Gene-guided identifications of a structure-chimeric cyclotide viphi I from Viola philippica: Potential functions against cadmium and nematodes.

The cyclic peptides, cyclotides, are identified mostly with 29-31-aa (amino acid residues) but rarely with ≥ 34-aa in plants. Viola philippica is a well-known medicinal plant but a rare metallophyte with cyclotides. A hypothesis was hence raised that the potential novel 34-aa cyclotide of Viola philippica would clearly broaden the structural and functional diversities of plant cyclotides. After homology-cloning the cyclotide precursor gene of VpCP5, a 34-aa cyclotide (viphi I) was identified to be larger than 22 other known cyclotides in V. philippica. It had a chimeric primary structure, due to its unusual loop structures (8 residues in loop 2 and 6 residues in loop 5) and aa composition (3 E and 5 R), by using phylogenetic analyses and an in-house cyclotide analysis tool, CyExcel_V1. A plasmid pCYC-viphi_I and a lab-used recombinant process were specially constructed for preparing viphi I. Typically, 0.12 or 0.25 mg ml-1 co-exposed viphi I could significantly remain cell activities with elevating Cd2+-exposed doses from 10-8 to 10-6 mol l-1 in MCF7 cells. In the model nematode Caenorhabditis elegans, IC50 values of viphi I to inhibit adult ratios and to induce death ratios, were 184.7 and 585.9 µg ml-1, respectively; the median lifespan of adult worms decreased from 14 to 2 d at viphi I doses ranging from 0.05 to 2 mg ml-1. Taken together, the newly identified viphi I exhibits functional potentials against cadmium and nematodes, providing new insights into structural and functional diversity of chimeric cyclotides in plants.

Positive feedback loop of c-myc/XTP6/NDH2/NF-κB to promote malignant progression in glioblastoma.

BACKGROUND: Recent studies have highlighted the significant role of the NF-κB signaling pathway in the initiation and progression of cancer. Furthermore, long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in sustaining the NF-κB signaling pathway's functionality. Despite these findings, the underlying molecular mechanisms through which lncRNAs influence the NF-κB pathway remain largely unexplored. METHODS: Bioinformatic analyses were utilized to investigate the differential expression and prognostic significance of XTP6. The functional roles of XTP6 were further elucidated through both in vitro and in vivo experimental approaches. To estimate the interaction between XTP6 and NDH2, RNA pulldown and RNA Immunoprecipitation (RIP) assays were conducted. The connection between XTP6 and the IκBα promoter was examined using Chromatin Isolation by RNA Purification (ChIRP) assays. Additionally, Chromatin Immunoprecipitation (ChIP) assays were implemented to analyze the binding affinity of c-myc to the XTP6 promoter, providing insights into the regulatory mechanisms at play. RESULTS: XTP6 was remarkedly upregulated in glioblastoma multiforme (GBM) tissues and was connected with adverse prognosis in GBM patients. Our investigations revealed that XTP6 can facilitate the malignant progression of GBM both in vitro and in vivo. Additionally, XTP6 downregulated IκBα expression by recruiting NDH2 to the IκBα promoter, which resulted in elevated levels of H3K27me3, thereby reducing the transcriptional activity of IκBα. Moreover, the progression of GBM was further driven by the c-myc-mediated upregulation of XTP6, establishing a positive feedback loop with IκBα that perpetuated the activation of the NF-κB signaling pathway. Notably, the application of an inhibitor targeting the NF-κB signaling pathway effectively inhibited the continuous activation induced by XTP6, leading to a significant reduction in tumor formation in vivo. CONCLUSION: The results reveal that XTP6 unveils an innovative epigenetic mechanism instrumental in the sustained activation of the NF-κB signaling pathway, suggesting a promising therapeutic target for the treatment of GBM.

Discovery of Diverse Sesquiterpenoids from Crossiella cryophila through Genome Mining and NMR Tracking.

