and systematically clarifies fatty acid metabolism’s potential roles and clinical significance in STS. The novel individualized score based on fatty acid metabolism may be provided as a potential marker and treatment strategy in STS.

Sepsis has a high mortality rate, and treating sepsis remains a significant challenge worldwide. In former studies, our group found that traditional Chinese medicine, Shen FuHuang formula (SFH), is a promising medicine in treating coronavirus disease 2019 (COVID-19) patients with the septic syndrome. However, the underlying mechanisms remain elusive. In the present study, we first investigated the therapeutic effects of SFH on septic mice. To investigate the mechanisms of SFH-treated sepsis, we identified the gut microbiome profile and exploited untargeted metabolomics analyses. The results demonstrated that SFH significantly enhanced the mice’s 7-day survival rate and hindered the release of inflammatory mediators, i.e., TNF-α, IL-6, and IL-1β. 16S rDNA sequencing further deciphered that SFH decreased the proportion of Campylobacterota and Proteobacteria at the phylum level. LEfSe analysis revealed that the treatment of SFH enriched Blautia while decreased Escherichia_Shigella. Furthermore, serum untargeted metabolomics analysis indicated that SFH could regulate the glucagon signaling pathway, PPAR signaling pathway, galactose metabolism, and pyrimidine metabolism. Finally, we found the relative abundance of Bacteroides, Lachnospiraceae_NK4A136_group, Escherichia_Shigella, Blautia, Ruminococcus, and Prevotella were closely related to the enrichment of the metabolic signaling pathways, including L-tryptophan, uracil, glucuronic acid, protocatechuic acid, and gamma-Glutamylcysteine. In conclusion, our study demonstrated that SFH alleviated sepsis by suppressing the inflammatory response and hence reduced mortality. The mechanism of SFH for treating sepsis may be ascribed to the enrichment of beneficial gut flora and modulation in glucagon signaling pathway, PPAR signaling pathway, galactose metabolism, and pyrimidine metabolism. To sum up, these findings provide a new scientific perspective for the clinical application of SFH in treating sepsis.

Chuanxiong rhizoma (CX) has been utilized for centuries as a traditional herb to treat blood stasis syndromes. However, the pharmacological mechanisms are still not completely revealed. This research was aimed at exploring the molecular mechanisms of CX treatment for thrombosis. Network pharmacology was used to predict the potential anti-thrombosis mechanism after correlating the targets of active components with targets of thrombosis. Furthermore, we verified the mechanism of using CX to treat thrombosis via molecular docking and in vitro experiments. Network pharmacology results showed that a total of 18 active ingredients and 65 targets of CX treatment for thrombosis were collected, including 8 core compounds and 6 core targets. We revealed for the first time that tissue factor (TF) had a close relationship with most core targets of CX in the treatment of thrombosis. TF is a primary coagulation factor in physiological hemostasis and pathological thrombosis. Furthermore, core components of CX have strong affinity for core targets and TF according to molecular docking analysis. The in vitro experiments indicated that Ligustilide (LIG), the representative component of CX, could inhibit TF procoagulant activity, TF mRNA and protein over-expression in a dose-dependent manner in EA.hy926 cells through the PI3K/Akt/NF-κB signaling pathway. This work demonstrated that hemostasis or blood coagulation was one of the important biological processes in the treatment of thrombosis with CX, and TF also might be a central target of CX when used for treating thrombosis. The inhibition of TF might be a novel mechanism of CX in the treatment of thrombosis.

IntroductionOsteosarcoma (OS) is a highly aggressive bone malignancy with a poor prognosis, mainly in children and adolescents. Immunogenic cell death (ICD) is classified as a type of programmed cell death associated with the tumor immune microenvironment, prognosis, and immunotherapy. However, the feature of the ICD molecular subtype and the related tumor microenvironment (TME) and immune cell infiltration has not been carefully investigated in OS.MethodsThe ICD-related genes were extracted from previous studies, and the RNA expression profiles and corresponding data of OS were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus database. The ICD-related molecular subtypes were classed by the "ConsensusclusterPlus" package and the construction of ICD-related signatures through univariate regression analysis. ROC curves, independent analysis, and internal validation were used to evaluate signature performance. Moreover, a series of bioinformatic analyses were used for Immunotherapy efficacy, tumor immune microenvironments, and chemotherapeutic drug sensitivity between the high- and low-risk groups.ResultsHerein, we identified two ICD-related subtypes and found significant heterogeneity in clinical prognosis, TME, and immune response signaling among distinct ICD subtypes. Subsequently, a novel ICD-related prognostic signature was developed to determine its predictive performance in OS. Also, a highly accurate nomogram was then constructed to improve the clinical applicability of the novel ICD-related signature. Furthermore, we observed significant correlations between ICD risk score and TME, immunotherapy response, and chemotherapeutic drug sensitivity. Notably, the in vitro experiments further verified that high GALNT14 expression is closely associated with poor prognosis and malignant progress of OS.DiscussionHence, we identified and validated that the novel ICD-related signature could serve as a promising biomarker for the OS's prognosis, chemotherapy, and immunotherapy response prediction, providing guidance for personalized and accurate immunotherapy strategies for OS.

