Spectrum of psychiatric adverse reactions to cyclin-dependent kinases 4/6 inhibitors: A pharmacovigilance analysis of the FDA adverse event reporting system.

BACKGROUND: The emergence of cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) represented a major breakthrough in the treatment of breast cancer over the past decade. In both clinical trials and real-world settings, it was observed that patients using CDK4/6i might experience psychiatric adverse events (PAEs). Herein, we conducted a pharmacovigilance study to comprehensively assess the correlation between CDK4/6i and PAEs. METHOD: We obtained individual case safety reports submitted to the FDA Adverse Events Reporting System (FAERS) during the period from January 2015 to December 2023. In disproportionality analysis, the reporting odds ratio (ROR) and information component (IC) values were calculated for each adverse event-drug combination. Univariate logistic regression analysis was utilized to explore factors associated with PAEs following CDK4/6i treatment. RESULTS: A total of 95,591 reports related to CDK4/6i were identified, with 6.72% reporting PAEs, and this proportion exhibited an annual upward trend. Based on the ROR and IC values, 17 categories of PAEs were defined as CDK4/6i-related PAEs. Among these PAEs, insomnia, stress, eating disorder, depressed mood, and sleep disorder were very common, each accounting for over 10% of CDK4/6i reports. Ribociclib showed the highest risk signal of CDK4/6i-related PAEs (ROR = 1.89[1.75-2.04], IC025 = 0.79), followed by palbociclib (ROR = 1.47[1.41-1.53], IC025 = 0.49), while abemaciclib did not exhibit a significant signal (ROR = 0.52[0.44-0.62], IC025 = -1.13). Female sex, younger age and weight exceeding 80 kg were significant risk factors for the incidence of CDK4/6i-related PAEs. CONCLUSIONS: Using data from a real-world, large-scale spontaneous reporting system for adverse drug reactions, our study delineated the spectrum of PAEs to CDK4/6i. This potentially offered valuable insights for healthcare professionals to manage the risk of PAEs in patients receiving CDK4/6i treatment, particularly those with psychiatric disorders.

Efficacy and safety of EGFR-TKIs for non-small cell lung cancer: A meta-analysis of randomized controlled clinical trials.

BACKGROUND: We conducted this meta-analysis based on updated literature and research to compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as treatments for patients with non-small cell lung cancer (NSCLC). METHODS: A literature search was conducted using PubMed, Embase, Medline and Web of Science databases to perform a systematic literature search based on random control trials. In these articles, EGFR-TKIs were compared with placebos, chemotherapy, or whole-brain irradiation as treatments for NSCLC. In this research, a meta-analysis of the literature was performed to produce a combined risk ratio (RR) with a 95% confidence interval (CI) for progression-free survival (PFS), overall survival (OS), and adverse events. The data were synthesized with Review Manager 5.3 software, which was used to manage the process. RESULTS: There were 15 random control trials included in the study, involving 4249 patients in total. There was evidence that EGFR-TKIs can significantly prolong OS (RR: 0.87, 95% CI: 0.75-1) and PFS (RR: 0.75, 95% CI: 0.66-0.86) in NSCLC patients. There was an increase in the incidence of adverse events after treatment with EGFR-TKI, including diarrhea (RR: 0.18, 95% CI: 0.10-0.26), infection (RR: 0.09, 95% CI: 0.02-0.16), and rash (RR: 0.37, 95% CI: 0.22-0.51). CONCLUSIONS: It has been shown that EGFR-TKIs prolong OS and PFS in patients with NSCLC. NSCLC patients may benefit from EGFR-TKIs as an important treatment option in order to prolong their survival.

Gastrodin alleviates the deterioration of depressive-like behavior and glucolipid metabolism promoted by chronic stress in type 2 diabetic mice.