Terpenoids, the largest and most structurally diverse natural product family, are predominantly found in fungi and plants, with bacterial terpenoids forming a minor fraction. Here, we established an efficient platform that integrates genome mining and NMR-tracking for prioritizing strains and tracking bacterial terpenoids. By employing this platform, we selected Crossiella cryophila for a comprehensive investigation of its capacity for terpenoid production, resulting in the characterization of 15 sesquiterpenoids. These compounds comprise nine new sesquiterpenoids (1-9), along with six known analogs (10-15), which are categorized into five distinctive carbon skeletons: bicyclogermacrane, maaliane, cadinane, eudesmane, and nor-eudesmane. Their chemical structures were determined through a combination of spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculations. Notably, the absolute configurations of compounds 1, 2, 5-7, 9, and 13-15 were determined via single-crystal X-ray diffraction analyses. The selected compounds were evaluated for their anticancer, antimicrobial, and anti-inflammatory bioactivities; however, none of these compounds displayed any significant bioactivity. This study enriches the repertoire of bacterial terpenoids, offers a practical process for prioritizing strains for bacterial terpenoids discovery, and establishes a foundation for exploring terpenoid biosynthesis.

Zinc Oxide Nanoparticles Induce Renal Injury by Initiating Oxidative Stress, Mitochondrial Damage and Apoptosis in Renal Tubular Epithelial Cells.

Zinc oxide nanoparticles (ZnO NPs) are widely used in many fields due to their unique physicochemical properties. However, the renal toxicity of ZnO NPs and the underlying mechanisms have not been well studied. We found that ZnO NPs induced injury in human renal proximal tubular epithelial cells (HK-2) in a dose- and size-dependent manner, as revealed by CCK-8, LDH and Annexin V-FITC assays. Mechanistically, ZnO NPs promoted oxidative stress and mitochondrial damage by generating ROS and induced apoptosis in HK-2 cells, as evidenced by the upregulation of Bax and Caspase 3 and downregulation of Beclin 1. In vivo, ZnO NPs induced tubular epithelial cell apoptosis and increased serum creatinine, serum urea nitrogen, and urinary protein in mice, suggesting damage to renal structure and function. These findings clarified our understanding of the biological mechanisms underlying ZnO NP-induced renal tubular epithelial cell injury and contributed to estimating the risk of ZnO NPs to the kidney.

Effects of Early Short-Course Corticosteroids on Immune-Related Adverse Events in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

INTRODUCTION: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown. METHODS: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either "corticosteroid group" or "non-corticosteroid group" depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed. RESULTS: Among 252 eligible patients, 137 patients were categorized as "corticosteroid group" and 115 patients as "non-corticosteroid group." The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35-1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12-0.85; p = 0.013). CONCLUSION: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs.

Blood plasma metagenomic next-generation sequencing for identifying pathogens of febrile neutropenia in acute leukemia patients.

To investigate the value of metagenomic next-generation sequencing (mNGS) in acute leukemia (AL) patients with febrile neutropenia (FN). We retrospectively reviewed 37 AL patients with FN and compared the results of mNGS with blood culture (BC) and the clinical features of the mNGS-positive group and the mNGS-negative group. A total of 14 detected pathogens were the final clinical diagnosis, of which 9 strains were detected only by mNGS and 5 strains were detected by both mNGS and BC. The top pathogens were Klebsiella pneumoniae, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. A total of 67.57% (25/37) were bacterial infections, and 2.7% (1/37) were fungal or viral infections. The diagnostic positivity rate of mNGS (25/37, 67.6%) was significantly higher than that of BC (7/37, 18.9%), and the difference was statistically significant (p < 0.05). Then, we explored the clinical distinction between the mNGS-positive group and the mNGS-negative group, and 3 features were filtered, including lymphocyte count (LY), creatinine levels (Cr), and white blood cell count (WBC). Our study demonstrated that early implementation of mNGS can effectively improve the efficacy of pathogen detection in AL patients with FN. The higher diagnostic positivity rate and the ability to detect additional pathogens compared to BC made mNGS a valuable tool in the management of infectious complications in this patient population. Furthermore, the identified clinical features associated with mNGS results provided additional insights for the clinical indication of infection in AL patients with FN.

Polystyrene nanoplastics induce apoptosis of human kidney proximal tubular epithelial cells via oxidative stress and MAPK signaling pathways.

