A pairwise radiomics algorithm-lesion pair relation estimation model for distinguishing multiple primary lung cancer from intrapulmonary metastasis.

Background: Distinguishing multiple primary lung cancer (MPLC) from intrapulmonary metastasis (IPM) is critical for their disparate treatment strategy and prognosis. This study aimed to establish a non-invasive model to make the differentiation pre-operatively. Methods: We retrospectively studied 168 patients with multiple lung cancers (307 pairs of lesions) including 118 cases for modeling and internal validation, and 50 cases for independent external validation. Radiomic features on computed tomography (CT) were extracted to calculate the absolute deviation of paired lesions. Features were then selected by correlation coefficients and random forest classifier 5-fold cross-validation, based on which the lesion pair relation estimation (PRE) model was developed. A major voting strategy was used to decide diagnosis for cases with multiple pairs of lesions. Cases from another institute were included as the external validation set for the PRE model to compete with two experienced clinicians. Results: Seven radiomic features were selected for the PRE model construction. With major voting strategy, the mean area under receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity of the training versus internal validation versus external validation cohort to distinguish MPLC were 0.983 versus 0.844 versus 0.793, 0.942 versus 0.846 versus 0.760, 0.905 versus 0.728 versus 0.727, and 0.962 versus 0.910 versus 0.769, respectively. AUCs of the two clinicians were 0.619 and 0.580. Conclusions: The CT radiomic feature-based lesion PRE model is potentially an accurate diagnostic tool for the differentiation of MPLC and IPM, which could help with clinical decision making.

Gut microbiota interactions with antitumor immunity in colorectal cancer: From understanding to application.

Colorectal cancer (CRC) is one of highly prevalent cancer. Immunotherapy with immune checkpoint inhibitors (ICIs) has dramatically changed the landscape of treatment for many advanced cancers, but CRC still exhibits suboptimal response to immunotherapy. The gut microbiota can affect both anti-tumor and pro-tumor immune responses, and further modulate the efficacy of cancer immunotherapy, particularly in the context of therapy with ICIs. Therefore, a deeper understanding of how the gut microbiota modulates immune responses is crucial to improve the outcomes of CRC patients receiving immunotherapy and to overcome resistance in nonresponders. The present review aims to describe the relationship between the gut microbiota, CRC, and antitumor immune responses, with a particular focus on key studies and recent findings on the effect of the gut microbiota on the antitumor immune activity. We also discuss the potential mechanisms by which the gut microbiota influences host antitumor immune responses as well as the prospective role of intestinal flora in CRC treatment. Furthermore, the therapeutic potential and limitations of different modulation strategies for the gut microbiota are also discussed. These insights may facilitate to better comprehend the interplay between the gut microbiota and the antitumor immune responses of CRC patients and provide new research pathways to enhance immunotherapy efficacy and expand the patient population that could be benefited by immunotherapy.

ERK/MAPK Signalling Pathway Regulates MMP2 Through ETS1 in Renal Clear Cell Carcinoma.

BACKGROUND: The c-ETS-1 (ETS1) expression is high in clear cell renal cell carcinoma (ccRCC) tissues; however, how it impacts ccRCC is currently unknown. METHOD: The online STRING web source was used to construct a protein network interacting with ETS1. The Cell Counting Kit-8 was used to detect the cell viability. A clonogenic assay, a wound-healing assay, and a Transwell assay were used to detect cell proliferation, invasion and migration abilities. Western blot was used to detect the expression of proteins. RESULT: The data showed the expression of ETS1 in ccRCC tissues to be significantly increased compared to adjacent tissues (p<0.05). The positive expression of ETS1 in ccRCC patients aged 20-100 was statistically significant compared to adjacent normal tissues (p<0.05). The grade of ETS1 positive expression (1-4) and lymph node metastasis (N1) in ccRCC were significantly higher than those in adjacent normal tissues (p<0.05). The tumour stage (stages 1-4) in ccRCC patients with positive ETS1 expression was significantly higher than that in adjacent normal tissues (p<0.05). Knockdown of ETS1 and PERK inhibitors significantly inhibited the proliferation, migration and invasion of ccRCC cells. Knockdown of ETS1 inhibited MMP-2 expression, and an extracellular signal-related kinase (ERK) inhibitor inhibited both ETS1 and MMP-2 expression. CONCLUSION: A high expression of ETS1 is associated with the progression of ccRCC. This study suggests that ETS1 promotes proliferation by increasing MMP2 expression in ccRCC, and combined knockdown of ETS1 and inhibition of ERK can significantly inhibit the proliferation, migration and invasion of ccRCC. ETS1 may be a therapeutic and prognostic target for renal cell carcinoma.