The growing burden of psychological stress among diabetes patients has contributed to a rising incidence of depression within this population. It is of significant importance to conduct research on the impact of stress on diabetes patients and to explore potential pharmacological interventions to counteract the stress-induced exacerbation of their condition. Gastrodin is a low molecular weight bioactive compound extracted from the rhizome of Gastrodiae elata Blume, and it may be a preventive strategy for diabetes and a novel treatment for depression symptoms. However, its relevant pharmacological mechanisms for protecting against the impacts of psychological stress in diabetic patients are unclear. In this study, we performed 5 weeks CUMS intervention and simultaneously administered gastrodin (140 mg/kg, once daily) on T2DM mice, to investigate the potential protective effects of gastrodin. The protective effect of gastrodin was evaluated by behavioral tests, biochemical analysis, histopathological examination, RT-qPCR and gut microbiota analysis. We found that the depressive-like behavior and glucolipid metabolism could be deteriorated by chronic stress in type 2 diabetic mice, while gastrodin showed a protective effect against these exacerbations by regulating HPA hormones, activating FXR and Cyp7a1, reducing inflammatory and oxidative stress responses, and regulating ileal gut microbiota abundance. Gastrodin might be a potential therapeutic agent for mitigating the deterioration of diabetes conditions due to chronic stress.

Human Eye Activity Monitoring Using Continuous Wave Doppler Radar: A Feasibility Study.

Human eye activity has been widely studied in many fields such as psychology, neuroscience, medicine, and human-computer interaction engineering. In previous studies, monitoring of human eye activity mainly depends on electrooculogram (EOG) that requires a contact sensor. This article proposes a novel eye movement monitoring method called continuous wave doppler oculogram (cDOG). Unlike the conventional EOG-based eye movement monitoring methods, cDOG based on continuous wave doppler radar sensor (cDRS) can remotely measure human eye activity without placing electrodes on the head. To verify the feasibility of using cDOG for eye movement monitoring, we first theoretically analyzed the association between the radar signal and the corresponding eye movements measured with EOG. Afterward, we conducted an experiment to compare EOG and cDOG measurements under the conditions of eyes closure and opening. In addition, different eye movement states were considered, including right-left saccade, up-down saccade, eye-blink, and fixation. Several representative time domain and frequency domain features obtained from cDOG and from EOG were compared in these states, allowing us to demonstrate the feasibility of using cDOG for monitoring eye movements. The experimental results show that there is a correlation between cDOG and EOG in the time and frequency domain features, the average time error of single eye movement is less than 280.5 ms, and the accuracy of cDOG in eye movement detection is higher than 92.35%, when the distance between the cDRS and the face is 10 cm and eyes is facing the radar directly.

A Review on Atrial Fibrillation Detection From Ambulatory ECG.

Atrial fibrillation (AF) is a prevalent clinical arrhythmia disease and is an important cause of stroke, heart failure, and sudden death. Due to the insidious onset and no obvious clinical symptoms of AF, the status of AF diagnosis and treatment is not optimal. Early AF screening or detection is essential. Internet of Things (IoT) and artificial intelligence (AI) technologies have driven the development of wearable electrocardiograph (ECG) devices used for health monitoring, which are an effective means of AF detection. The main challenges of AF analysis using ambulatory ECG include ECG signal quality assessment to select available ECG, the robust and accurate detection of QRS complex waves to monitor heart rate, and AF identification under the interference of abnormal ECG rhythm. Through ambulatory ECG measurement and intelligent detection technology, the probability of postoperative recurrence of AF can be reduced, and personalized treatment and management of patients with AF can be realized. This work describes the status of AF monitoring technology in terms of devices, algorithms, clinical applications, and future directions.

Structural characterization of chia seed polysaccharides and evaluation of its immunomodulatory and antioxidant activities.

This study aims to extract an active heteropolysaccharide Chia seed polysaccharide (CSP-A) and further purified by DEAE Sepharose Fast Flow and Sepharose CL-6B chromatographic column, characterize its structure, and evaluate its antioxidant and immunomodulatory activities. Structural analysis revealed that CSP-A was composed of d-mannose, d-glucuronic acid and d-xylose in a molar ratio of 1:3:4 with molecular weight of 1.688 × 105 Da, owning 4 sugar residues of ß-d-Manp-(1→, →4)-α-d-GlcpA-(1→, →2,4)-ß-d-Xylp-(1→, and â†’ 4)-ß-d-Manp-(1 â†’. Congo red assay and microscopic characteristics showed that CSP-A in its solution may possess a helical conformation. In vitro experiments showed that CSP-A had moderate DPPH· and OH· scavenging activities. CSP-A also enhanced the phagocytosis ability of RAW 264.7 cells and prompted the release of NO, TNF-α, IL-6 and IL-1ß from RAW 264.7 cells, which indicated CSP-A had immune regulation effect. This experiment provides scientific basis for further utilization and development of chia seeds, a kind of functional food.

