Untargeted metabolomics reveals potential plasma biomarkers for diagnosis of primary aldosteronism using liquid chromatography-mass spectrometry.

Metabolite profiling has the potential to comprehensively bridge phenotypes and complex heterogeneous physiological and pathological states. We performed a metabolomics study using parallel liquid chromatography-mass spectrometry (LC-MS) combined with multivariate data analysis to screen for biomarkers of primary aldosteronism (PA) from a cohort of 111 PA patients and 218 primary hypertension (PH) patients. Hydrophilic interaction chromatography and reversed-phase liquid chromatography separations were employed to obtain a global plasma metabolome of endogenous metabolites. The satisfactory classification between PA and PH patients was obtained using the MVDA model. A total of 35 differential metabolites were screened out and identified. A diagnostic biomarker panel was established using the least absolute shrinkage and selection operator (LASSO) binary logistic regression model and receiver operating characteristic analysis. Joint analysis with clinical indicators, including plasma supine aldosterone level, plasma orthostatic aldosterone level, body mass index, and blood potassium, revealed that the combination of metabolite biomarker panel and plasma supine aldosterone has the best clinical diagnostic efficacy.

A novel comprehensive strategy for high-thoroughly studying released compounds during the combustion process of herbs. A case study for Artemisia argyi Levl. et Vant.

The comprehensive study of compound variations in released smoke during the combustion process is a great challenge in many scientific fields related to analytical chemistry like traditional Chinese medicine, environment analysis, food analysis, etc. In this work, we propose a new comprehensive strategy for efficiently and high-thoroughly characterizing compounds in the online released complex smokes: (i) A smoke capture device was designed for efficiently collecting chemical constituents to perform gas chromatography-mass spectrometry (GC-MS) based untargeted analysis. (ii) An advanced data analysis tool, AntDAS-GCMS, was used for automatically extracting compounds in the original acquired GC-MS data files. Additionally, a GC-MS data analysis guided instrumental parameter optimizing strategy was proposed for the optimization of parameters in the smoke capture device. The developed strategy was demonstrated by the study of compound variations in the smoke of traditional Chinese medicine, Artemisia argyi Levl. et Vant. The results indicated that more than 590 components showed significant differences among released smokes of various moxa velvet ratios. Finally, about 88 compounds were identified, of which phenolic compounds were the most abundant, followed by aromatics, alkenes, alcohols and furans. In conclusion, we may provide a novel approach to the studies of compounds in online released smoke.

Negative serum (1,3) -ß-D-glucan has a low power to exclude Pneumocystis jirovecii pneumonia (PJP) in HIV-uninfected patients with positive qPCR.

OBJECTIVE: The current study evaluated the diagnostic performance of serum (1,3)-beta-D Glucan (BDG) in differentiating PJP from P. jirovecii-colonization in HIV-uninfected patients with P. jirovecii PCR-positive results. METHODS: This was a single-center retrospective study between 2019 and 2021. The diagnosis of PJP was based on the following criteria: detection of P. jirovecii in sputum or BAL specimen by qPCR or microscopy; Meet at least two of the three criteria: (1) have respiratory symptoms of cough and/or dyspnea, hypoxia; (2) typical radiological picture findings; (3) receiving a complete PJP treatment. After exclusion, the participants were divided into derivation and validation cohorts. The derivation cohort defined the cut-off value of serum BDG. Then, it was verified using the validation cohort. RESULTS: Two hundred and thirteen HIV-uninfected patients were enrolled, with 159 PJP and 54 P. jirovecii-colonized patients. BDG had outstanding specificity, LR, and PPV for PJP in both the derivation (90.00%, 8.900, and 96.43%) and the validation (91.67%, 9.176, and 96.30%) cohorts at ≥ 117.7 pg/mL. However, it had lower sensitivity and NPV in the derivation cohort (89.01% and 72.97%), which was even lower in the validation cohort (76.47% and 57.89%). Of note, BDG ≥ 117.7 pg/mL has insufficient diagnostic efficacy for PJP in patients with lung cancer, interstitial lung disease (ILD) and nephrotic syndrome. And although lymphocytes, B cells, and CD4+ T cells in PJP patients were significantly lower than those in P. jirovecii-colonized patients, the number and proportion of peripheral blood lymphocytes did not affect the diagnostic efficacy of serum BDG. CONCLUSIONS: Serum BDG ≥ 117.7 pg/mL could effectively distinguish P. jirovecii-colonization from infection in qPCR-positive HIV-uninfected patients with infectious diseases, solid tumors (excluding lung cancer), autoimmune or inflammatory disorders, and hematological malignancies. Of note, for patients with lung cancer, ILD, and nephrotic diseases, PJP should be cautiously excluded at BDG < 117.7 pg/mL.