The risk of all-cause death with dapagliflozin versus placebo: a systematic review and meta-analysis of phase III randomized controlled trials.

BACKGROUND: Dapagliflozin has proven cardioprotective and nephroprotective effects. However, the risk of all-cause death with dapagliflozin remains unclear. RESEARCH DESIGN AND METHODS: We performed a meta-analysis of phase III randomized controlled trials (RCTs) for the risk of all-cause death and safety events with dapagliflozin compared to placebo. PubMed and EMBASE were searched from inception to 20 September 2022. RESULTS: Five trials were included in the final analysis. Compared with the placebo, dapagliflozin demonstrated an 11.2% reduction in the risk of all-cause death (OR 0.88, 95% CI 0.81-0.94). No statistically significant difference in urinary tract infection (OR: 0.95, 95% CI: 0.78 to 1.17), bone fracture (OR: 1.06, 95% CI: 0.94 to 1.20), and amputation (OR: 1.01, 95% CI: 0.82 to 1.23) was observed between patients treated with dapagliflozin and placebo. Compared with placebo, dapagliflozin was associated with a significant reduction in acute kidney injury (OR: 0.71, 95% CI: 0.60 to 0.83), and increased the risk of genital infection (OR: 8.21, 95% CI: 4.19 to 16.12). CONCLUSIONS: Dapagliflozin was associated with significantly reduced all-cause death and increased genital infection. Dapagliflozin was safe concerning urinary tract infection, bone fracture, amputation, and acute kidney injury, compared with the placebo.

Indirect comparison of SGLT2 inhibitors in patients with established heart failure: evidence based on Bayesian methods.

AIMS: Head-to-head comparisons among SGLT2 inhibitors treatments in established heart failure remain absent. We conducted a systematic review of dedicated heart failure trials to assess indirectly the composite outcomes and individual clinical endpoints among SGLT2 inhibitor treatments. METHODS AND RESULTS: We systematically reviewed randomized controlled trials comparing SGLT2 inhibitors versus placebo in patients with established heart failure. A Bayesian approach to network meta-analysis was applied. Five trials including four treatment strategies were included in this study. The composite of cardiovascular death or hospitalization for heart failure showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 1.00, 95% CI 0.66-1.55), dapagliflozin and sotagliflozin (OR 1.54, 95% CI 0.91-2.65), and empagliflozin and sotagliflozin (OR 1.53, 95% CI 0.90-2.69). All-cause mortality showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 0.92, 95% CI 0.711-1.18), dapagliflozin and sotagliflozin (OR 1.05, 95% CI 0.68-1.59), and empagliflozin and sotagliflozin (OR 1.14, 95% CI 0.74-1.73). Cardiovascular death showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 0.94, 95% CI 0.71-1.23), dapagliflozin and sotagliflozin (OR 0.96, 95% CI 0.61-1.55), and empagliflozin and sotagliflozin (OR 1.03, 95% CI 0.64-1.66). Hospitalization for heart failure showed no significant difference in the comparison between dapagliflozin and empagliflozin (OR 1.13, 95% CI 0.64-1.97), dapagliflozin and sotagliflozin (OR 1.56, 95% CI 0.74-3.15), and empagliflozin and sotagliflozin (OR 1.39, 95% CI 0.68-2.78). CONCLUSIONS: In patients with established heart failure, there was no significant difference of the major efficacy outcomes among SGLT2 inhibitor treatments; however, sotagliflozin may be associated with the lowest risk of the composite of cardiovascular death or hospitalization for heart failure, and dapagliflozin may be associated with the lowest risk of all-cause and cardiovascular mortality.

A bibliometric and visual analysis of cancer-associated fibroblasts.