Background: A crucial part of the malignant processes of soft tissue sarcoma (STS) is played by cuproptosis and lncRNAs. However, the connection between cuproptosis-related lncRNAs (CRLs) and STS is nevertheless unclear. As a result, our objective was to look into the immunological activity, clinical significance, and predictive accuracy of CRLs in STS.Methods: The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, respectively, provided information on the expression patterns of STS patients and the general population. Cuproptosis-related lncRNA signature (CRLncSig) construction involved the univariate, multivariate, and least absolute shrinkage and selection operator Cox regression analysis. The predictive performance of the CRLncSig was evaluated using a serial analysis. Further research was done on the connections between the CRLncSig and the tumor immune milieu, somatic mutation, immunotherapy response, and chemotherapeutic drug susceptibility. Notably, an in vitro investigation served to finally validate the expression of the hallmark CRLs.Results: A novel efficient CRLncSig composed of seven CRLs was successfully constructed. Additionally, the low-CRLncSig group’s prognosis was better than that of the high-CRLncSig group’s based on the new CRLncSig. The innovative CRLncSig then demonstrated outstanding, consistent, and independent prognostic and predictive usefulness for patients with STS, according to the evaluation and validation data. The low-CRLncSig group’s patients also displayed improved immunoreactivity phenotype, increased immune infiltration abundance and checkpoint expression, and superior immunotherapy response, whereas those in the high-CRLncSig group with worse immune status, increased tumor stemness, and higher collagen levels in the extracellular matrix. Additionally, there is a noticeable disparity in the sensitivity of widely used anti-cancer drugs amongst various populations. What’s more, the nomogram constructed based on CRLncSig and clinical characteristics of patients also showed good predictive ability. Importantly, Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) demonstrated that the signature CRLs exhibited a significantly differential expression level in STS cell lines.Conclusion: In summary, this study revealed the novel CRLncSig could be used as a promising predictor for prognosis prediction, immune activity, tumor immune microenvironment, immune response, and chemotherapeutic drug susceptibility in patients with STS. This may provide an important direction for the clinical decision-making and personalized therapy of STS.

Summary: Background: Induction chemotherapy regimens of docetaxel and cisplatin plus fluorouracil (TPF) are currently clinically used for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) but have well-known side effects, such as myelosuppression and diarrhea. A docetaxel plus cisplatin (TP) regimen was developed to decrease the toxic effects induced by fluorouracil. In this trial, we assessed whether the TP induction chemotherapy regimen was noninferior to the TPF regimen. Methods: We performed an open-label, noninferiority, phase 3, multicentre, randomised, controlled trial at six centres in China. Eligible patients with NPC (stage III-IVA (excluding T3-4N0), Karnofsky's Performance Scoring ≥70) were randomly assigned (1:1) to receive either TP (docetaxel (75 mg per square meter, d1, intravenous infusion) and cisplatin (75 mg per square meter of body-surface area, d1, intravenous infusion)) or TPF (docetaxel (60 mg per square meter, d1, intravenous infusion) plus cisplatin (60 mg per square meter, d1, intravenous infusion) and 5-fluorouracil (600 mg per square meter, d1-d5, intravenous 120-hour infusion)) administered every 3 weeks for 3 cycles followed by concurrent chemoradiotherapy. The primary endpoint was failure-free survival at 2 years. Secondary endpoints included overall survival, safety, and treatment compliance. The trial was stopped early because of strong evidence for noninferiority (margin was -10%) of TP in failure-free survival. Efficacy analyses were performed in both the intention-to-treat and per-protocol trial populations and we included the patients who started treatment in each group for the safety analysis. The study was registered with chictr.org.cn, ChiCTR1800016337. Findings: Between June 1, 2018 and October 31, 2021, we randomly assigned 361 patients to the TP (n = 181) or TPF (n = 180) induction chemotherapy group. The 2-year failure-free survival was 91·3% (95% CI 86·2-96·4) in the TP group and 82·4% (84·8-88·9) in the TPF group (P = 0·029). Patients in the TPF group had a higher frequency of grade 1 or 2 neutropenia (53 (30·0%) vs. 28 (15·7%); P = 0·0010), grade 1 or 2 diarrhea (20 (11·3%) vs. 9 (5·1%); P = 0·032), and grade 3 or 4 neutropenia (43 (24·3%) vs. 25 (14·0%); P = 0·014) in the induction chemotherapy period. There was no treatment-related death. Interpretation: The preliminary results revealed that TP induction chemotherapy regimen was found to be clearly non-inferior compared to the TPF regimen in failure-free survival, with a lower frequency of neutropenia, anaemia and diarrhoea. The more convenient and beneficial survival regimen of the TP regimen should be recommended in patients with LA-NPC. Funding: This study was supported by grants from the Natural Science Foundation of Guangdong Province, China [grant number 2021A1515011182], Natural Science Foundation of Guangdong Province, China [grant number 2022A1515012272], National Natural Science Foundation of China [grant number 82072029] and National Natural Science Foundation of China [grant number 81903037].