Polystyrene nanoplastics (PS-NPs) have recently been found to be present in human blood and kidney. However, the renal toxicity of PS-NPs and the underlying mechanisms have not been fully elucidated. Here, we found that exposure of PS-NPs induced apoptosis of human renal proximal tubular epithelial cells (HK-2) in a size- and dose-dependent manner as revealed by AnnexinV-FITC assay. In addition, PS-NPs promoted ROS production and caused structure changes of mitochondrial and endoplasmic reticulum. Mechanistically, transcriptional sequencing indicated the involvement of MAPK pathway in apoptosis, which was further confirmed by the upregulation of p-p38, p-ERK, CHOP, BAX, cytochrome C, and caspase 3 expression. This study clarified the molecular mechanism underlying PS-NP-induced apoptosis in HK-2 cells and contributed to our risk estimation of PS-NPs in human kidney.

A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study).

Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44-3.12) years. The ORR was 50.9% (95% CI 41.2-60.6) and the DCR was 84.5% (95% CI 76.4-90.7). Median PFS was 7.4 (95% CI 6.0-9.3) months; median OS was 1.63 (95% CI 1.35-2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs.

Knowledge mapping of therapeutic cancer vaccine from 2013 to 2022: A bibliometric and visual analysis.

The investigation of therapeutic cancer vaccines has been ongoing for the past century. Herein, we used VOSviewer and CiteSpace to perform the first global bibliometric analysis of the literature on therapeutic cancer vaccines from 2013 to 2022 aiming to explore the current status and potential research trends. The findings revealed a consistent upward trend in both publication counts and citations. The United States emerged as the leading contributor with the highest number of published papers. Additionally, the analysis of references and keywords indicated that therapeutic cancer vaccines have long been popular topics, whereas neoantigen vaccines, mRNA vaccines, combination strategies, and vaccine delivery systems are emerging research hotspots. This bibliometric study provides a comprehensive and important overview of the current knowledge and potential developments in therapeutic cancer vaccines from 2013 to 2022, which may serve as a valuable reference for scholars interested in further exploring this promising field.

Identification and prediction of immune checkpoint inhibitors-related pneumonitis by machine learning.

Background: Immune checkpoint inhibitor (ICI)-related pneumonitis (IRP) is a common and potentially fatal clinical adverse event. The identification and prediction of the risk of ICI-related IRP is a major clinical issue. The objective of this study was to apply a machine learning method to explore risk factors and establish a prediction model. Methods: We retrospectively analyzed 48 patients with IRP (IRP group) and 142 patients without IRP (control group) who were treated with ICIs. An Elastic Net model was constructed using a repeated k-fold cross-validation framework (repeat = 10; k = 3). The prediction models were validated internally and the final prediction model was built on the entire training set using hyperparameters with the best interval validation performance. The generalizability of the final prediction model was assessed by applying it to an independent test set. The overall performance, discrimination, and calibration of the prediction model were evaluated. Results: Eleven predictors were included in the final predictive model: sindillizumab, number of ≥2 underlying diseases, history of lung diseases, tirelizumab, non-small cell lung cancer (NSCLC), percentage of CD4+ lymphocytes, body temperature, KPS score ≤70, hemoglobin, cancer stage IV, and history of antitumor therapy. The external validation of the risk prediction model on an independent test set of 37 patients and showed good discrimination and acceptable calibration ability: with AUC of 0.81 (95% CI 0.58-0.90), AP of 0.76, scaled Brier score of 0.31, and Spiegelhalter-z of -0.29 (P-value:0.77). We also designed an online IRP risk calculator for use in clinical practice. Conclusion: The prediction model of ICI-related IRP provides a tool for accurately predicting the occurrence of IRP in patients with cancer who received ICIs.

Improving Mechanical and Barrier Properties of Antibacterial Poly(Phenylene Sulfide) Nanocomposites Reinforced with Nano Zinc Oxide-Decorated Graphene.