Background: Cancer-associated fibroblasts (CAFs) represent the predominant stromal component within the tumour microenvironment (TME), exhibiting considerable heterogeneity and plasticity that significantly impact immune response and metabolic reprogramming within the TME, thereby influencing tumour progression. Consequently, investigating CAFs is of utmost importance. The objective of this study is to employ bibliometric analysis in order to evaluate the current state of research on CAFs and predict future areas of research and emerging trends. Methods: Conduct a comprehensive search for scholarly publications within the Web of Science Core Collection database, encompassing the time period from January 1, 2001, to December 31, 2022. Apply VOSviewer, CiteSpace, R software and Microsoft Excel for bibliometric analysis and visualisation. Results: This study involved a comprehensive analysis of 5,925 publications authored by 33,628 individuals affiliated with 4,978 institutions across 79 countries/regions. These publications were published in 908 journals, covering 14,495 keywords and 203,947 references. Notably, there was a significant increase in articles published between 2019 and 2022. China had the highest count of articles, while the United States emerged as the most frequently cited country. The primary research institutions in this field were Shanghai Jiao Tong University, Harvard University, and the University of Texas MD Anderson Cancer Center. Sotgia, Federica and Lisanti, Michael P from the University of Manchester, and Martinet, Wim from the University of Antwerp were the most prolific and highly cited authors. The journal Cancers had the highest number of publications, while Cancer Research was the most frequently cited journal. Molecular, biology, immunology, medicine and genetics were the main research disciplines in the field of CAFs. Key directions in CAFs research encompassed the study of transforming growth factor-ß, Fibroblast Activation Protein, breast cancer, as well as growth and metastasis. The findings from the analysis of keyword co-occurrence and literature co-citation have revealed several emerging hotspots and trends within the field of CAFs. These include STAT3, multidrug resistance, pancreatic ductal adenocarcinoma, pan-cancer analysis, preclinical evaluation, ionizing radiation, and gold nanoparticles. Conclusion: Targeting CAFs is anticipated to be a novel and effective strategy for cancer treatment. This study provides a comprehensive overview of the existing research on CAFs from 2001 to 2022, utilizing bibliometric analysis. The study identified the prominent areas of investigation and anticipated future research directions, with the aim of providing valuable insights and recommendations for future studies in the field of CAFs.

Transcriptomic Analysis Revealed Antimicrobial Mechanisms of Lactobacillus rhamnosus SCB0119 against Escherichia coli and Staphylococcus aureus.

Lactic acid bacteria were reported as a promising alternative to antibiotics against pathogens. Among them, Lactobacillus rhamnosus could be used as probiotics and inhibit several pathogens, but its antibacterial mechanisms are still less known. Here, L. rhamnosus SCB0119 isolated from fermented pickles could inhibit bacterial growth or even cause cell death in Escherichia coli ATCC25922 and Staphylococcus aureus ATCC6538, which was mainly attributed to the cell-free culture supernatant (CFS). Moreover, CFS induced the accumulation of reactive oxygen species and destroyed the structure of the cell wall and membrane, including the deformation in cell shape and cell wall, the impairment of the integrity of the cell wall and inner membrane, and the increases in outer membrane permeability, the membrane potential, and pH gradient in E. coli and S. aureus. Furthermore, the transcriptomic analysis demonstrated that CFS altered the transcripts of several genes involved in fatty acid degradation, ion transport, and the biosynthesis of amino acids in E. coli, and fatty acid degradation, protein synthesis, DNA replication, and ATP hydrolysis in S. aureus, which are important for bacterial survival and growth. In conclusion, L. rhamnosus SCB0119 and its CFS could be used as a biocontrol agent against E. coli and S. aureus.

SGLT2 inhibitors for the composite of cardiorenal outcome in patients with chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials.

To conduct a systematic review and meta-analysis of specific chronic kidney disease (CKD) trials focusing on the composite of cardiorenal outcome, and assess indirectly the clinical outcome of treatments with three inhibitors of sodium-glucose cotransporter-2 (SGLT2) by Bayesian network meta-analysis, we used PubMed and Embase for randomized controlled trials comparing the efficacy of SGLT2 inhibitors in patients with established CKD. We estimated the composite of cardiorenal outcome of SGLT2 inhibitors versus control by pairwise meta-analysis. We included three trials including four treatment strategies (canagliflozin, dapagliflozin, sotagliflozin, and placebo) that met our inclusion criteria. SGLT2 inhibitors reduced the composite of cardiorenal outcome by 27.5% (OR 0.70, 95% CI 0.57-0.86, I2 = 72%). Results were corroborated in subgroup analysis. SGLT2 inhibitors reduced the composite of cardiorenal outcome in patients with and without diabetes (OR 0.72, 95% CI 0.60-0.86, and OR 0.51, 95% CI 0.35-0.75, respectively). The composite of cardiorenal outcome showed no significant difference in the comparison among three drugs: canagliflozin and dapagliflozin (OR 1.14, 95% CI 0.46-3.16), canagliflozin and sotagliflozin (OR 0.79, 95% CI 0.30-2.06), dapagliflozin and sotagliflozin (OR 0.69, 95% CI 0.26-1.73). Dapagliflozin was identified as having the lowest risk of the composite of cardiorenal outcome. In conclusion, SGLT2 inhibitors have robust benefits on the composite of cardiorenal outcome in patients with CKD. There was no significant difference in the composite of cardiorenal outcome among treatments with three SGLT2 inhibitors; however, dapagliflozin may be associated with the lowest risk of the composite of cardiorenal outcome.