Qin-Qiao-Xiao-Du (QQXD), a traditional Chinese medicine (TCM) formula, has been used in the clinical treatment of influenza virus pneumonia. However, the effects and mechanisms of QQXD on influenza virus pneumonia remain unknown. Therefore, this study explores the mechanisms of QQXD in the treatment of influenza virus pneumonia from the point of view of intestinal flora and metabolism. The results showed that QQXD was able to reduce mortality, weight loss, lung viral load, lung index, and lung injury in influenza virus mice. A cytokine array found that the QQXD attenuated the expression of serum IL-1α, IL-4, IL-12(P70), and TNF-α. Subsequently, 16s rRNA gene sequencing showed that QQXD could increase the relative abundances of Gemmiger, Anaerofustis, Adlercreutzia, and Streptococcus and decrease those of Dehalobacteriu, Burkholderia, Prevotella, Butyrimimonas, Delftia, and others. Meanwhile, targeted metabolic profiling analysis showed that QQXD could regulate nitrogen metabolism, phenylalanine metabolism, valine, leucine, and isoleucine biosynthesis. Correlation analysis demonstrated that the regulatory effect of QQXD on the cyanoamino acid metabolism pathway was associated with changes in the abundance of Parabacteroides, Pediococcus, and Clostridium in influenza mice. In conclusion, our study revealed that QQXD can inhibit influenza virus replication, suppress cytokine storms, and protect mice from influenza virus infection pneumonia. The mechanisms are likely to be related to improved gut microbiota dysbiosis, increased intestinal carbohydrate metabolism, and up-regulated cyanoamino acid metabolism pathways.

BackgroundCopper is an indispensably mineral element involved in various metabolic processes and functions in the active sites of many metalloproteins. Copper dysregulation is associated with cancers such as osteosarcoma (OS), the most common primary bone malignancy with invasiveness and metastasis. However, the causality between cuproptosis and OS remains elusive. We aim to identify cuproptosis-related long non-coding RNAs (lncRNAs) for osteosarcomatous prognosis, immune microenvironment response, and immunotherapy.MethodsThe Person correlation and differential expression analysis were used to identify differentially expressed cuproptosis-related lncRNAs (CRLs). The univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis were performed to construct the CRL signature. The Kaplan–Meier (K-M) survival analysis, receiver operating characteristic (ROC) curve, internal validation, independent prognostic analysis, and nomograph were used to evaluate the prognostic value. The functional enrichment, tumor microenvironment, immunotherapy and chemotherapy response between the two distinct groups were further explored using a series of algorithms. The expression of signature CRLs was verified by real-time quantitative polymerase chain reaction (RT-qPCR) in OS cell lines.ResultsA novel CRL signature consisting of four CRLs were successfully identified. The K-M survival analysis indicated that the OS patients in the low-risk groups had a better prognosis than that in the high-risk group. Then, the ROC curve and subgroup survival analysis confirmed the prognostic evaluation performance of the signature. Equally, the independent prognostic analysis demonstrated that the CRL signature was an independently predicted factor for OS. Friends analysis determined the hub genes that played a critical role in differentially expressed genes between two distinct risk groups. In addition, the risk score was related to immunity status, immunotherapy response, and chemotherapeutic drug sensitivity. Finally, the expression of these signature CRLs detected by RT-qPCR was consistent with the bioinformatic analysis results.ConclusionIn summary, our study confirmed that the novel CRL signature could effectively evaluate prognosis, tumor immune microenvironment, and immunotherapy response in OS. It may benefit for clinical decision-making and provide new insights for personalized therapeutics.

BackgroundOncoprotein-Induced Transcript 3 Protein (OIT3) was identified as a liver-specific gene with abnormal expression in hepatocellular carcinoma (HCC). Herein, we aimed to examine the function and specific mechanism of OIT3 in HCC.MethodsBioinformatic analyses and tissue microarray via immunohistochemistry were used to validate the expression of OIT3 in HCC. The biofunctions of OIT3 in HCC were determined in vitro and in vivo. The mechanism was confirmed by RNA-Sequence and Western blotting. The uni- and multivariate analyses were used to identify the independent predictors for HCC.ResultsLow expression of OIT3 was observed in HCC and predicted a poor clinical outcome. Ectopic expression of OIT3 could inhibit the proliferation, migration, and invasion abilities of HCC cells. Mechanistically, OIT3 upregulated the expression of ALOX15 and CYP4F3, thus inducing arachidonic acid increase, ROS accumulation, and lipid peroxidation, and eventually causing ferroptosis. OIT3 was validated as a prognostic predictor for HCC patients.ConclusionsOur findings revealed a novel role of OIT3 in the process of tumorigenesis of HCC. OIT3 inhibited reproliferation, migration, and invasion of HCC cells by triggering ferroptosis, which indicates that OIT3 could serve as a potential biomarker in HCC.

Proteolysis targeting chimeras (PROTACs) is an effective alternative to modulate protein homeostasis but can lead to uncontrollable protein degradation and off-target side effects. Here, the authors developed semiconducting polymer nano-PROTACs with phototherapeutic and activatable protein degradation abilities for photo-immunometabolic cancer therapy.