Multi-cohort validation study of a four-gene signature for risk stratification and treatment response prediction in hepatocellular carcinoma.

BACKGROUND: The intricate molecular landscape of hepatocellular carcinoma (HCC) presents a significant challenge to achieving precise risk stratification through clinical genetic testing. At present, there is a paucity of robust gene signatures that could assist clinicians in making clinical decisions for patients with HCC. METHODS: We obtained gene expression profiles of patients with HCC from 20 independent cohorts available in public databases. A gene signature was developed by employing two machine learning algorithms. In addition to validating the signature with high-throughput data in public cohorts, we external validated the signature in 64 HCC cases by RT-PCR method. We compared genomic, transcriptomic and proteomic features between different subgroups. We also compared our signature to 130 gene signatures that have already been published. RESULTS: We developed a novel four-gene signature, designated as HCC4, that demonstrates significant potential for the prediction of survival outcomes in more than 1300 patients with HCC. The HCC4 also has potential for predicting recurrence and tumor volume doubling time, assessing transcatheter arterial chemoembolization and immunotherapy responses, and non-invasive detection of HCC. The high HCC4 score group shows a higher frequency of mutations in genes TP53, RB1 and TSC1/2, as well as increased activity of cell-cycle, glycolysis and hypoxia signaling pathways, higher cancer stemness score, and lower lipid metabolism activity. In seven HCC cohorts, HCC4 exhibited a higher average C-index in predicting overall survival compared to the 130 signatures previously published. Drug screening indicated that patients with high HCC4 scores were more sensitive to agents targeting AURKA, TUBB, JMJD6 and KIFC1. CONCLUSIONS: Our findings demonstrated that HCC4 is a powerful tool for improving risk stratification and for identifying HCC patients who are most likely to benefit from TACE treatment, immunotherapy, and other experimental therapies.

FOXP3 expression in esophageal squamous cell carcinoma : Implications for cetuximab sensitivity and therapeutic strategies.

OBJECTIVE: Investigating the impact of FOXP3 (transcription factor forkhead box P3) expression on the biological behavior of esophageal squamous cell carcinoma (ESCC) and its influence on the sensitivity of ESCC cells towards cetuximab-targeted (an EGFR monoclonal antibody inhibitor) therapy. METHODS: A specifically designed recombinant FOXP3 shRNA plasmid was synthesized to target the human FOXP3 gene, and the plasmid was transfected into TE12 cells using a liposome method. Multiple assays were conducted to evaluate the effect of FOXP3 expression on ESCC cells and their response to cetuximab treatment. Proliferation activity and cetuximab sensitivity of ESCC cells were measured using the CCK­8 assay. The invasion ability of cells was assessed using an in vitro invasion assay. Furthermore, the efficacy of cetuximab in treating ESCC was analyzed using a tumorigenesis assay in nude mice. RESULTS: Silencing the FOXP3 gene in the TE12 cell line (shFOXP3 group) resulted in a significant reduction in FOXP3 mRNA and protein expression (p = 0.013). The shFOXP3 group exhibited slowed cell growth (p = 0.035), decreased invasion rate (p = 0.031), and increased sensitivity to cetuximab treatment (p = 0.039) compared to the control group (shNC group). In the in vivo tumorigenesis assay, the shFOXP3 group demonstrated a significant reduction in tumor volume and lung metastasis rate following cetuximab treatment (p = 0.028 and 0.007, respectively). CONCLUSION: High FOXP3 expression promotes the proliferation and migration of ESCC cells, while negatively affecting their sensitivity to cetuximab-targeted therapy. Consequently, targeting FOXP3 shows potential therapeutic implications for enhancing the effectiveness of cetuximab treatment in ESCC patients.

Evaluation of skin sympathetic nervous activity for classification of intracerebral hemorrhage and outcome prediction.