NOTCH1 mutation associates with impaired immune response and decreased relapse-free survival in patients with resected T1-2N0 laryngeal cancer.

Background: Patients with early-stage laryngeal cancer, even stage T1-2N0, are at considerable risk of recurrence and death. The genetic and immunologic characteristics of recurrent laryngeal cancer remain unclear. Methods: A total of 52 T1-2N0 laryngeal cancer patients were enrolled. Of these, 42 tissue samples were performed by targeted DNA sequencing, and 21 cases were performed by NanoString immuno-oncology targeted RNA sequencing to identify the distinct molecular bases and immunologic features associated with relapse in patients with early laryngeal cancer, respectively. Results: To the best to our knowledge, we present for the first time an overview of the genomic mutation spectrum of early-stage laryngeal cancers. A total of 469 genomic alterations were detected in 211 distinct cancer-relevant genes, and the genes found to be mutated in more than five patients (>10%) included tumor protein p53 (TP53, 78.5%), FAT atypical cadherin 1 (FAT1, 26%), LDL receptor related protein 1B (LRP1B, 19%), cyclin dependent kinase inhibitor 2A (CDKN2A, 17%), tet methylcytosine dioxygenase 2 (TET2, 17%), notch receptor 1 (NOTCH1, 12%) and neuregulin 1 (NRG1, 12%). Recurrent laryngeal cancer demonstrated a higher tumor mutation burden (TMB), as well as higher LRP1B mutation and NOTCH1 mutation rates. Univariate and multivariate analyses revealed that high TMB (TMB-H) and NOTCH1 mutation are independent genetic factors that are significantly associated with shorter relapse-free survival (RFS). Simultaneously, the results of the transcriptome analysis presented recurrent tumors with NOTCH1 mutation displayed upregulation of the cell cycle pathway, along with decreased B cells score, T cells score, immune signature score and tumor-infiltrating lymphocytes (TILs) score. The Cancer Genome Atlas (TCGA)-laryngeal cancer dataset also revealed weakened immune response and impaired adhesion functions in NOTCH1-mutant patients. Conclusions: Genomic instability and impaired immune response are key features of the immunosurveillance escape and recurrence of early laryngeal cancer after surgery. These findings revealed immunophenotypic attenuation in recurrent tumors and provided valuable information for improving the management of these high-risk patients. Due to the small number of patients in this study, these differences need to be further validated in a larger cohort.

Novel Plasma Proteomic Biomarkers for Early Identification of Induction Chemotherapy Beneficiaries in Locoregionally Advanced Nasopharyngeal Carcinoma.