The triglyceride-glucose index as a potential protective factor for hypertrophic obstructive cardiomyopathy without diabetes: evidence from a two-center study.

OBJECTIVE: This study aimed to investigate the relationship between the TyG (Triglyceride-glucose index) and the prognosis of patients with HOCM (hypertrophic obstructive cardiomyopathy) without diabetes. RESEARCH DESIGN AND METHODS: A total of 713 eligible patients with HOCM were enrolled in this study and divided into two groups based on treatment: an invasive treatment group (n = 461) and a non-invasive treatment group (n = 252). The patients in both two groups were then divided into three groups based on their TyG index levels. The primary endpoints of this study were Cardiogenic death during long-term follow-up. Kaplan-Meier analysis was used to study the cumulative survival of different groups. Restricted cubic spline was used to model nonlinear relationships between the TyG index and primary endpoints. Myocardial perfusion imaging/Myocardial metabolic imaging examinations were performed to assess glucose metabolism in the ventricular septum of the HOCM patients. RESULTS: The follow-up time of this study was 41.47 ± 17.63 months. The results showed that patients with higher TyG index levels had better clinical outcomes (HR, 0.215; 95% CI 0.051,0.902; P = 0.036, invasive treatment group; HR, 0.179; 95% CI 0.063,0.508; P = 0.001, non-invasive treatment group). Further analysis showed that glucose metabolism in the ventricular septum was enhanced in HOCM patients. CONCLUSIONS: The findings of this study suggest that the TyG index may serve as a potential protective factor for patients with HOCM without diabetes. The enhanced glucose metabolism in the ventricular septum of HOCM patients may provide a potential explanation for the relationship between the TyG index and HOCM prognosis.

Immunomodulation: The next target of mesenchymal stem cell-derived exosomes in the context of ischemic stroke.

Ischemic stroke (IS) is the most prevalent form of brain disease, characterized by high morbidity, disability, and mortality. However, there is still a lack of ideal prevention and treatment measures in clinical practice. Notably, the transplantation therapy of mesenchymal stem cells (MSCs) has been a hot research topic in stroke. Nevertheless, there are risks associated with this cell therapy, including tumor formation, coagulation dysfunction, and vascular occlusion. Also, a growing number of studies suggest that the therapeutic effect after transplantation of MSCs is mainly attributed to MSC-derived exosomes (MSC-Exos). And this cell-free mediated therapy appears to circumvent many risks and difficulties when compared to cell therapy, and it may be the most promising new strategy for treating stroke as stem cell replacement therapy. Studies suggest that suppressing inflammation via modulation of the immune response is an additional treatment option for IS. Intriguingly, MSC-Exos mediates the inflammatory immune response following IS by modulating the central nervous system, the peripheral immune system, and immunomodulatory molecules, thereby promoting neurofunctional recovery after stroke. Thus, this paper reviews the role, potential mechanisms, and therapeutic potential of MSC-Exos in post-IS inflammation in order to identify new research targets.

Association of triglyceride-glucose index with atherosclerotic cardiovascular disease and mortality among familial hypercholesterolemia patients.