Classification and outcome prediction of intracerebral hemorrhage (ICH) is critical for improving the survival rate of patients. Early or delayed neurological deterioration is common in ICH patients, which may lead to changes in the autonomic nervous system (ANS). Therefore, we proposed a new framework for ICH classification and outcome prediction based on skin sympathetic nervous activity (SKNA) signals. A customized measurement device presented in our previous papers was used to collect data. 117 subjects (50 healthy control subjects and 67 ICH patients) were recruited for this study to obtain their 5-min electrocardiogram (ECG) and SKNA signals. We extracted the signal's time-domain, frequency-domain, and nonlinear features and analyzed their differences between healthy control subjects and ICH patients. Subsequently, we established the ICH classification and outcome evaluation model based on the eXtreme Gradient Boosting (XGBoost). In addition, heart rate variability (HRV) as an ANS assessment method was also included as a comparison method in this study. The results showed significant differences in most features of the SKNA signal between healthy control subjects and ICH patients. The ICH patients with good outcomes have a higher change rate and complexity of SKNA signal than those with bad outcomes. In addition, the accuracy of the model for ICH classification and outcome prediction based on the SKNA signal was more than 91% and 83%, respectively. The ICH classification and outcome prediction based on the SKNA signal proved to be a feasible method in this study. Furthermore, the features of change rate and complexity, such as entropy measures, can be used to characterize the difference in SKNA signals of different groups. The method can potentially provide a new tool for rapid classification and outcome prediction of ICH patients. Index Terms-intracerebral hemorrhage (ICH), skin sympathetic nervous activity (SKNA), classification, outcome prediction, cardiovascular and cerebrovascular diseases.

Young Adults' Perception of Forests Using Landscape-Image-Sketching Technique: A Case Study of Changsha, Central China.

The forest-landscape image is the bridge for communication between human beings and the forest. The aim of this paper is to construct the landscape-image conceptual model from the personal perception of the forest, with what people are looking at and how they are viewing themselves as a part of the forest. This research constructed a forest-landscape image by young adults by utilizing the landscape-image-sketching technique and selecting 140 young adults who had lived in Changsha, Central China for ten years, using convenience sampling, during April and May 2018. The results demonstrated that the forest was considered as the people's life world, as rural scenery around the respondents' homes, instead of the perception of the objective forest, an important habitat for animals and a limited resource supplier for human living. In fact, the natural values of the forest, such as the ecological and aesthetic values, received more attention than the social ones of the forest, including the life, production, and cultural values. Finally, it is important to raise the public's awareness of the objective entity of the forest and to guide the variety of experiences for the respondents in the forest.

Jujuboside B Reverse CUMS-Promoted Tumor Progression via Blocking PI3K/Akt and MAPK/ERK and Dephosphorylating CREB Signaling.

Background: Jujuboside B (JUB) is a saponins isolated from the seeds of Zizyphi jujuba var. spinosi, which is used to treat mental illness and is reported recently to induce cancer cell apoptosis. As our previous research showed chronic stress promoted tumor growth, this work aims to investigate whether JUB exert antitumor effect in addition to its antidepressant effect and possible mechanism. Methods: 56 female C57BL/6 mice were grouped into 7 groups: A (blank control), B (tumor-bearing control), C (tumor-bearing + JUB), D (CUMS control), E (CUMS + JUB), F (tumor-bearing + CUMS), and G (tumor-bearing + CUMS + JUB). Groups C, E, G, B, D, and F were administered, respectively, with JUB (40 mg/kg/day) or vehicle for 2 weeks. Serum 5-HT, Trp (tryptophane), inflammatory cytokines TNF-α, IL-4, -6, and -10 levels were detected by ELISA. The tumors in groups B and F were isolated for RNA-seq sequencing. Protein and mRNA expression of Bax, Bcl-2, p-PI3K, p-Akt, p-MAPK, p-ERK, and p-CREB in tumor tissues were detected. In vitro, A549 cells were stimulated with JUB (60 µmol/L), in which proliferation rate and colony formation rate were detected. The PI3K/Akt and, MAPK/ERK pathway were measured. Results: Chronic stress successfully induced the depression-like phenotype (group D vs. A) and promoted tumor growth (group B vs. F). JUB significantly ameliorated the depression-like phenotype and increased 5-HT, Trp levels (group D vs. E), and reversing CUMS-induced tumor progression. Meanwhile, JUB decreased inflammatory cytokine levels. Chronic stress upregulated the phosphorylation levels of PI3K/Akt/MAPK/ERK/CREB; JUB reversed this regulation. JUB significantly inhibited cell viability, colony formation rate, and downregulated the phosphorylation levels of PI3K/Akt/MAPK/ERK/CREB in vitro. Conclusions: JUB reverses CUMS-promoted tumor progression in tumor-bearing mice with depression-like phenotype. JUB exerts the dual beneficial effect on tumor growth and depression-like phenotype by blocking the signal transduction pathway of PI3K/Akt, MAPK/ERK, and dephosphorylating the downstream signaling regulator CREB.