Background: Induction chemotherapy (IC) can alleviate locoregionally advanced nasopharyngeal carcinoma (LA-NPC), but effectiveness differs between patients, toxicity is problematic, and effective blood-based IC efficacy predictors are lacking. Here, we aimed to identify biomarkers for early identification of IC beneficiaries. Methods: Sixty-four pairs of matched plasma samples collected before and after IC from LA-NPC patients including 34 responders and 30 non-responders, as well as 50 plasma samples of healthy individuals, were tested using data-independent acquisition mass spectrometry. The proteins associated with clinical traits or IC benefits were investigated by weighted gene co-expression network analysis (WGCNA) and soft cluster analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional annotations were performed to determine the potential function of the identified proteins. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of candidate biomarkers in predicting IC beneficiaries. Results: Compared with healthy individuals, 1027 differentially expressed proteins (DEPs) were found in the plasma of LA-NPC patients. Based on feedback from IC outcomes, 463 DEPs were identified in the pre-IC plasma between responders and non-responders. A total of 1212 DEPs represented the proteomic changes before and after IC in responders, while 276 DEPs were identified in post-IC plasma between responders and non-responders. WGCNA identified nine protein co-expression modules correlated with clinical traits. Soft cluster analysis identified four IC benefits-related protein clusters. Functional enrichment analysis showed that these proteins may play a role in IC via immunity, complement, coagulation, glycosaminoglycan and serine. Four proteins differentially expressed in all group comparisons, paraoxonase/arylesterase 1 (PON1), insulin-like growth factor-binding protein 3 (IGFBP-3), rheumatoid factor D5 light chain (v-kappa-3) and RNA helicase (DDX55), were associated with clinical traits or IC benefits. A four-protein model accurately identified potential IC beneficiaries (AUC=0.95) while diagnosing LA-NPC (AUC=0.92), and the prediction performance was verified using the models to confirm the effective IC (AUC=0.97) and evaluate IC outcome (AUC=0.94). Conclusion: The plasma protein profiles among IC responders and non-responders were different. PON1, IGFBP3, v-kappa-3 and DDX55 could serve as potential biomarkers for early identification of IC beneficiaries for individualised treatment of LA-NPC.

A novel three-microRNA signature for predicting survival in patients with nasopharyngeal carcinoma.

BACKGROUND/PURPOSE: Nasopharyngeal carcinoma (NPC) is a malignant neoplasm of the head and neck. This study aims to use integrated bioinformatics technologies to develop a predictive miRNA-signature correlated with the prognosis of NPC. MATERIALS AND METHODS: Initially, the differentially expressed miRNAs (DEMs) in NPC were identified, and then DEMs related to the prognosis of NPC were further screened. Subsequently, the relatively important DEMs identified by random forest algorithm were used to construct a predictive signature by multivariate COX regression analysis. Moreover, PCA, Kaplan-Meier analysis, time-dependent ROC analysis, and univariate and multivariate COX regression analysis were performed to evaluate the ability of the signature in risk identification and prognosis prediction in NPC. RESULTS: Hsa-miR-29c, hsa-miR-30e and hsa-miR-93 were selected from DEMs to construct a signature, and their abnormal expression was significantly associated with poor prognosis of NPC. The average AUC values of 1- to 5-year OS, DFS and DMFS predicted by the signature were all above 0.7, and showed better clinical independence than other indexes. In addition, 295 differentially expressed mRNAs could be used as potential target genes of the 3 DEMs. Among them, 56 differentially expressed mRNAs were related to PFS. GO and KEGG enrichment analysis indicated that the poor prognosis of NPC was related to the abnormality of chromosomes, cytokines, and chemokines. CONCLUSION: We constructed a three-miRNA signature with good independent performance in predicting the prognosis for NPC. This study may lay the foundation for exploring new therapeutic targets and improving survival outcomes in NPC patients.

Research status and prospects of acupuncture for prevention and treatment of chemo- and radiotherapy-induced salivary gland dysfunction in head and neck cancer.

Salivary gland dysfunction (SGD) induced by chemo- and radiotherapy for head and neck cancer (HNC) has always been a difficult problem in modern medicine. The quality of life of a large number of HNC patients is severely impaired by SGD such as xerostomia and dysphagia. In recent years, several studies have found that acupuncture can improve patients' salivary secretion, but it has not yet been approved as an alternative therapy for SGD. For this reason, we collected the clinical study reports on acupuncture in the treatment of SGD induced by chemo- and radiotherapy in HNC patients in the past 20 years, and analyzed and discussed the advantages and disadvantages of these studies with respect to tumor types, group setting, intervention modality, acupoints selection, outcome evaluation, and safety. We believed that acupuncture is beneficial for SGD, but the existing objective evidence is insufficient to support its effectiveness. Therefore, improving the Standards for Reporting Interventions in Clinical Trials of Acupuncture, selecting the optimal combination of acupoints through scientific and rigorous study design, and exploring the potential mechanism of acupuncture in the treatment of diseases combined with the meridian theory may be effective ways to promote the acceptance of acupuncture as an alternative therapy for SGD in future. The significance of this review is to provide a reference for researchers to carry out high-quality clinical trials of acupuncture in the treatment of SGD in future from the perspective of the combination of modern medicine and traditional Chinese medicine.

Celastrol induces caspase-dependent apoptosis of hepatocellular carcinoma cells by suppression of mammalian target of rapamycin.