BACKGROUND: Familial hypercholesterolemia (FH) is an inherited metabolic disorder with a high level of low-density lipoprotein cholesterol and the worse prognosis. The triglyceride-glucose (TyG) index, an emerging tool to reflect insulin resistance (IR), is positively associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD) in healthy individuals, but the value of TyG index has never been evaluated in FH patients. This study aimed to determine the association between the TyG index and glucose metabolic indicators, insulin resistance (IR) status, the risk of ASCVD and mortality among FH patients. METHODS: Data from National Health and Nutrition Examination Survey (NHANES) 1999-2018 were utilized. 941 FH individuals with TyG index information were included and categorized into three groups: < 8.5, 8.5-9.0, and > 9.0. Spearman correlation analysis was used to test the association of TyG index and various established glucose metabolism-related indicators. Logistic and Cox regression analysis were used to assess the association of TyG index with ASCVD and mortality. The possible nonlinear relationships between TyG index and the all-cause or cardiovascular death were further evaluated on a continuous scale with restricted cubic spline (RCS) curves. RESULTS: TyG index was positively associated with fasting glucose, HbA1c, fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR) index (all p < 0.001). The risk of ASCVD increased by 74% with every 1 unit increase of TyG index (95%CI: 1.15-2.63, p = 0.01). During the median 114-month follow-up, 151 all-cause death and 57 cardiovascular death were recorded. Strong U/J-shaped relations were observed according to the RCS results (p = 0.0083 and 0.0046 for all-cause and cardiovascular death). A higher TyG index was independently associated with both all-cause death and cardiovascular death. Results remained similar among FH patients with IR (HOMA-IR ≥ 2.69). Moreover, addition of TyG index showed helpful discrimination of both survival from all-cause death and cardiovascular death (p < 0.05). CONCLUSION: TyG index was applicable to reflect glucose metabolism status in FH adults, and a high TyG index was an independent risk factor of both ASCVD and mortality.

Oridonin ameliorates caspase-9-mediated brain neuronal apoptosis in mouse with ischemic stroke by inhibiting RIPK3-mediated mitophagy.

Neuronal loss is a primary factor in determining the outcome of ischemic stroke. Oridonin (Ori), a natural diterpenoid compound extracted from the Chinese herb Rabdosia rubescens, has been shown to exert anti-inflammatory and neuroregulatory effects in various models of neurological diseases. In this study we investigated whether Ori exerted a protective effect against reperfusion injury-induced neuronal loss and the underlying mechanisms. Mice were subjected to transient middle cerebral artery occlusion (tMCAO), and were injected with Ori (5, 10, 20 mg/kg, i.p.) at the beginning of reperfusion. We showed that Ori treatment rescued neuronal loss in a dose-dependent manner by specifically inhibiting caspase-9-mediated neuronal apoptosis and exerted neuroprotective effects against reperfusion injury. Furthermore, we found that Ori treatment reversed neuronal mitochondrial damage and loss after reperfusion injury. In N2a cells and primary neurons, Ori (1, 3, 6 µM) exerted similar protective effects against oxygen-glucose deprivation and reoxygenation (OGD/R)-induced injury. We then conducted an RNA-sequencing assay of the ipsilateral brain tissue of tMCAO mice, and identified receptor-interacting protein kinase-3 (RIPK3) as the most significantly changed apoptosis-associated gene. In N2a cells after OGD/R and in the ipsilateral brain region, we found that RIPK3 mediated excessive neuronal mitophagy by activating AMPK mitophagy signaling, which was inhibited by Ori or 3-MA. Using in vitro and in vivo RIPK3 knockdown models, we demonstrated that the anti-apoptotic and neuroprotective effects of Ori were RIPK3-dependent. Collectively, our results show that Ori effectively inhibits RIPK3-induced excessive mitophagy and thereby rescues the neuronal loss in the early stage of ischemic stroke.

Vessels that encapsulate tumor clusters (VETC) pattern predicts the efficacy of adjuvant TACE in hepatocellular carcinoma.