Abstract Background The implementation of early intervention (EI) in medical settings is time-consuming and resource-intensive, which limits its extensive use. In 2018, the Chinese Eugenics Association developed a home-based, post-discharge EI program. This study aims at evaluating the impact of this EI program on neurodevelopment and physical growth of early preterm infants. Methods This study was a prospective, partially blinded, randomized controlled trial (RCT), followed by an open phase. A total of 73 infants born at 28+ 0 ~ 31+ 6 weeks’ gestation who were admitted to the Children’s Hospital of Chongqing Medical University between December 1, 2019, and June 31, 2020, were enrolled. Another 33 infants were retrospectively recruited as the reference group. Thirty-seven infants randomized in the first early intervention, then standard care (EI-SC) group performed a 30-day EI during RCT period, while 36 infants allocated to SC-EI group were given EI in the following open phase. The test of infant motor performance (TIMP), development quotient (DQ), and anthropometric measures (length, weight, head circumference) were measured at the baseline (T0), termination of the RCT (T1), and termination of the open phase (T2). Repeated measures analysis was performed for comparison among groups. Results From T0 to T1, both groups had significant improvements in all outcome measures (all p 0.05). At the endpoint of T2, the EI-SC and SC-EI group had similar TIMP and anthropometric measures, but much higher than the reference group (all p

Cao Huang Gui Xiang (CHGX) formula, a Chinese herbal medicine, has been empirically used for the treatment of Candida infections. In the present study, we discovered that the CHGX showed potent antifungal activities against the major human fungal pathogen Candida albicans and other clinical Candida species. Besides, we indicated that CHGX had in vivo efficacy on treating C. albicans infection in mice without noticeable toxicity at the clinical therapeutic concentration. We then set out to investigate the antifungal mechanisms of CHGX against C. albicans. We found that CHGX played an important role in inhibiting biofilm formation and filament development, two critical virulence factors of C. albicans. We further demonstrated that CHGX disrupted cell membrane integrity, triggered the accumulation of reactive oxygen species (ROS) and consumption of adenosine triphosphate (ATP), followed by a rapid fungal cell death in C. albicans. Multiple pathways, including the conserved Ras1-cAMP pathway and mitochondrial protein Mcu1 are involved in CHGX-induced cell death. Our finding expands the understanding of antifungal mechanism of CHGX against C. albicans, and provides new insights in treating patients with Candida infections in clinical practice.

Abstract Background Bladder cancer (BC) is a common urinary neoplasm with high incidence worldwide. Long noncoding RNA zinc ribbon domain containing 1 antisense RNA 1 (ZNRD1‐AS1) has been reported to be upregulated in BC. However, the exact role of ZNRD1‐AS1 as well as its mechanism remains poorly understood. Methods Zinc ribbon domain containing 1 antisense RNA 1, and its potential downstream genes microRNA‐194 (miR‐194) and zinc finger E‐box binding homeobox 1 (ZEB1) levels were detected via quantitative real‐time polymerase chain reaction or western blot. Cell proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) were detected to assess the influences of ZNRD1‐AS1, miR‐194 and ZEB1 on BC cells by colony formation, cell counting kit‐8 (CCK‐8), transwell analysis or western blot. The relationship between miR‐194 and ZNRD1‐AS1 or ZEB1 was analyzed by luciferase activity analysis. The xenograft experiment was performed to assess the function of ZNRD1‐AS1 in vivo. Results Zinc ribbon domain containing 1 antisense RNA 1level was upregulated in BC. ZNRD1‐AS1 silence repressed proliferation, migration, invasion and EMT in BC cells. MiR‐194 was identified as a target of ZNRD1‐AS1, and miR‐194 upregulation repressed proliferation, migration, invasion, and EMT by ZNRD1‐AS1 sponging. ZEB1 was targeted via miR‐194 and its interference impeded proliferation, migration, invasion, and EMT. Moreover, ZNRD1‐AS1 regulated ZEB1 expression via miR‐194. Besides, inhibition of ZNRD1‐AS1 attenuated tumor growth by miR‐194/ZEB1 axis in vivo. Conclusion Knockdown of ZNRD1‐AS1 suppressed BC cell development in vitro and in vivo via targeting miR‐194 to regulate ZEB1, indicating a novel avenue for treatment of BC.

BackgroundIn this trial, we aimed to assess the efficacy and safety of radiotherapy with nedaplatin or cisplatin in patients with locally advanced cervical cancer.MethodsWe conducted an open-label, non-inferiority, phase III, randomized, controlled trial. Eligible patients with stage IIB-IVA cervical carcinoma were randomly assigned to receive either nedaplatin or cisplatin for two cycles concurrently with radiotherapy. We reported the therapy-associated harms and survival. The study was registered with chictr.org.cn, number ChiCTR1800020527.ResultsWe randomly assigned 68 patients to nedaplatin-based or cisplatin-based concurrent chemoradiotherapy. Study treatment was stopped early after a data analysis found a higher number of patients suffered severe hematologic harms in the nedaplatin group than in the cisplatin group. Patients in the nedaplatin group had a significantly higher frequency of grade 3-4 neutropenia (19·4% vs. 13%; P < 0·001), severe thrombocytopenia (16·1% vs. 4·3%), and grade 1-2 anemia (51·6% vs. 43·5%) than patients in the cisplatin group. The 1-year PFS and OS in the nedaplatin and cisplatin groups were similar.ConclusionOur findings showed that nedaplatin-based concurrent chemoradiotherapy expressed remarkably higher severe hematologic harms which were mortal. Though the results were negative, the experiences and lessons we learned from it were important.