OBJECTIVE: To investigate the efficacy of celastrol treatment of hepatocellular carcinoma (HCC) cells in vitro and in vivo and to propose a mechanism of action. METHODS: A human HepG2 liver cancer cell line and a xenograft tumor model were used to investigate the effects of celastrol on HCC in vitro and in vivo. A CCK-8 kit was used to detect cell viability. Flow cytometry and terminal-deoxynucleoitidyl transferase mediated nick end labeling staining were used to detect apoptosis. Western blotting and immunohistochemistry were used to detect the expression of cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9, cleaved-PARP, mammalian target of rapamycin (mTOR), and p-mTOR. Hematoxylin-eosin staining was used to observe the tissue morphology. RESULTS: Celastrol decreased the viability of HepG2 cells and induced apoptosis. Western blot assays indicated that celastrol up-regulated cleaved-caspase-3, cleaved-caspase-8, cleaved-caspase-9, and cleaved-PARP by inhibiting the phosphorylation of mTOR in HepG2 cells. Moreover, celastrol inhibited the tumor growth in a xenograft model. Celastrol also induced caspase-dependent apoptosis (up-regulation of cleaved-caspase- 3, -8, -9, and cleaved-PARP) and inhibited the activation of mTOR in vivo. CONCLUSION: Celastrol induces caspase-dependent apoptosis in HCC cells by inhibiting the activation of mTOR.

Improving the Thermostability and Activity of Transaminase From Aspergillus terreus by Charge-Charge Interaction.

Transaminases that promote the amination of ketones into amines are an emerging class of biocatalysts for preparing a series of drugs and their intermediates. One of the main limitations of (R)-selective amine transaminase from Aspergillus terreus (At-ATA) is its weak thermostability, with a half-life (t 1/2) of only 6.9 min at 40°C. To improve its thermostability, four important residue sites (E133, D224, E253, and E262) located on the surface of At-ATA were identified using the enzyme thermal stability system (ETSS). Subsequently, 13 mutants (E133A, E133H, E133K, E133R, E133Q, D224A, D224H, D224K, D224R, E253A, E253H, E253K, and E262A) were constructed by site-directed mutagenesis according to the principle of turning the residues into opposite charged ones. Among them, three substitutions, E133Q, D224K, and E253A, displayed higher thermal stability than the wild-type enzyme. Molecular dynamics simulations indicated that these three mutations limited the random vibration amplitude in the two α-helix regions of 130-135 and 148-158, thereby increasing the rigidity of the protein. Compared to the wild-type, the best mutant, D224K, showed improved thermostability with a 4.23-fold increase in t 1/2 at 40°C, and 6.08°C increase in T 50 10 . Exploring the three-dimensional structure of D224K at the atomic level, three strong hydrogen bonds were added to form a special "claw structure" of the α-helix 8, and the residues located at 151-156 also stabilized the α-helix 9 by interacting with each other alternately.

Research status and prospects of biomarkers for nasopharyngeal carcinoma in the era of high­throughput omics (Review).

As a malignant tumor type, nasopharyngeal carcinoma (NPC) is characterized by distinct geographical, ethnic and genetic differences; presenting a major threat to human health in many countries, especially in Southern China. At present, no accurate and effective methods are available for the early diagnosis, efficacious evaluation or prognosis prediction for NPC. As such, a large number of patients have locoregionally advanced NPC at the time of initial diagnosis. Many patients show toxic reactions to overtreatment and have risks of cancer recurrence and distant metastasis owing to insufficient treatment. To solve these clinical problems, high­throughput '­omics' technologies are being used to screen and identify specific molecular biomarkers for NPC. Because of the lack of comprehensive descriptions regarding NPC biomarkers, the present study summarized the research progress that has been made in recent years to discover NPC biomarkers, highlighting the existing problems that require exploration. In view of the lack of authoritative reports at present, study design factors that affect the screening of biomarkers are also discussed here and prospects for future research are proposed to provide references for follow­up studies of NPC biomarkers.

Alterations in hematological and biochemical parameters, oxidative stress, and immune response in Takifugu rubripes under acute ammonia exposure.