PURPOSE: Postoperative adjuvant trans-catheter arterial chemoembolization (TACE) is regarded as a common strategy for hepatocellular carcinoma (HCC) patients at a high risk of recurrence. However, there are currently no clinically available biomarkers to predict adjuvant TACE response. Vessels that encapsulate tumor clusters (VETC) can be used as an independent predictor of HCC prognosis. In this study, we aimed to explore whether the VETC pattern could predict adjuvant TACE benefit. METHODS: Vascular pattern and HIF-1α expression were detected in immunohistochemistry. The survival benefit of adjuvant TACE therapy for patients with or without VETC pattern (VETC+ /VETC-) was evaluated. RESULTS: The adjuvant TACE therapy obviously improved the TTR and OS in VETC+ patients, while adjuvant TACE therapy could not benefit from VETC- patients. Univariate and multivariate analysis revealed that adjuvant TACE therapy significantly improved the TTR and OS in VETC+ patients, but not in VETC- patients. In addition, the VETC+ , but not VETC- , patients could benefit from adjuvant TACE therapy in patients with high-risk factors of vascular invasion, larger tumor or multiple tumor. The mechanistic investigations revealed that the favorable efficacy of adjuvant TACE on VETC+ patients, but not VETC- ones, may be not due to the activation of HIF-1α pathway. CONCLUSION: The VETC pattern may represent a novel and reliable factor for selecting HCC patients who may benefit from adjuvant TACE therapy, and the combination of VETC pattern and tumor characteristics may help stratify patients' outcomes and responses to adjuvant TACE therapy.

Erythropoietin signaling in peripheral macrophages is required for systemic ß-amyloid clearance.

Impaired clearance of beta-amyloid (Aß) is a primary cause of sporadic Alzheimer's disease (AD). Aß clearance in the periphery contributes to reducing brain Aß levels and preventing Alzheimer's disease pathogenesis. We show here that erythropoietin (EPO) increases phagocytic activity, levels of Aß-degrading enzymes, and Aß clearance in peripheral macrophages via PPARγ. Erythropoietin is also shown to suppress Aß-induced inflammatory responses. Deletion of EPO receptor in peripheral macrophages leads to increased peripheral and brain Aß levels and exacerbates Alzheimer's-associated brain pathologies and behavioral deficits in AD-model mice. Moreover, erythropoietin signaling is impaired in peripheral macrophages of old AD-model mice. Exogenous erythropoietin normalizes impaired EPO signaling and dysregulated functions of peripheral macrophages in old AD-model mice, promotes systemic Aß clearance, and alleviates disease progression. Erythropoietin treatment may represent a potential therapeutic approach for Alzheimer's disease.

The Association Between High-Sensitivity C-Reactive Protein/Albumin Ratio and Cardiovascular Prognosis in Patients Undergoing Percutaneous Coronary Intervention.

Limited studies have focused on the impact of high-sensitivity C-reactive protein (hsCRP) to albumin ratio (CAR) on cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI). Hence, the present study evaluates the association between CAR and cardiovascular outcomes in patients undergoing drug-eluting stent (DES) implantation. We consecutively enrolled 9375 CHD patients undergoing DES implantation. All patients were divided into 3 groups according to their CAR: tertile 1 (CAR ≤.02, n=3125), tertile 2 (.02.06, n = 3125). The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE). Kaplan-Meier analysis indicated that the incidences of MACCE and MI increased with high tertiles of the CAR (MACCE: 8.7 vs 10.5 vs 12.3%, log-rank P < .001; MI: 3.3 vs 4.0 vs 4.7%, long-rank P = .015). Cox regression analysis suggested that CAR was an independent risk factors for MACCE (HR per standard deviation (SD) increase: 1.07, 95% CI, 1.01-1.14, P = .024), and MI (HR per SD increase: 1.11, 95% CI, 1.01-1.22, P = .028). In conclusion, the CAR is an independent predictor of MACCE and MI in CHD patients.

Development and validation of a nomogram predicting one-year mortality in patients undergoing percutaneous coronary intervention.