Wearable Fetal ECG Monitoring System from Abdominal Electrocardiography Recording.

Fetal electrocardiography (ECG) monitoring during pregnancy can provide crucial information for assessing the fetus's health status and making timely decisions. This paper proposes a portable ECG monitoring system to record the abdominal ECG (AECG) of the pregnant woman, comprising both maternal ECG (MECG) and fetal ECG (FECG), which could be applied to fetal heart rate (FHR) monitoring at the home setting. The ECG monitoring system is based on data acquisition circuits, data transmission module, and signal analysis platform, which consists of low input-referred noise, high input impedance, and high resolution. The combination of the adaptive dual threshold (ADT) and the independent component analysis (ICA) algorithm is employed to extract the FECG from the AECG signals. To validate the performance of the proposed system, AECG is recorded and analyzed of pregnant women in three different postures (supine, seated, and standing). The result shows that the proposed system can record the AECG in different postures with good signal quality and high accuracy in fetal ECG and heart rate information. Sensitivity (Se), positive predictive accuracy (PPV), accuracy (ACC), and their harmonic mean (F1) are utilized as the metrics to evaluate the performance of the fetal QRS (fQRS) complexes extraction. The average Se, PPV, ACC, and F1 score are 99.62%, 97.90%, 97.40%, and 98.66% for the fQRS complexes extraction,, respectively. This paper shows the proposed system has a promising application in fetal health monitoring.

An Artifact-Resistant Feature SKNAER for Quantifying the Burst of Skin Sympathetic Nerve Activity Signal.

Evaluation of sympathetic nerve activity (SNA) using skin sympathetic nerve activity (SKNA) signal has attracted interest in recent studies. However, signal noises may obstruct the accurate location for the burst of SKNA, leading to the quantification error of the signal. In this study, we use the Teager−Kaiser energy (TKE) operator to preprocess the SKNA signal, and then candidates of burst areas were segmented by an envelope-based method. Since the burst of SKNA can also be discriminated by the high-frequency component in QRS complexes of electrocardiogram (ECG), a strategy was designed to reject their influence. Finally, a feature of the SKNA energy ratio (SKNAER) was proposed for quantifying the SKNA. The method was verified by both sympathetic nerve stimulation and hemodialysis experiments compared with traditional heart rate variability (HRV) and a recently developed integral skin sympathetic nerve activity (iSKNA) method. The results showed that SKNAER correlated well with HRV features (r = 0.60 with the standard deviation of NN intervals, 0.67 with low frequency/high frequency, 0.47 with very low frequency) and the average of iSKNA (r = 0.67). SKNAER improved the detection accuracy for the burst of SKNA, with 98.2% for detection rate and 91.9% for precision, inducing increases of 3.7% and 29.1% compared with iSKNA (detection rate: 94.5% (p < 0.01), precision: 62.8% (p < 0.001)). The results from the hemodialysis experiment showed that SKNAER had more significant differences than aSKNA in the long-term SNA evaluation (p < 0.001 vs. p = 0.07 in the fourth period, p < 0.01 vs. p = 0.11 in the sixth period). The newly developed feature may play an important role in continuously monitoring SNA and keeping potential for further clinical tests.

Chronic Stress-Induced Gene Changes In Vitro and In Vivo: Potential Biomarkers Associated With Depression and Cancer Based on circRNA- and lncRNA-Associated ceRNA Networks.

Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) have been considered as biomarkers or regulators in many diseases. However, the exact role of circRNA- or lncRNA-mediated competing endogenous RNA (ceRNA) networks in the modulation of depression pathogenesis-relevant processes is not clear. In this study, we profiled whole transcriptome in depression patients' blood samples via microarray analysis. As a result, a total of 340 circRNAs, 398 lncRNAs, 206 miRNAs, and 92 mRNAs were differentially expressed between the depression and control groups. Then, we constructed ceRNA networks according to the differentially expressed genes (DEGs). Using bioinformatics analysis, 89 pairs of circRNA-ceRNA and 49 pairs of lncRNA-ceRNA networks were obtained. Since depression is a broad and heterogeneous condition that is known as promoter for many chronic diseases including cancer, so we further dug out 28 circRNAs, 61 lncRNAs, 26 miRNAs, and 29 mRNAs that are associated with cancer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that the DEGs were significantly enriched in cancer-related signaling pathways such as MAPK, Wnt, IL-17, Ras, and PI3K-Akt. Genes involved in the above pathways such as S100A9, GATA2, SRFP5, SLC45A3, NTRK1, FRZB, has_circ_0014221, has_circ_0014220, and has_circ_0087100 were dysregulated in various cancer cell lines by stress hormones induced. HDC, GATA2, SLC45A3, and NTRK1 were downregulated in tumor-bearing mice subjected to chronic unpredictable mild stress (CUMS). LncRNA-mediated ceRNA network validation showed that overexpression of miR-4530 declined HDC level. Our findings highlight the potential circRNA- and lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of depression and as potential biomarkers in depression cancer comorbidity through the pathways of IL-17 or histidine metabolism.

Antitumor Effect of Fluoxetine on Chronic Stress-Promoted Lung Cancer Growth via Suppressing Kynurenine Pathway and Enhancing Cellular Immunity.

Background: Chronic stress promotes cancer growth. Antidepressant fluoxetine (FLX) is usually prescribed for cancer patients with comorbid depression. FLX displays inhibition on cancer cell proliferation, however, the in vivo activity has not been investigated. Methods: We explored the antitumor effect of FLX in subcutaneous transplanted lung cancer cells in a tumor-bearing mouse model. Fifty-six C57BL/6 mice were randomly divided into group A (blank control), group B (tumor-bearing control), group C (tumor-bearing + FLX), group D (CUMS control), group E (CUMS + FLX), group F (tumor-bearing + CUMS), and group G (tumor-bearing + CUMS + FLX). 5-HT, tryptophane (Trp), kynurenine, IFN-γ, TNF-α, IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-17A levels were measured by ELISA. T helper (Th), cytotoxic T (Tc) and regulatory T cells (Tregs) subtype were measured by flow cytometry. The antitumor effects of FLX were evaluated by tumor weight. The expression of kynurenine pathway related genes TDO, IDO1, IDO2, and apoptosis-related genes caspase1, 3, 4, 5, 7, 12 in tumor tissues were measured by western blotting and qRT-PCR. A549 cells were exposed with FLX (15 µmol/L) and its effect on cell proliferation, migration, and clonal formation were detected. Kynurenine pathway and apoptosis related gene expression were also measured. Results: In vivo, chronic stress promoted tumor growth in C57BL/6 mice. FLX administration not only significantly reversed chronic unpredictable mild stress (CUMS)-induced reduction of 5-HT and Trp, increment of kynurenine, but increased CD4+ Th and CD8+ Tc cells, and reduced CD25+ FOXP3+ Tregs. FLX promoted Th to differentiate into Th1 cells and increased IL-2 and IFN-γ, meanwhile inhibited Th differentiate into Th2 and Th17 cells and decreased the concentrations of IL-4, IL-6, IL-10, and IL-17A. Chronic stress obviously up-regulated IDO1 and IDO2 expression, down-regulated caspase 4, 7, and 12 expression, meanwhile FLX administration reversed this regulation. However, there was no significant change in TDO, caspase 1, 3, 5. Similarly, in vitro, FLX administration significantly inhibited the proliferation, migration, and clonal formation of A549 cells and induced cell apoptosis. FLX administration down-regulated the expression of IDO1, IDO2, and up-regulated caspase 4, 5, and 7. Conclusion: Fluoxetine administration could inhibit tumor growth. The inhibition might be via suppressing kynurenine pathway and enhancing cellular immunity.