Ammonia is a major pollutant in aquatic environments and poses a considerable threat to the survival of fish. In this study, we investigated the toxic effects of ammonia on the hematological and biochemical parameters, oxidative stress, and immune responses in Takifugu rubripes. Juvenile T. rubripes (average weight 246.17 ± 3.54 g) were exposed to different concentrations of ammonia (0, 5, 50, 100, and 150 mg/L) for 96 h. The results showed that the hematological parameters (hemoglobin, hematocrit, red blood cell, and white blood cell count) were significantly reduced in response to ammonia exposure. Of the plasma components, such as serum total protein, albumin, glucose, glutamic-oxalacetic transaminase, and glutamic-pyruvic transaminase, were significantly altered in response to ammonia exposure. Additionally, the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx) were increased after exposure to low concentration ammonia exposure. However, when fish were exposed to a high concentration of ammonia, these parameters showed the opposite trend, suggesting that an increase in antioxidant enzymes during the early stages of ammonia exposure may contribute to the removal of the induced reactive oxygen species (ROS) and protect the cells from oxidative damage. However, as the ammonia concentration and exposure time increased, the overproduction of ROS accelerated the depletion of antioxidant enzymes. Ammonia exposure significantly increased the expression of heat shock proteins (HSP70 and HSP90). Ammonia poisoning elevated gene expressions of TLR-3, TNF-α, IL-6, IL-12, and IL-1ß in the gills, causing an inflammatory response. Our findings provide new insights into the mechanisms involved in ammonia-induced aquatic toxicology in marine fish, which may aid in their captive management.

The risk of bleeding and all-cause mortality with edoxaban versus vitamin K antagonists: A meta-analysis of phase III randomized controlled trials.

INTRODUCTION: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. However, the risk of bleeding and all-cause mortality in patients with edoxaban versus vitamin K antagonists (VKAs) is unclear. METHODS: We systematically searched all published studies of edoxaban versus VKAs. PubMed, CENTRAL databases and www.clinicaltrial.gov were searched for relevant articles published from January 1966 to 20 February 2020. All phase III randomized controlled trials (RCTs) comparing the risk of bleeding and all-cause mortality in patients with edoxaban versus VKAs were included in our meta-analysis. Both random- and fixed-effects models were used to pool data across phase III RCTs. RESULTS: We included four trials that met our inclusion criteria (n = 33,077). They included patients with atrial fibrillation (3 trials, n = 24,847), venous thromboembolism (VTE) or pulmonary embolism (PE) (1 trial, n = 8240). Edoxaban was associated with reduced risks of major or clinically relevant nonmajor bleeding (CRNM) events (OR: 0.78, 95% CI: 0.68-0.89), any bleeding events (OR: 0.76, 95% CI: 0.72-0.80), and intracranial bleeding events (OR: 0.38, 95% CI: 0.29-0.48). They had a similar risk of gastro-intestinal bleeding (OR: 0.95, 95% CI: 0.79-1.13), death from any cause (OR: 0.97, 95% CI: 0.80-1.19), stroke (OR: 1.00, 95% CI: 0.88-1.14) and systemic embolic events (OR: 0.93, 95% CI: 0.57-1.51) between edoxaban and VKAs. CONCLUSIONS: Compared to VKAs, edoxaban is safe as a direct oral anticoagulant, with respect to reduced risk of major or CRNM, intracranial bleeding events, and similar risk of gastro-intestinal bleeding events and all-cause mortality.

Natural selection and genetic diversity of domain I of Plasmodium falciparum apical membrane antigen-1 on Bioko Island.

BACKGROUND: Plasmodium falciparum apical membrane antigen-1 (PfAMA-1) is a promising candidate antigen for a blood-stage malaria vaccine. However, antigenic variation and diversity of PfAMA-1 are still major problems to design a universal malaria vaccine based on this antigen, especially against domain I (DI). Detail understanding of the PfAMA-1 gene polymorphism can provide useful information on this potential vaccine component. Here, general characteristics of genetic structure and the effect of natural selection of DIs among Bioko P. falciparum isolates were analysed. METHODS: 214 blood samples were collected from Bioko Island patients with P. falciparum malaria between 2011 and 2017. A fragment spanning DI of PfAMA-1 was amplified by nested polymerase chain reaction and sequenced. Polymorphic characteristics and the effect of natural selection were analysed using MEGA 5.0, DnaSP 6.0 and Popart programs. Genetic diversity in 576 global PfAMA-1 DIs were also analysed. Protein function prediction of new amino acid mutation sites was performed using PolyPhen-2 program. RESULTS: 131 different haplotypes of PfAMA-1 were identified in 214 Bioko Island P. falciparum isolates. Most amino acid changes identified on Bioko Island were found in C1L. 32 amino acid changes identified in PfAMA-1 sequences from Bioko Island were found in predicted RBC-binding sites, B cell epitopes or IUR regions. Overall patterns of amino acid changes of Bioko PfAMA-1 DIs were similar to those in global PfAMA-1 isolates. Differential amino acid substitution frequencies were observed for samples from different geographical regions. Eight new amino acid changes of Bioko island isolates were also identified and their three-dimensional protein structural consequences were predicted. Evidence for natural selection and recombination event were observed in global isolates. CONCLUSIONS: Patterns of nucleotide diversity and amino acid polymorphisms of Bioko Island isolates were similar to those of global PfAMA-1 DIs. Balancing natural selection across DIs might play a major role in generating genetic diversity in global isolates. Most amino acid changes in DIs occurred in predicted B-cell epitopes. Novel sites mapped on a three dimensional structure of PfAMA-1 showed that these regions were located at the corner. These results may provide significant value in the design of a malaria vaccine based on this antigen.