Nano zinc oxide-decorated graphene (G-ZnO) was blended with polyphenylene sulfide (PPS) to improve its tensile, thermal, crystalline, and barrier properties. The properties of neat PPS and PPS/G-ZnO nanocomposites were characterized and compared using various tests, including tensile tests, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, evaluation of Escherichia coli inhibition, and barrier performance. The results demonstrated that G-ZnO played a crucial role in heterogeneous nucleation and reinforcement. When the concentration of G-ZnO was 0.3%, the tensile strength, elongation at break, thermostability, crystallinity, and water vapor permeability coefficients (WVPC) approached their maximum values, and the microscopic morphology changed from the original brittle fracture to a relatively tough fracture. In addition, when G-ZnO was added to PPS at a ratio of 0.3%, the tensile strength, elongation at break, and WVPC of PPS were increased by 129%, 150%, and 283%, respectively, compared to pure PPS. G-ZnO endowed the nanocomposites with antibacterial properties. The improvement in barrier performance can be attributed to three reasons: (1) the presence of G-ZnO extended the penetration path of molecules; (2) the coordination and hydrogen bonds between PPS polymer matrix and G-ZnO nanofiller narrowed the H2O transmission path; and (3) due to its more hydrophobic surface, water molecules were less likely to enter the interior of PPS/G-ZnO nanocomposites. This study provides valuable insights for developing high-performance PPS-based nanocomposites for various applications.

MiR-146a-5p deficiency in extracellular vesicles of glioma-associated macrophages promotes epithelial-mesenchymal transition through the NF-κB signaling pathway.

Glioma-associated macrophages (GAMs) are pivotal chains in the tumor immune microenvironment (TIME). GAMs mostly display M2-like phenotypes with anti-inflammatory features related to the malignancy and progression of cancers. Extracellular vesicles derived from immunosuppressive GAMs (M2-EVs), the essential components of the TIME, greatly impact the malignant behavior of GBM cells. M1- or M2-EVs were isolated in vitro, and human GBM cell invasion and migration were reinforced under M2-EV treatment. Signatures of the epithelial-mesenchymal transition (EMT) were also enhanced by M2-EVs. Compared with M1-EVs, miR-146a-5p, considered the key factor in TIME regulation, was deficient in M2-EVs according to miRNA-sequencing. When the miR-146a-5p mimic was added, EMT signatures and the invasive and migratory abilities of GBM cells were correspondingly weakened. Public databases predicted the miRNA binding targets and interleukin 1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) were screened as miR-146a-5p binding genes. Bimolecular fluorescent complementation and coimmunoprecipitation confirmed interactions between TRAF6 and IRAK1. The correlation between TRAF6 and IRAK1 was evaluated with immunofluorescence (IF)-stained clinical glioma samples. The TRAF6-IRAK1 complex is the switch and the brake that modulates IKK complex phosphorylation and NF-κB pathway activation, as well as the EMT behaviors of GBM cells. Furthermore, a homograft nude mouse model was explored and mice transplanted with TRAF6/IRAK1-overexpressing glioma cells had shorter survival times while mice transplanted with glioma cells with miR-146a-5p overexpression or TRAF6/IRAK1 knockdown lived longer. This work indicated that in the TIME of GBM, the deficiency of miR-146a-5p in M2-EVs enhances tumor EMT through disinhibition of the TRAF6-IRAK1 complex and IKK-dependent NF-κB signaling pathway providing a novel therapeutic strategy targeting the TIME of GBM.

Diagnostic value of IL-22, IL-23, and IL-17 for NK/T cell lymphoma.

NK/T cell lymphoma (NKTCL) is a common blood cancer, and early diagnosis of this disease is crucial. This study is aimed to investigate the roles of IL-17, IL-22 as well as IL-23 for the diagnosis of NKTCL. Sixty-five patients with NKTCL were included and the blood samples were collected, and sixty healthy objectives served as the controls. Serums of the patients and controls were collected. The expression levels of IL-17, IL-22, and IL-23 were examined using enzyme-linked immunosorbent (ELISA) assay. The receiver operator characteristic (ROC) curve was drawn for determining the potential diagnostic value of these cytokines. The serum levels of IL-17 (156.0 ± 67.75 pg/mL), IL-22 (39.98 ± 23.88 pg/mL), and IL-23 (43.05 ± 25.69 pg/mL) were all markedly increased in NKTCL patients (P<0.001); ROC analysis showed the serum level of IL-17, IL-22, and IL-23 could serve as the potential diagnostic biomarker for NKTCL with high sensitivity and specificity. The AUC of IL-17 was 0.9487 (95% confidence interval (CI), 0.9052 to 0.9922). Area under the curve (AUC) of IL-22 was 0.7321 (95% CI, 0.6449 to 0.8192). The AUC of IL-23 was 0.7885 (95% CI, 0.7070 to 0.8699). Our data indicated that IL-17, IL-22, and IL-23 were all increased in NKTCL and may function as potential diagnostic biomarkers for NKTCL.

Clinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma.

Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival [PFS], clinical benefit rate, adverse events, duration of response, time to progression, overall survival [OS]) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC.

Quantitative Proteomic Analysis Reveals the Mechanisms of Sinapine Alleviate Macrophage Foaming.

Rapeseed polyphenols have cardiovascular protective effects. Sinapine, one main rapeseed polyphenol, possesses antioxidative, anti-inflammatory, and antitumor properties. However, no research has been published about the role of sinapine in alleviating macrophage foaming. This study aimed to reveal the macrophage foaming alleviation mechanism of sinapine by applying quantitative proteomics and bioinformatics analyses. A new approach was developed to retrieve sinapine from rapeseed meals by using hot-alcohol-reflux-assisted sonication combined with anti-solvent precipitation. The sinapine yield of the new approach was significantly higher than in traditional methods. Proteomics was performed to investigate the effects of sinapine on foam cells, and it showed that sinapine can alleviate foam cell formation. Moreover, sinapine suppressed CD36 expression, enhanced the CDC42 expression, and activated the JAK2 and the STAT3 in the foam cells. These findings suggest that the action of sinapine on foam cells inhibits cholesterol uptake, activates cholesterol efflux, and converts macrophages from pro-inflammatory M1 to anti-inflammatory M2. This study confirms the abundance of sinapine in rapeseed oil by-products and elucidates the biochemical mechanisms of sinapine that alleviates macrophage foaming, which may provide new perspectives for reprocessing rapeseed oil by-products.

Multi-Omics Integration Analysis of TK1 in Glioma: A Potential Biomarker for Predictive, Preventive, and Personalized Medical Approaches.

Multi-omics expression datasets obtained from multiple public databases were used to elucidate the biological function of TK1 and its effects on clinical outcomes. The Kaplan-Meier curve, a predictive nomogram mode, and the time-dependent receiver operating characteristic (ROC) curve were established to assess the role of TK1 expression in glioma prognosis. TK1 was overexpressed in glioma compared with normal samples, and patients with elevated expression of TK1 had poor overall survival. The ROC curves indicated a high diagnostic value of TK1 expression in patients of glioma; the areas under the ROC curve (AUC) were 0.682, 0.735, and 0.758 for 1 year, 3 years, and 5 years of glioma survival, respectively. For a model based on TK1 expression and other clinical characteristics, the values of AUC were 0.864, 0.896, and 0.898 for 1 year, 3 years, and 5 years, respectively. Additionally, the calibration curve indicated that the predicted and observed areas at 1 year, 3 years, and 5 years of survival were in excellent agreement. Three types of TK1 alterations-missense mutations, splice mutations, and amplifications-were identified in 25 of 2706 glioma samples. The TK1-altered group had better overall survival than the unaltered group. Single-cell function analysis showed that TK1 was positively associated with proliferation, the cell cycle, DNA repair, DNA damage, and epithelial-mesenchymal transition in glioma. Immunoinfiltration analysis indicated that TK1 expression might play different roles in low-grade glioma and glioblastoma multiforme tumor microenvironments, but TK1 expression was positively associated with activated CD4 and Th2, regardless of tumor grade. In summary, our findings identified TK1 as a novel marker for predicting clinical outcomes and a potential target for glioma.

Experimental checking and modeling of the influence of operation conditions on the first order kinetic constants in free water surface wetlands.

The most commonly used model in constructed wetlands is the first-order removal model, and first order kinetic constants (k) are the key parameters. The presumption is often made that k are constants. However, it is possible that k are functions of operating conditions, but the influence of operation conditions on k is unclear. In this study, response surface methodology was used to explore the variation patterns of ka (area rate constants) and kV (volume rate constants) for the removal of total nitrogen (TN) and total phosphorus (TP) in free water surface (FWS) wetlands. The experimental variables included hydraulic loading rate (HLR), water depth, and inlet concentration (Cin). The results showed that kV was more variable than ka, and the area-based first-order model is more suitable for simulating TN and TP in FWS wetlands. Inlet concentration (Cin) was significant for ka; Cin and water depth were significant for kV; HLR and the interaction between factors were insignificant. The effects of Cin on ka and kV can be described by an upward convex quadratic curve, while the effect of water depth on kV demonstrates a downward convex quadratic curve. The first-order area rate constant for TN removal was given by k = -47.66 + 22.01 Cin - 1.154 Cin2; the first-order area rate constant for TP removal was given by k = -27.75 + 95.88 Cin - 30.73 Cin2. Based on the variation patterns, the traditional k-C model was modified to the kψ-C model. The kψ-C model produced the best results at simulating the outlet concentration and removal efficiency (RE).