OBJECTIVE: To formulate a nomogram to predict the risk of one-year mortality after percutaneous coronary intervention (PCI) based on a large-scale real-world Asian cohort. METHODS: This study cohort included consecutive patients undergoing PCI in the National Center for Cardiovascular Diseases of China. The endpoint was all-cause mortality. Least absolute shrinkage and selection operator Cox regression and backward stepwise regression were used to select potential risk factors. A nomogram based on the predictors was accordingly constructed to predict one-year mortality. The performance of the nomogram was evaluated. Patients were stratified into low-, intermediate- and high-risk groups according to the tertile points in the nomogram and compared by the Kaplan-Meier analysis. RESULTS: A total of 9603 individuals were included in this study and randomly divided into the derivation cohort (60%) and the validation cohort (40%). Six variables were selected to formulate the nomogram, including age, renal insufficiency, cardiac dysfunction, previous cerebrovascular disease, previous PCI, and TIMI 0-1 before PCI. The area under the curve of this nomogram regarding one-year mortality risks were 0.792 and 0.754 in the derivation cohort and validation cohort, respectively. Kaplan-Meier curve successfully stratified the patients according to three risk groups. This nomogram calibrated well and exhibited satisfactory clinical utility in the decision curve analysis. CONCLUSIONS: This study developed and validated a simple-to-use nomogram predicting one-year mortality risk in Asian patients undergoing PCI and could help clinicians make risk-dependent decisions.

Inhibition of Smad3 in macrophages promotes Aß efflux from the brain and thereby ameliorates Alzheimer's pathology.

Impaired amyloid-ß (Aß) clearance is believed to be a primary cause of Alzheimer's disease (AD), and peripheral abnormalities in Aß clearance have recently been linked to AD pathogenesis and progression. Data from recent genome-wide association studies have linked genetic risk factors associated with altered functions of more immune cells to AD pathology. Here, we first identified correlations of Smad3 signaling activation in peripheral macrophages with AD progression and phagocytosis of Aß. Then, manipulating the Smad3 signaling regulated macrophage phagocytosis of Aß and induced switch of macrophage inflammatory phenotypes in our cell cultures. In our mouse models, flag-tagged or fluorescent-dye conjugated Aß was injected into the lateral ventricles or tail veins, and traced. Interestingly, blocking Smad3 signaling efficiently increased Aß clearance by macrophages, reduced Aß in the periphery and thereby enhanced Aß efflux from the brain. Moreover, in our APP/PS1 transgenic AD model mice, Smad3 inhibition significantly attenuated Aß deposition and neuroinflammation, and ameliorated cognitive deficits, probably by enhancing the peripheral clearance of Aß. In conclusion, enhancing Aß clearance by peripheral macrophages through Smad3 inhibition attenuated AD-related pathology and cognitive deficits, which may provide a new perspective for understanding AD and finding novel therapeutic approaches.

Imaging Changes and Clinical Complications After Drug-Eluting Bead Versus Conventional Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: Multicenter Study.