Internal Versus External Drainage With a Pancreatic Duct Stent For Pancreaticojejunostomy During Pancreaticoduodenectomy for Patients at High Risk for Pancreatic Fistula: A Comparative Study.

BACKGROUND: The aim of this study was to determine whether internal or external drainage with a pancreatic duct stent is the optimal pancreaticojejunostomy method to prevent pancreatic fistula (PF) after pancreaticoduodenectomy (PD) for subgroups of patients at high risk for PF. MATERIALS AND METHODS: A total of 495 patients who underwent PD were reviewed. Univariate and multivariate analyses were used to identify risk factors for PF after PD. We further compared the incidence of PF and outcomes between the internal and external drainage groups for subgroups of patients at high risk for PF. RESULTS: There was no difference in the incidence of complications according to the Clavien-Dindo classification or the rate of PF after PD in both groups (P = 0.961 and P = 0.505, respectively). The incidence of mortality was 3.8% in the internal drainage group and 3.9% in the external drainage group (P = 0.980). Univariate and multivariate analyses identified male gender (odds ratio [OR] = 2.93; 95% confidence interval [CI], 1.78-4.83; P = 0.000), pancreatic duct diameter (<3 mm) (OR = 2.58; 95% CI, 1.57-4.23; P = 0.000), and soft pancreatic texture (OR = 2.92; 95% CI, 1.71-4.98; P = 0.000) as independent risk factors for PF after PD. No differences in the incidence of PF for the subgroups of patients with one, two, or three risk factors were observed between the internal and external drainage groups (P = 0.334, P = 1.000, and P = 0.936, respectively). No differences in total complications, delayed gastric emptying, postpancreatectomy hemorrhage, biliary fistula, infection complications, reoperation, perioperative mortality, or postoperative hospital stay were noted. In addition, liquid loss and tube-related complications occurred in the external drainage group. CONCLUSIONS: Internal drainage is the optimal method to prevent PF after PD for subgroups of patients at high risk for PF because the surgical procedure is simple and prevents liquid loss and tube-related complications associated with external drainage. However, no differences in the incidence of PF and other complications after PD were observed between the two approaches.

Incorporating C60 as Nucleation Sites Optimizing PbI2 Films To Achieve Perovskite Solar Cells Showing Excellent Efficiency and Stability via Vapor-Assisted Deposition Method.

To achieve high-quality perovskite solar cells (PSCs), the morphology and carrier transportation of perovskite films need to be optimized. Herein, C60 is employed as nucleation sites in PbI2 precursor solution to optimize the morphology of perovskite films via vapor-assisted deposition process. Accompanying the homogeneous nucleation of PbI2, the incorporation of C60 as heterogeneous nucleation sites can lower the nucleation free energy of PbI2, which facilitates the diffusion and reaction between PbI2 and organic source. Meanwhile, C60 could enhance carrier transportation and reduce charge recombination in the perovskite layer due to its high electron mobility and conductivity. In addition, the grain sizes of perovskite get larger with C60 optimizing, which can reduce the grain boundaries and voids in perovskite and prevent the corrosion because of moisture. As a result, we obtain PSCs with a power conversion efficiency (PCE) of 18.33% and excellent stability. The PCEs of unsealed devices drop less than 10% in a dehumidification cabinet after 100 days and remain at 75% of the initial PCE during exposure to ambient air (humidity > 60% RH, temperature > 30 °C) for 30 days.