Sepsis-induced inflammatory response leads to intestinal damage and secondary bacterial translocation, causing systemic infections and eventually death. Emodin is a natural anthraquinone derivative in many plants with promising bioactivities. However, the effects and mechanisms of emodin on sepsis-induced intestinal dysfunctions have not been well clarified yet. We found that emodin treatment suppressed the inflammatory response in the intestines of septic mice. Intestinal barrier function was also improved by emodin through enhancing ZO-1 and occludin expression, which prevented the secondary translocation of Escherichia coli. By proteome microarray investigation, JNK2 was identified as a direct target of emodin. In vitro study also showed that emodin inhibited LPS-induced inflammatory response in intestinal epithelial cells. Nuclear factors including NF-κB and AP-1 were further identified as downstream effectors of JNK2. Bioinformatic analysis based on 16s rRNA gene sequencing illustrated that emodin treatment significantly increased the alpha- and beta-diversity of gut microbiota in septic mice. Moreover, data according to functional prediction showed that emodin decreased the abundance of potential pathogenic bacteria in gut. Our findings have shown that emodin treatment prevented inflammatory induced barrier dysfunction and decreased the potential pathogenicity of lumen bacteria, reducing the hazard of lumen bacterial translocation during sepsis.

Cervical cancer is a highly prevalent female malignancy. Presently, cisplatin (DDP) is a first-line agent for cervical cancer chemotherapy. However, its curative effect is limited because of chemo-resistance. It has been previously reported that SOX9 targeted and activated oncogenic genes, enhancing cervical cancer cell resistance to DDP. The effects of the SOX9/lncRNA ANXA2P2/miR-361-3p/SOX9 regulatory loop on cervical cancer cell growth and resistance to DDP have been demonstrated. miR-361-3p expression was decreased in DDP-resistant cervical cancer cells and tissues. Moreover, miR-361-3p overexpression inhibited the growth of resistant cervical cancer cells and the resistance to DDP, whereas miR-361-3p inhibition exerted opposite effects. miR-361-3p inhibited SOX9 expression through binding; the effects of miR-361-3p inhibition were partially reversed by SOX9 knockdown. LncRNA ANXA2P2 expression was elevated in DDP-resistant cervical cancer cells and tissues. LncRNA ANXA2P2 inhibited miR-361-3p expression by binding, thereby upregulating SOX9. LncRNA ANXA2P2 knockdown inhibited DDP-resistant cervical cancer cell growth and resistance to DDP, whereas the effects of lncRNA ANXA2P2 knockdown were partially reversed by miR-361-3p inhibition. SOX9 expression was elevated in DDP-resistant cervical cancer cells and tissues, and SOX9 activated lncRNA ANXA2P2 transcription by binding. Collectively, SOX9, lncRNA ANXA2P2, and miR-361-3p form a regulatory loop, modulating DDP-resistant cervical cancer cell growth and response to DDP treatment.

The current research examined the influence of subjective loss on financial risk-taking tendency and negative emotional experience through inducing the experience of subjective loss in auction scenarios. In Study 1, we found that the subjective loss experience (compared to no-loss experience) in an auction scenario induced greater financial risk propensity, especially in gambling, greater negative emotion, and greater decision regret. In addition, we found that the subjective loss experience induced stronger negative emotion but less risk propensity in investment than the actual loss experience did, but these two types of loss did not yield a difference in risk propensity in gambling in Study 2. These results implicate that subjective loss is a distinct experience from no-loss and actual loss experiences, which is reflected by the degree of associated emotional experience and subsequent risk-taking propensity. The current research highlights the complex psychological processes of the experience of loss in decision-making contexts.

Based on the concept of high-quality development, this paper constructs an urban ecological welfare evaluation framework, measures the urban ecological welfare performance in Jiangsu Province from 2005 to 2019 using a stochastic frontier production function model, and conducts a spatial and temporal divergence feature analysis, combining a spatial panel econometric model and a threshold panel regression model to explore the spatial effects and mechanisms of urban ecological welfare performance. The results show that: (1) The urban ecological welfare performance in Jiangsu province has been increasing every year, and the spatial divergence between north and south is significant, with the overall trend of southern Jiangsu > central Jiangsu > northern Jiangsu. (2) The differences in urban ecological welfare performance among the three regions are gradually decreasing, with the high values expanding and the low values decreasing, and the urban ecological welfare performance in northern Jiangsu Province is gradually approaching that in southern Jiangsu Province, and the urban ecological welfare performance level tends to be balanced. (3) There are significant negative spillover effects of industrial structure, city scale, and economic development level on urban ecological welfare performance, as well as significant threshold effects of innovation level, industrial structure, foreign trade dependence, and economic development, and significant differences in the degree of influence of urbanization on urban ecological welfare performance under different threshold variables. (4) The urbanization and economic development levels are the fundamental factors driving urban ecological welfare performance improvement. Industrial structure optimization, city scale, technological innovation, and foreign trade dependence positively contribute to urban welfare performance, and government financial pressure constrains the performance level improvement. In the future, a long-term mechanism for high-quality green development should be constructed, spatial spillover channels should be continuously improved, welfare thresholds should be effectively circumvented, and urban ecological welfare performance should be promoted in a concerted manner.