An Inflammatory Response Related Gene Signature Associated with Survival Outcome and Gemcitabine Response in Patients with Pancreatic Ductal Adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with an extremely low 5-year survival rate. Accumulating evidence has unveiled that inflammatory response promotes tumor progression, enhances angiogenesis, and causes local immunosuppression. Herein, we aim to develop an inflammatory related prognostic signature, and found it could be used to predict gemcitabine response in PDAC. Methods: PDAC cohorts with mRNA expression profiles and clinical information were systematically collected from the four public databases. An inflammatory response related genes (IRRGs) prognostic signature was constructed by LASSO regression analysis. Kaplan-Meier survival analysis, receiver operating characteristic analysis, principal component analysis, and univariate and multivariate Cox analyses were carried out to evaluate effectiveness, and reliability of the signature. The correlation between gemcitabine response and risk score was evaluated in the TCGA-PAAD cohort. The GDSC database, pRRophetic algorithm, and connectivity map analysis were used to predict gemcitabine sensitivity and identify potential drugs for the treatment of PDAC. Finally, we analyzed differences in frequencies of gene mutations, infiltration of immune cells, as well as biological functions between different subgroups divided by the prognostic signature. Results: We established a seven IRRGs (ADM, DCBLD2, EREG, ITGA5, MIF, TREM1, and BTG2) signature which divided the PDAC patients into low- and high-risk groups. Prognostic value of the signature was validated in 11 PDAC cohorts consisting of 1337 PDAC patients from 6 countries. A nomogram that integrated the IRRGs signature and clinicopathologic factors of PDAC patients was constructed. The risk score showed positive correlation with gemcitabine resistance. Two drugs (BMS-536924 and dasatinib) might have potential therapeutic implications in high-risk PDAC patients. We found that the high-risk group had higher frequencies of KRAS, TP53, and CDKN2A mutations, increased infiltration of macrophages M0, neutrophils, and macrophages M2 cells, as well as upregulated hypoxia and glycolysis pathways, while the low-risk group had increased infiltration of CD8+ T, naïve B, and plasma and macrophages M1 cells. Conclusion: We constructed and validated an IRRGs signature that could be used to predict the prognosis and gemcitabine response of patients with PDAC, as well as two drugs (BMS-536924 and dasatinib) may contribute to PDAC treatment.

[Research progress on chemical composition and pharmacological effects of Periplocae Cortex and predictive analysis on Q-marker].

Periplocae Cortex is a traditional Chinese medicine in China, which is mainly produced in northeast China, north China, northwest China, southwest China. In recent years, the increasing in-depth research resulted in the discovery of anti-tumor and cardiac pharmacological activities of Periplocae Cortex, which has broad application prospects. On the basis of summarizing chemical components and pharmacological effects, combined with the theoretical system of Q-marker, the quality control components of Periplocae Cortex were predicted from the aspects of the correlation between chemical composition and traditional medicinal properties, traditional efficacy, and new clinical use, plasma composition, measurable composition, storage time by analyzing literature. Among the components, periplocoside, periplocin, periplogenin, 4-methoxy salicylaldehyde showed significant activity, which provides a scientific basis for quality evaluation of Periplocae Cortex.

[Qualitative and quantitative analysis of major cholic acids in Suis Fellis Pulvis].

