Mechanoluminescence Affected by Trap Types and Excitation State Positions in Mg3Ca3(PO4)4:Eu2+/Mn2+/Ce3+ for Multimode Anticounterfeiting.

Mechanoluminescence (ML) materials with tunable emissions can serve in many practical applications; however, their underlying mechanism still needs further clarification. Herein, we developed Eu2+-/Mn2+-/Ce3+-activated Mg3Ca3(PO4)4 (MCP) phosphors and studied their luminescence properties by device fabrication. The intense blue ML is obtained by fabricating MCP:Eu2+ into the polydimethylsiloxane elastomer matrix. The red ML of relatively weak intensity is received in Mn2+ activator, but the ML for the Ce3+ dopant is nearly quenched in the same host. The possible reason is proposed from the analysis of the relative positions between the excitation state and conduction band, together with the trap types. The appropriate location of the excited energy levels in the band gap allows for a larger probability of efficient ML when shallow traps near the excitation states are created synchronously as an effective energy transfer (ET) channel. The concentration-dependent ML for the MCP:Eu2+,Mn2+-based devices indicates that the emitting light color can be tailored, where several ET processes among oxygen vacancies, Eu2+, Ce3+, and Mn2+, occur. The luminescence manipulation with dopants and excitation sources demonstrates the potential applications in visualized multimode anticounterfeiting. These findings open up many possibilities for constructing new ML materials by introducing appropriate traps into the band structures.

Generalized Radon transform approach to target motion parameter estimation using a stationary underwater vector hydrophone.

Underwater platforms provide long-term detection of undersea targets. In this paper, we propose a method for the estimation of target motion parameters by submerged static acoustic detection equipment. The proposed method is based on the Radon transform of modeling the target moving in a uniform straight line. The heading angle, the time to the closest point of approach (CPA), and the ratio of velocity to the horizontal range of the target at the CPA to the sensor are obtained by applying the generalized Radon transform (GRT) to bearing-time records. The velocity of the target is determined by applying the GRT to the line-spectrum-time records. Furthermore, the motion trajectory of the target with respect to the detection equipment can be calculated from the above parameters. To validate the feasibility and performance of the proposed method, computer simulations and sea trials based on a fixed single vector measurement system were analyzed in this paper. The results suggest that the proposed method can accurately estimate the motion parameters and can calculate the trajectory of the moving vessel along a straight line at constant velocity.

Platelets promote invasion and induce epithelial to mesenchymal transition in ovarian cancer cells by TGF-ß signaling pathway.

OBJECTIVE: To test whether platelets could increase invasion potential and initiate EMT in ovarian cancer cells via a TGF-ß signaling pathway. METHODS: Blood samples were collected in 69 patients with ovarian cancer, 16 patients with benign ovarian tumor and 64 healthy donors. SK-OV-3 and OVCAR-3 ovarian cancer cells were treated with platelets. Transwell assays were used to analyze the invasive capacity, and EMT was assessed by microarray analysis, quantitative real-time PCR (qPCR) and Western blotting. Activation of TGF-ß pathway was examined by ELISA and Western blotting. TGF-ß type I receptor (TßR I) inhibitor A83-01 was used to confirm the role of TGF-ß pathway in vitro and in vivo. RESULTS: Clinical data showed ovarian cancer patients with elevated platelet counts had a higher incidence of advanced stages. Treatment with platelets increased the invasive properties of both cell lines. Mesenchymal markers (snail family transcriptional repressor-1, vimentin, neural cadherin, fibronectin-1 and matrix metalloproteinase-2) were up-regulated in platelet-treated cells, while the epithelial marker (epithelial cadherin) was down-regulated. Higher TGF-ß level was observed in patients with elevated platelet counts when compared to the subjects. Higher levels of TGF-ß were also found in culture medium treated with platelets, and cells treated with platelets also showed increased phosphorylation of Smad2. TßR I inhibitor A83-01 reversed the EMT-like alterations and inhibited platelet-induced invasion in vitro and in vivo. CONCLUSION: Platelet increased invasion potential and induced EMT in ovarian cancer cells in a TGF-ß dependent pathway. Platelet-derived TGF-ß may be useful as a new target treatment for ovarian cancer.

Prognostic value of CALR vs. JAK2V617F mutations on splenomegaly, leukemic transformation, thrombosis, and overall survival in patients with primary fibrosis: a meta-analysis.