Although ovarian cancer, a gynecological malignancy, has the highest fatality rate, it still lacks highly specific biomarkers, and the differential diagnosis of ovarian masses remains difficult to determine for gynecologists. Our study aimed to obtain ovarian cancer-specific protein candidates from the circulating small extracellular vesicles (sEVs) and develop a protein panel for ovarian cancer screening and differential diagnosis of ovarian masses. In our study, sEVs derived from the serum of healthy controls and patients with cystadenoma and ovarian cancer were investigated to obtain a cancer-specific proteomic profile. In a discovery cohort, 1119 proteins were identified, and significant differences in the protein profiles of EVs were observed among groups. Then, 23 differentially expressed proteins were assessed using the parallel reaction monitoring in a validation cohort. Through univariate and multivariate logistic regression analyses, a novel model comprising three proteins (fibrinogen gamma gene (FGG), mucin 16 (MUC16), and apolipoprotein (APOA4)) was established to screen patients with ovarian cancer. This model exhibited an area under the receiver operating characteristic curve (AUC) of 0.936 (95% CI, 0.888–0.984) with 92.0% sensitivity and 82.9% specificity. Another panel comprising serum CA125, sEV-APOA4, and sEV-CD5L showed excellent performance (AUC 0.945 (95% CI, 0.890–1.000), sensitivity of 88.0%, specificity of 93.3%, and accuracy of 89.2%) to distinguish malignancy from benign ovarian masses. Altogether, our study provided a proteomic signature of circulating sEVs in ovarian cancer. The diagnostic proteomic panel may complement current clinical diagnostic measures for screening ovarian cancer in the general population and the differential diagnosis of ovarian masses.

Abstract Background We compared the survival outcomes and acute toxicities of weekly and triweekly cisplatin regimens during concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. Methods Patients were treated with CCRT alone. CCRT was initiated on the first day of RT. Cisplatin 30–40 mg/m2 was infused on days 1, 8, 15, 22, 29, 36 and 43 in the Weekly Group, while cisplatin 80–100 mg/m2 was delivered on days 1, 22 and 43 in the Triweekly Group. The survival outcomes were revealed by the Kaplan-Meier method and Cox regression modelling to measure 5-year overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS). Results Ninety-three (28.9%) patients received three to 7 cycles of cisplatin weekly (Weekly Group) and 229 (71.1%) patients received two to 3 cycles of cisplatin triweekly (Triweekly Group). Five-year OS (weekly vs. triweekly, 96.7% vs. 88.3%, P = 0.036) and DFS (weekly vs. triweekly, 90.7% vs. 80.5%, P = 0.028) were better in the Weekly Group than in the Triweekly Group. The weekly vs. triweekly 5-year DMFS and LRFS rates were: DMFS, 96.7% vs. 91.4%, χ2 = 2.694, P = 0.101; LRFS, 96.3% vs. 93.5%, χ2 = 1.317, P = 0.251. Cisplatin delivery regimen was not an independent prognostic factor. The incidence rate of acute toxicities was similar between the groups. Conclusions Compared with Triweekly cisplatin regimen, Weekly regimen may be a better choice during CCRT.

The relationship between urbanization and ecology environment is a current research hotspot. Most literature to date focuses on the interaction between urbanization and a single component of the ecosystem (e.g., water, forests, and ecosystem services), while little attention has been given to the relationship between urbanization quality and ecosystem health. Accordingly, this paper used the entropy method and vigor—organization–resilience model to measure the urbanization quality and ecosystem health in Jiangsu Province. Based on the results, this paper analyzed the spatial-temporal pattern and evolution characteristics of the coordination degree between urbanization quality and ecosystem health in Jiangsu Province in 2000, 2005, 2010, 2015, and 2017 and then used the geographic detector and Tobit regression model to explore its internal driving forces and external influencing factors. The results show the following: 1. The changing trend of urbanization quality and ecosystem health in the Jiangsu Province share some traits; it first descends and then ascends; 2. The cities in Jiangsu Province are all between primary coordination and high-quality coordination. Central Jiangsu has the best coupling coordination degree, and Northern Jiangsu has the worst coupling coordination degree, but the overall coordination degree is on the rise; 3. The internal and external factors that drive the coordinated development of urbanization and ecosystem health differ based on periodic and regional characteristics. We need to tailor policies to ensure the sustainable development of the region.