This study is to establish a qualitative method for rapid identification of bile acids in Suis Fellis Pulvis based on UHPLC-LTQ-Orbitrap-MS technology,and an HPLC-ELSD internal standard method for the quantitative determination of two glycine-conjugated BAs in Suis Fellis Pulvis.The chromatographic separation of the UHPLC-LTQ-Orbitrap-MS qualitative analysis was achieved on a Waters Acquity UPLC HSS T_3column(2.1 mm×100 mm,1.8µm),with 0.2%formic acid aqueous solution(A)-acetonitrile(B)as mobile phase ingradient elution.Electrospray ionization(ESI)source was applied and operated in negative ion mode.Quantitative analysis was performed at 30℃on a Diamonsil-C_(18)column(4.6 mm×250 mm,5µm).The mobile phase consisted of 0.2%formic acid solution and acetonitrile with gradient elution and the flow rate was 1.0 m L·min~(-1).An ELSD was used with a nitrogen flow-rate of1.4 L·min~(-1)at a drift tube temperature of 60℃and the gain was 1.A total of 14 bile acids in Suis Fellis Pulvis were characterized based on the accurate mass measurements,fragmentation patterns,chromatographic retention times,and reference materials.For the quantitative analysis method,the glycohyodeoxycholic acid and glycochenodeoxycholic acid had good linear relationship in the range of26.52-265.20 mg·L~(-1)(r=0.999 8)and 19.84-198.40 mg·L~(-1)(r=0.999 1),respectively.The average recoveries(n=6)were104.1%and 103.1%,and the RSD were 2.0%and 2.4%.The UHPLC-LTQ-Orbitrap-MS technology provides a fast and efficient qualitative analysis method for identification of bile acids in Suis Fellis Pulvis.The HPLC-ELSD internal standard method is accurate and reliable,which has reference value for the quality control of Suis Fellis Pulvis.

Chronic Stress Disturbs Metabolome of Blood Plasma and Urine in Diabetic Rats.

About 30% of diabetes patients suffer from varying degrees of depression. Diabetes itself is associated with abnormal carbohydrate and energy metabolism. Whether chronic stress-induced depression-like behavior impacts the metabolome of blood plasma and urine in diabetes is not clear. This study aimed to investigate the effect of chronic stress on metabolome of plasma and urine in spontaneously diabetic Goto-Kakizaki (GK) rats. The GK rats were subjected to 8 weeks' chronic unpredictable mild stress (CUMS) to induce depression-like behavior. Metabolome analysis of blood plasma and urine using liquid chromatography mass spectrometry (LC/MS) was performed. Multivariate data analysis was used to evaluate the data. Behavior and biochemical assay confirmed the successful establishment of CUMS-induced depression-like behavior model in rats. Disturbance of 20 plasma metabolites and 16 urine metabolites were altered in CUMS-induced depression GK rats as compared to control ones. These disturbed metabolites were involved in fatty acid metabolism, sphingolipid metabolism, phenylalanine metabolism, citrate cycle, glycolysis, glutathione metabolism, and nicotinate and nicotinamide metabolism. This study suggest that chronic stress-induced depression-like behavior may further disturb diabetes-itself energy metabolome. The plasma and urine lipid metabolites monitoring may be useful for early detection of depression in patients with diabetes mellitus.

Alkyne-DNA-Functionalized Alloyed Au/Ag Nanospheres for Ratiometric Surface-Enhanced Raman Scattering Imaging Assay of Endonuclease Activity in Live Cells.

A novel ratiometric surface-enhanced Raman scattering (SERS) nanosensor has been developed to probe the activity of endonuclease under in vitro and in living cells conditions. The optimized alloyed Au/Ag nanoparticles (NPs) were synthesized as the SERS substrate, which combined the superior properties of both pure Au and pure Ag nanoparticles: they exhibit excellent plasmonic property with high chemical stability and low cytotoxicity. They were then employed for quantitative detection of endonuclease through functionalization with single-stranded DNA (ssDNA) carrying 3-[4-(phenylethynyl)benzylthio]propanoic acid (PEB) as endonuclease-responsive SERS signaling molecule and 4-thiophenylacetylene (TPA) as the internal standard SERS signaling molecule. In the presence of endonuclease, the ssDNA was cleaved, releasing PEB molecules from the particle surface and decreasing the SERS signal at 2215 cm-1 from PEB. Since the SERS signal at 1983 cm-1 from alkynyl TPA remained the same, quantitative detection of endonuclease was achieved, based on the ratiometric peak intensity of I1983/ I2215, with a detection limit as low as 0.056 unit/mL. A highly biocompatible and antijamming ratiometric SERS sensor was established by combining the alloyed Au/AgNPs with two unique alkynes molecules with Raman signals in the cellular silent region. The ratiometric sensor was successfully employed to detect intracellular endonuclease activity as well as endonuclease in living cells for the first time.