A novel twelve-gene signature to predict neoadjuvant chemotherapy response and prognosis in breast cancer.

Background: Accurate evaluation of the response to neoadjuvant chemotherapy (NAC) provides important information about systemic therapies for breast cancer, which implies pharmacological response, prognosis, and guide further therapy. Gene profiles overcome the shortcomings of the relatively limited detection indicators of the classical pathological evaluation criteria and the subjectivity of observation, but are complicated and expensive. Therefore, it is essential to develop a more accurate, repeatable, and economical evaluation approach for neoadjuvant chemotherapy responses. Methods: We analyzed the transcriptional profiles of chemo-resistant breast cancer cell lines and tumors of chemo-resistant breast cancer patients in the GSE25066 dataset. We preliminarily screened out common significantly differentially expressed genes and constructed a NAC response risk model using LASSO regression and univariate and multivariate analyses. The differences in bioinformatic features of tumor cells, immune characteristics, and prognosis were compared between high and low-risk group. The potential drugs that could reverse chemotherapy resistance in breast cancer were screened by the CMap database. Results: Thirty-six genes were commonly up/down-regulated in both NAC chemo-resistant tumors and cells compared to the sensitive tumors and wild-type cells. Through LASSO regression, we obtained a risk model composed of 12 genes. The risk model divided patients into high and low-risk groups. Univariate and multivariate Cox regression analyses suggested that the risk score is an independent prognostic factor for evaluating NAC response in breast cancer. Tumors in risk groups exhibited significant differences in molecular biological characteristics, tumor-infiltrating lymphocytes, and immunosuppressive molecule expression. Our results suggested that the risk score was also a good prognostic factor for breast cancer. Finally, we screened potential drugs that could reverse chemotherapy resistance in breast cancer. Conclusion: A novel 12 gene-signature could be used to predict NAC response and predict prognosis in breast cancer.

Short-course pembrolizumab and continuous afatinib therapy for recurrent or metastatic head and neck squamous cell carcinoma: a real-world data analysis.

OBJECTIVES: The optimal duration of anti-PD-1 for cancer therapy has not been tested, especially when using combination therapy. Epidermal growth factor receptor (EGFR) pathway blocker was the top compound that enhanced T-cell killing of tumor cells in a high-throughput immune-oncology screen, possibly by stimulate the antigen presentation machinery and other mechanisms. We explored the effect of combination of EGFR inhibition with a short course of anti-PD-1 therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). METHOD: We analyzed the effect of a short course of anti-PD-1 with continuous afatinib on the survival of a real-world cohort of R/M HNSCC patients. Patient characteristics, treatments, efficacies, and toxicities were reviewed and recorded for analysis. RESULTS: From November 2016 to May 2018, 51 consecutive patients received pembrolizumab and afatinib. The cutoff date was June 30, 2022. The most common toxicities (all grades) were diarrhea (62.7%), skin rash (43.1%), mucositis (31.4%), and paronychia (23.5%). The objective response rate was 54.9% (95% confidence interval [CI] 40.3-68.9%). Median progression-free survival was 5.9 months (95% CI: 4.4-7.6 months), and the median overall survival was 10.5 months (95% CI: 6.8-16.5 months). The 12-month, 24-month, 36-month, and 48-month survival rate was 47.0%, 22.5%, 17.7%, and 12.6% respectively. CONCLUSIONS: This retrospective study showed that short course pembrolizumab with afatinib therapy has acceptable efficacy in R/M HNSCC patients. The durable response and long-term survival rates were similar to prospective clinical trials. Short course anti-PD-1 therapy, especially in combination with EGFR blocker, is worth for further prospective study.