BACKGROUND. Drug-eluting bead transarterial chemoembolization (DEB-TACE) has emerged as an alternative to conventional TACE (cTACE) for treatment of hepatocellular carcinoma (HCC), although selection between the approaches remains controversial. OBJECTIVE. The purpose of this study was to compare DEB-TACE and cTACE in the treatment of patients with unresectable HCC in terms of hepatobiliary changes on imaging and clinical complications. METHODS. This retrospective study included 1002 patients (871 men, 131 women; mean age, 59 ± 12 years) from three centers who had previously untreated unresectable HCC and underwent DEB-TACE with epirubicin (780 procedures in 394 patients) or cTACE with ethiodized oil mixed with doxorubicin and oxaliplatin (1187 procedures in 608 patients) between May 2016 and November 2018. Among these patients 83.4% had hepatitis B-related liver disease, 57.6% had Barcelona Clinic Liver Cancer (BCLC) stage A or B HCC, and 42.4% had three or more nodules. Mean tumor size was 6.3 ± 4.2 cm. Hepatobiliary changes and tumor response were evaluated with CT or MRI 1 month after TACE. Clinical records were reviewed for adverse events. RESULTS. Bile duct dilatation (p < .001) and portal vein narrowing (p = .006) on imaging and liver failure (p = .03) and grade 3 abdominal pain (p < .001) in clinical follow-up occurred at higher frequency in the DEB-TACE group (15.5%, 4.6%, 2.3%, and 6.1%) than in the cTACE (7.4%, 1.6%, 0.7%, and 2.1%) group. Higher frequency of bile duct dilation in patients who underwent DEB-TACE was observed in subgroup analyses that included patients with BCLC stage A or B HCC (p = .001), with cirrhosis (p < .001), without cirrhosis (p = .04), and without main portal vein tumor thrombus (p = .002). Total bilirubin level 1 month after treatment was 1.5 ± 2.4 mg/dL (95% CI, 1.2-1.8 mg/dL) for DEB-TACE versus 1.3 ± 2.0 mg/dL (95% CI, 1.1-1.5 mg/dL) for cTACE (p = .02). The cTACE and DEB-TACE groups did not differ in other manifestations of postembolization syndrome or systemic toxicity (p > .05). Local tumor disease control rates did not differ between the cTACE and DEB-TACE groups (1 month, 96.7% vs 98.5%, p = .06; 3 months, 81.8% vs 82.4%, p = .87), but overall DCR was significantly higher in the cTACE than in the DEB-TACE group (1 month, 87.5% vs 80.0%, p = .001; 3 months, 78.5% vs 72.1%, p = .02). CONCLUSION. Compared with cTACE, DEB-TACE was associated with greater frequency of hepatobiliary injury and severe abdominal pain. CLINICAL IMPACT. Greater caution and closer follow-up are warranted for patients who undergo DEB-TACE for unresectable HCC than for those who undergo cTACE.

Membrane disruptive antimicrobial potential of NK-lysin from yellow catfish (Pelteobagrus fulvidraco).

NK-lysins, a type of broad-spectrum antimicrobial peptide (AMP), act as an essential effector of innate defense against microbial attack in higher vertebrates and so in fish. The present study delineates the structural and functional characterization of NK-lysin from yellow catfish (Pelteobagrus fulvidrac) (Pelteobagrus fulvidraco). PfNK-lysin encodes a 153-residue peptide, which displays the hallmark features of other known NK-lysins with the ordered array of six well-conserved cysteine residues and five-exon/four-intron structure. It was found to be ubiquitous in tissues, being detected most abundantly in gill and head kidney. In vivo exposure to stimuli (LPS, PolyI:C, and Edwardsiella ictaluri) induced PfNK-lysin expression in head kidney and spleen. Synthetic PfNK-lysin-derived peptide exhibited in vitro bactericidal potency against both Gram-positive and Gram-negative bacteria, with the highest inhibitory effect on pathogen Edwardsiella ictaluri. Fluorescence microscopy and scanning electron microscopy further confirmed its capacity to cause damage to the bacterial plasma membrane. Taken together, these data suggest that PfNK-lysin might participate in antimicrobial defense of yellow catfish by membrane-disruptive action.

The efficacy and safety of erlotinib compared with chemotherapy in previously treated NSCLC: A meta-analysis.