The outbreak of coronavirus disease 2019 (COVID-19) has affected millions of people worldwide. Critically ill COVID-19 patients develop viral septic syndrome, including inflammatory damage, immune dysfunction, and coagulation disorder. In this study, we investigated ShenFuHuang formula (SFH), a traditional Chinese medicine, which has been widely used as complementary therapy for clinical treatment of COVID-19 in Wuhan, to understand its pharmacological properties. Results of systems pharmacology identified 49 active compounds of SFH and their 69 potential targets, including GSK3β, ESR1, PPARG, PTGS2, AKR1B10, and MAPK14. Network analysis illustrated that the targets of SFH may be involved in viral disease, bacterial infection/mycosis, and metabolic disease. Moreover, signaling pathway analysis showed that Toll-like receptors, MAPK, PPAR, VEGF, NOD-like receptor, and NF-kappa B signaling pathways are highly connected with the potential targets of SFH. We further employed multiple zebrafish models to confirm the pharmacological effects of SFH. Results showed that SFH treatment significantly inhibited the inflammatory damage by reducing the generation of neutrophils in Poly (I:C)-induced viral infection model. Moreover, SFH treatment could improve the phagocytosis of macrophages and enhance the expression of immune genes in an immune deficiency model. Furthermore, SFH treatment exhibited promising anti-thrombosis effect in a thrombus model. This study provided additional evidence of SFH formula for treating COVID-19 patients with septic syndrome using multiple-scale estimation.

Sepsis commonly leads to acute and long-term cognitive and affective impairments which are associated with increased mortality in patients. Neuroinflammation characterized by excessive cytokine release and immune cell activation underlies the behavioral changes associated with sepsis. We previously reported that the administration of a traditional Chinese herbal Qiang Xin 1 (QX1) formula improves survival in septic mice. This study was performed to better understand the effects and the mechanisms of QX1 formula treatment on behavioral changes in a preclinical septic model induced by cecal ligation and puncture. Oral administration of QX1 formula significantly improved survival, alleviated overall cognitive impairment and emotional dysfunction as assessed by the Morris water maze, novel object recognition testing, elevated plus maze and open field testing in septic mice. QX1 formula administration dramatically inhibited short and long-term excessive pro-inflammatory cytokine production both peripherally and centrally, and was accompanied by diminished microglial activation in septic mice. Biological processes including synaptic transmission, microglia cell activation, cytokine production, microglia cell polarization, as well as inflammatory responses related to signaling pathways including the MAPK signaling pathway and the NF-κB signaling pathway were altered prominently by QX1 formula treatment in the hippocampus of septic mice. In addition, QX1 formula administration decreased the expression of the M1 phenotype microglia gene markers such as Cd32, Socs3, and Cd68, while up-regulated M2 phenotype marker genes including Myc, Arg-1, and Cd206 as revealed by microarray analysis and Real-time PCR. In conclusion, QX1 formula administration attenuates cognitive deficits, emotional dysfunction, and reduces neuroinflammatory responses to improve survival in septic mice. Diminished microglial activation and altered microglial polarization are involved in the neuroprotective mechanism of QX1 formula.

Intestinal barrier dysfunction is an important clinical problem in various acute and chronic pathological conditions. Ferulic acid (FA) can attenuate the intestinal epithelial barrier dysfunction, however, the underlying mechanism remains unclear. The present study aimed to uncover the protective effect of FA on intestinal epithelial barrier dysfunction in a Caco-2 cell model of lipopolysaccharide (LPS) stimulation and the underlying mechanism. Caco-2 cells were pretreated with FA and then exposed to LPS stimulation. The barrier function of Caco-2 cells was evaluated by measuring trans-epithelial resistance (TER) and 4-kDa fluorescein isothiocyanate (FITC)-dextran (FD4) flux, and analyzing the tight junction protein expression and structure. The results showed that decreased TER and increased FITC-FD4 flux were observed in Caco-2 cells stimulated with LPS, but these effects were attenuated by FA pretreatment. FA pretreatment inhibited LPS-induced decrease in occludin and ZO-1 mRNA and protein expression. LPS stimulation decreased miR-200c-3p expression, whereas this decrease was inhibited by FA pretreatment. Furthermore, overexpression of miR-200c-3p strengthened the protective effects of FA on LPS-induced Caco-2 cell barrier dysfunction by decreasing epithelial permeability, increasing occludin and ZO-1 protein expression, and maintaining of ZO-1 protein distribution, while suppression of miR-200c-3p reversed the protective effects of FA. LPS treatment increased the expression of PTEN protein and decreased expression of phosphorylated PI3K and AKT proteins. However, pretreatment of FA inhibited expression of PTEN protein and promoted activation of PI3K/AKT signaling pathway in the LPS-treated Caco-2 cells, and this regulatory effect of FA on the PTEN/PI3K/AKT signaling pathway was strengthened or weakened by miR-200c-3p overexpression or suppression, respectively. Our findings suggested that in Caco-2 cells, FA promotes activation of PI3K/AKT pathway by miR-200c-3p-mediated suppression of the negative mediator PTEN, which, in turn, maintains TJ function and thus ameliorates LPS-induced intestinal epithelial barrier dysfunction.