Background: An increasing number of patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and develop progressive disease after receiving conventional treatments. In recent years, several novel therapies have been approved for later lines of therapy of previously treated NSCLC. Erlotinib, an EGFR tyrosine kinase inhibitor, was recommended as the second-line therapy for pre-treated patients. However, the use of erlotinib has been reported to represent different clinical effects and adverse effects. Objectives: The current study was aim to investigate the efficacy and safety of erlotinib versus chemotherapy in pre-treated patients with advanced NSCLC. Methods: Electronic databases were searched for eligible literatures updated on June 2018. Randomized-controlled trials assessing the efficacy and safety of erlotinib in pre-treated NSCLC were included, of which the main outcomes were ORR (objective response rate), PFS (progression-free survival), OS (overall survival) and AEs (adverse events). All the data were pooled with the corresponding 95% confidence interval using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated. Results: A total of 11 randomized controlled trials were included in this analysis. The group of erlotinib did not achieved benefit in progression-free survival (OR = 0.61, 95%CI = 0.33-1.12, P = 0.11), overall survival (OR = 0.98, 95%CI = 0.84-1.15, P = 0.81) as well with the objective response rate (OR = 0.77, 95%CI = 0.36-1.63, P = 0.49), respectively. In the results of subgroup analysis among the patients with EGFR wild-type, there is also no significant differences in overall survival with erlotinib (OR = 0.90, 95%CI = 0.78-1.04, P = 0.15) and progression-free survival (OR = 0.33, 95%CI = 0.09-1.18, P = 0.09). The most common treatment-related adverse events in the erlotinib group is rash (OR = 5.79, 95%CI = 2.12-15.77, P = 0.0006), and neutropenia (OR = 0.02, 95%CI = 0.01-0.10, P ≤ 0.00001) is more found in the control group. In addition, fatigue (P = 0.09) and diarrhea (P = 0.52), the difference between the two groups had no statistical significance. Conclusions: There was no significant difference noted with regard to efficacy and safety between erlotinib vs. chemotherapy as the later-line therapy for previously treated patients with NSCLC, even with subgroup patients who have wild-type EGFR tumors. While, erlotinib might increase the risk of rash, and decrease the risk of neutropenia, compared with the chemotherapy. Further research is needed to develop a database of all EGFR mutations and their individual impact on the differing treatments.

The identification of a common different gene expression signature in patients with colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies, giving rise to serious financial burden globally. This study was designed to explore the potential mechanisms implicated with CRC and identify some key biomarkers. CRC-associated gene expression dataset (GSE32323) was downloaded from GEO database. The differentially expressed genes (DEGs) were selected out based on the GEO2R tool. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to search the enriched pathways of these DEGs. Additionally, a protein-protein interaction (PPI) network was also constructed to visualize interactions between these DEGs. Quantitative Real-time PCR (qPCR) was further performed to valid the top5 up-regulated and top5 down-regulated genes in patients with CRC. Finally, the survival analysis of the top5 up-regulated and top5 down-regulated genes was conducted using GEPIA, aiming to clarify their potential effects on CRC. In this study, a total of 451 DEGs were captured (306 down-regulated genes and 145 up-regulated genes). Among these DEGs, the top5 up-regulated genes were DPEP1, KRT23, CLDN1, LGR5 and FOXQ1 while the top5 down-regulated genes were CLCA4, ZG16, SLC4A4, ADH1B and GCG. GO analysis revealed that these DEGs were mainly enriched in cell adhesion, cell proliferation, RNA polymerase II promoter and chemokine activity. KEGG analysis disclosed that the enriched pathway included mineral absorption, chemokine signaling pathway, transcriptional misregulation in cancer, pathways in cancer and PPAR signaling pathway. Survival analysis showed that the expression level of ZG16 may correlate with the prognosis of CRC patients. Furthermore, according to the connectivity degree of these DEGs, we selected out the top15 hub genes, namely MYC, CXCR1, TOP2A, CXCL12, SST, TIMP1, SPP1, PPBP, CDK1, THBS1, CXCL1, PYY, LPAR1, BMP2 and MMP3, which were expected to be promising therapeutic target in CRC. Collectively, our analysis unveiled potential biomarkers and candidate targets in CRC, which could be helpful to the diagnosis and treatment of CRC.

Nomogram and Artificial Neural Network for Prognostic Performance on the Albumin-Bilirubin Grade for Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

PURPOSE: To construct the albumin-bilirubin (ALBI) grade and the Child-Turcotte-Pugh (CTP) score based on nomograms, as well as to develop an artificial neural network (ANN) to compare the prognostic performance of the 2 scores for hepatocellular carcinoma (HCC) that has undergone transarterial chemoembolization. MATERIALS AND METHODS: This multicentric retrospective study included patients with HCC who underwent transarterial chemoembolization monotherapy as an initial treatment at 4 institutions between January 2008 and December 2016. In the training cohort, significant risk factors associated with overall survival (OS) were identified by univariate and multivariate analyses. The prognostic nomograms and ANN were established and then validated in 2 validation cohorts. RESULTS: A total of 838 patients (548, 115, and 175 in the training cohort and validation cohorts 1 and 2, respectively) were included. The median OS was 10.4, 15.7, and 9.2 months in the training cohort and validation cohorts 1 and 2, respectively. In the training cohort, both ALBI grade and CTP score were identified as significant risk factors. The ALBI grade and CTP score based on nomograms were established separately and showed similar prognostic performance when assessed externally in validation cohorts (C-index in validation cohort 1: 0.823 vs 0.802, P = .417; in validation cohort 2: 0.716 vs 0.729, P = .793). ANN showed that ALBI grade had higher importance on survival prediction than CTP score. CONCLUSIONS: ALBI grade performs at least no worse than CTP score regarding survival prediction for HCC receiving transarterial chemoembolization. Considering the easy application, ALBI grade has the potential to be regarded as an alternative to CTP score.

Automatic untargeted metabolic profiling analysis coupled with Chemometrics for improving metabolite identification quality to enhance geographical origin discrimination capability.

Untargeted metabolic profiling analysis is employed to screen metabolites for specific purposes, such as geographical origin discrimination. However, the data analysis remains a challenging task. In this work, a new automatic untargeted metabolic profiling analysis coupled with a chemometric strategy was developed to improve the metabolite identification results and to enhance the geographical origin discrimination capability. Automatic untargeted metabolic profiling analysis with chemometrics (AuMPAC) was used to screen the total ion chromatographic (TIC) peaks that showed significant differences among the various geographical regions. Then, a chemometric peak resolution strategy is employed for the screened TIC peaks. The retrieved components were further analyzed using ANOVA, and those that showed significant differences were used to build a geographical origin discrimination model by using two-way encoding partial least squares. To demonstrate its performance, a geographical origin discrimination of flaxseed samples from six geographical regions in China was conducted, and 18 TIC peaks were screened. A total of 19 significant different metabolites were obtained after the peak resolution. The accuracy of the geographical origin discrimination was up to 98%. A comparison of the AuMPAC, AMDIS, and XCMS indicated that AuMPACobtained the best geographical origin discrimination results. In conclusion, AuMPAC provided another method for data analysis.

CB1 cannabinoid receptor agonist mouse VD-hemopressin(α) produced supraspinal analgesic activity in the preclinical models of pain.

Mouse VD-hemopressin(α) (VD-Hpα) is an undecapeptide that selectively activates CB1 cannabinoid receptor in in vitro functional tests, and exerts CB1-mediated central antinociception in the mouse tail-flick assay. The aim of the present study was to further investigate the analgesic properties of supraspinal mouse VD-Hpα in a range of preclinical pain models. Our results indicated that the classical cannabinoid agonist WIN 55,212-2 produced supraspinal analgesia in preclinical pain models, which was selectively antagonized by the CB1 antagonist/inverse agonist AM251, but not by the CB2 antagonist AM630. In contrast, in post-operative pain model and phase I of formalin test, intracerebroventricular administration of mouse VD-Hpα induced dose-related analgesia in mice, which were markedly reduced by pretreatment with the CB1 neutral antagonist AM4113, but not AM251, AM630 and the selective antagonists of opioid and Transient Receptor Potential Vanilloid Type 1 (TRPV1) receptors. Furthermore, in the acetic acid-induced visceral pain model, supraspinal administration of mouse VD-Hpα dose-dependently produced analgesic activities and the effects were significantly antagonized by both AM4113 and the TRPV1 receptor antagonist SB366791, but not AM251, AM630 and naloxone. In addition, central injection of mouse VD-Hpα did not have significant effect in phase II of formalin test. Taken together, the present work suggests that the CB1 receptor peptidic agonist mouse VD-Hpα produces supraspinal analgesia in preclinical pain models via a novel CB1 receptor-mediated mechanism, in a manner pharmacologically dissociable from WIN 55,212-2. In addition, TRPV1 receptor might also be involved in mouse VD-Hpα-induced analgesia in a visceral pain model.