To investigate the potential applications and the molecular mechanisms of transcranial direct current stimulation (tDCS) on cognitive impairment in a vascular dementia (VD) animal model. Sprague-Dawley rats were used in this study. VD rat model was induced by modified permanent bilateral common carotid artery occlusion (2-VO) approach. Anodal tDCS was applied to the animals. Morris water maze was used to analyze spatial memory and navigation ability. The pathological changes in the hippocampal CA1 region and cerebral cortex were examined via Hematoxylin-Eosin staining. The rats were sacrificed for the measurement of the level of superoxide (SOD), glutathione (GSH), reactive oxidative species (ROS), malondialdehyd (MDA), Interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α level in the hippocampus. Western blot was carried out to measure the hippocampal expression of microtubule-associated protein 1 light chain 3 (LC-3) and p62. Rats with VD have decreased number of neurons in the hippocampus and cerebral cortex, as well as worse cognitive impairment. The proliferation of activated microglia and astroglia, accompanied with attenuation of myelination were observed in the white matter about 1 month after 2-VO operation. These abnormalities were significantly ameliorated by tDCS treatment. Further study revealed that anodal tDCS could suppress the MDA and ROS level, while enhance the SOD and GSH level to reduce the oxidative stress. Anodal tDCS could inhibit hypoperfusion-induced IL-1β, IL-6, and TNF-α expression to attenuate inflammatory response in hippocampus. Moreover, anodal tDCS treatment could alleviate autophagy level. The study has demonstrated a possible therapeutic role of tDCS in the treatment of cognitive impairment in VD.

Abstract Background The Rab27 family of small GTPases promotes the progression of breast cancer, melanoma, and other human cancers. In this review, we discuss the role of Rab27 GTPases in cancer progression and the potential applications of these targets in cancer treatment. Main body Elevated expression of Rab27 GTPases is associated with poor prognosis and cancer metastasis. Moreover, these GTPases govern a variety of oncogenic functions, including cell proliferation, cell motility, and chemosensitivity. In addition, small GTPases promote tumor growth and metastasis by enhancing exosome secretion, which alters intracellular microRNA levels, signaling molecule expression, and the tumor microenvironment. Conclusion Rab27 GTPases may have applications as prognostic markers and therapeutic targets in cancer treatment.

Abstract Background The skeletal system is the most common site of distant metastasis in nasopharyngeal carcinoma (NPC); various prognostic factors have been reported for skeletal metastasis, though most studies have focused on a single factor. We aimed to establish nomograms to effectively predict skeletal metastasis at initial diagnosis (SMAD) and skeletal metastasis-free survival (SMFS) in NPC. Methods A total of 2685 patients with NPC who received bone scintigraphy (BS) and/or 18F–deoxyglucose positron emission tomography/computed tomography (18F–FDG PET/CT) and 2496 patients without skeletal metastasis were retrospectively assessed to develop individual nomograms for SMAD and SMFS. The models were validated externally using separate cohorts of 1329 and 1231 patients treated at two other institutions. Results Five independent prognostic factors were included in each nomogram. The SMAD nomogram had a significantly higher c-index than the TNM staging system (training cohort, P = 0.005; validation cohort, P

Osteosarcoma is the most common primary bone malignancy in children and adolescents. Although improvements in therapeutic strategies were achieved, the outcome remains poor for most patients with metastatic or recurrent osteosarcoma. Therefore, it is imperative to identify novel and effective prognostic biomarker and therapeutic targets for the disease. Long noncoding RNAs (lncRNAs) are a novel class of RNA molecules defined as transcripts >200 nucleotides that lack protein coding potential. Many lncRNAs are deregulated in cancer and are important regulators for malignancies. Nine lncRNAs (91H, BCAR4, FGFR3-AS1, HIF2PUT, HOTTIP, HULC, MALAT-1, TUG1, UCA1) are upregulated and considered oncogenic for osteosarcoma. Loc285194 and MEG3 are two lncRNAs downregulated and as tumor suppressor for the disease. Moreover, the expressions of LINC00161 and ODRUL are associated with chemo-resistance of osteosarcoma. The mechanisms for these lncRNAs in regulating development of osteosarcoma are diverse, e.g. ceRNA, Wnt/β-catenin pathway, etc. The lncRNAs identified may serve as potential biomarkers or therapeutic targets for osteosarcoma.

Sepsis is a life-threatening condition that often occurs in the intensive care unit. The excessive activation of the host's immune system at early stages contributes to multiple organ damage. Mitogen-activated protein kinase phosphatase-1 (MKP1) exerts an important effect on the inflammatory process. In our recent bioinformatic analysis, we confirmed that the inhibition of protein tyrosine phosphatase-1B (PTP1B) significantly promoted the expression of MKP1 in murine macrophages. However, the underlying mechanism and its effect on macrophage polarization remain unclear. In this study, we show that the suppression of PTP1B induced upregulation of MKP1 in M1 macrophages. A RayBiotech mouse inflammation antibody assay further revealed that MKP1-knockdown promoted pro-inflammatory cytokine (IL-1β, IL12p70, IL-17, IL-21, IL-23, and TNF-α) secretion but suppressed anti-proinflammatory cytokine (IL-10) production in M2 macrophages. Phospho-proteomics analysis further identified ERK1/2 and p38 as downstream molecules of MKP1. Moreover, we found that the inhibition of PTP1B lowered the expression of miR-26a, showing a negative correlation with MKP1 protein expression. Thus, we concluded that the inhibition of PTP1B contributes to M2 macrophage polarization via reducing mir-26a and afterwards enhancing MKP1 expression in murine macrophages.