The understanding of genetic basis for Philadelphia-negative myeloproliferative neoplasm (MPN) has got much progress in recent years. But the effect of CALR vs. JAK2V617F mutations on the clinical progression and prognosis of primary fibrosis (PMF) remains relatively obscure. In this meta-analysis, we searched Pubmed, Embase, and Web of Science databases for observational studies published until February 2016. Researches that evaluated CALR vs. JAK2V617F mutations on PMF-relevant complications (splenomegaly, leukemic transformation, or thrombosis) and overall survival were selected. Pooled adjust odds ratio (OR), hazard risk (HR), and the corresponding 95 % confidence intervals (CI) were calculated for the CALR-mutant versus the JAK2-mutant categories. Twelve studies involving 435 CALR-mutated and 1116 JAK2V617F PMF patients were analyzed. CALR-mutated patients displayed a lower risk of splenomegaly (OR 0.47, 95 % CI 0.29-0.78) and thrombosis (OR 0.52, 95 % CI 0.29-0.92) but showed no significant difference in the risk of leukemic transformation (OR 0.90, 95 % CI 0.55-1.47) when compared with JAK2-mutated patients. CALR mutation favorably affected overall survival while JAK2 mutation led to poorer survival rate (HR 2.58, 95 % CI 2.08-3.20). This meta-analysis confirmed that a genetic classification of PMF by CALR and JAK2 mutations carried significant prognostic relevance.

Elevated INR in a COVID-19 patient after concomitant administration of azvudine and anticoagulants.

Background: Azvudine (FNC) is a promising treatment candidate for managing coronavirus disease 2019 (COVID-19). However, drug interactions with azvudine have been poorly studied, especially with no reported cases of azvudine with anticoagulants such as warfarin and rivaroxaban. Case summary: The patient was diagnosed with lower limb venous thrombosis and took warfarin regularly. The international normalized ratio (INR) was stable (2.0-3.0). However, the INR increased to 7.52 after administering azvudine. The patient had no other factors justifying this change. This increase in INR occurred again with the administration of azvudine in combination with rivaroxaban, and the INR increased to 18.91. After azvudine administration was stopped, the INR did not increase when rivaroxaban was used alone. Conclusion: Azvudine, warfarin, and rivaroxaban might have previously unidentified drug interactions that increased the INR. Therefore, the INR must be closely monitored when they are concomitantly administered in COVID-19 patients.

HNRNPA2B1-Mediated MicroRNA-92a Upregulation and Section Acts as a Promising Noninvasive Diagnostic Biomarker in Colorectal Cancer.

MicroRNA-92a (miR-92a) may serve as a novel promising biomarker in multiple cancers, including colorectal cancer (CRC); however, the diagnostic accuracy and the underlying molecular mechanism of miR-92a in CRC is poorly understood. We first carried out meta-analysis and found that serum/plasma miR-92a yield better diagnostic efficacy when compared to stool samples and CRC tissues, and this finding was validated by our independent study through stool sample. Multiple bioinformatics assay indicated that miR-92a expression was positively correlated with heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) expression and closely related with the clinical characteristics of CRC. Experimental evidence showed that knockdown of HNRNPA2B1 could significantly decrease miR-92a expression and secretion in RKO cells. HNRNPA2B1 mediated miR-92a via m6A RNA modification. These findings indicate that HNRNPA2B1-m6A RNA modification-derived MicroRNA-92a upregulation and section from the local CRC acts a candidate noninvasive serum biomarker in colorectal cancer. Our study provides a novel insight into miR-92a mechanisms in relation to both expression and secretion for CRC diagnosis.

[Corrigendum] miR­1299/NOTCH3/TUG1 feedback loop contributes to the malignant proliferation of ovarian cancer.

Following the publication of the above article, a concerned reader drew to the authors' attention that the data shown for the 'CAOV3/NC mimics' experiment in Fig. 2D on p. 443 appeared to be the same as that shown for the 'TUG1­sh+miR­1299 inhibitors' experiment in Fig. 4H on p. 444. The authors have examined their original data, and realize that the same data was inadvertently included in the two figures. Consequently, the corrected version of Fig. 2, featuring the correct data for the 'CAOV3/NC mimics' experiment in Fig. 2D, is shown opposite. The overall conclusions of this study were not affected by this error. All the authors agree to the publication of this corrigendum, and are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this; furthermore, they apologize to the readership for any inconvenience caused. [Oncology Reports 44: 438-448, 2020; DOI: 10.3892/or.2020.7623].

DNA N6-methyladenine modification in hypertension.

DNA methylation has a role in the pathogenesis of essential hypertension. DNA N6-methyladenine (6mA) modification as a novel adenine methylation exists in human tissues, but whether it plays a role in hypertension development remains unclear. Here, we reported that the global 6mA DNA level in leukocytes was significantly reduced in patients with hypertension and was reversed with successful treatment. Age, systolic blood pressure, and serum total cholesterol and high-density lipoprotein levels were associated with decreased leukocyte 6mA DNA level. Elevated ALKBH1 (AlkB homolog 1), a demethylase of 6mA, level mediated this dynamic change in 6mA level in leukocytes and vascular smooth muscle cells in hypertension mouse and rat models. Knockdown of ALKBH1 suppressed angiotensin II-induced vascular smooth muscle phenotype transformation, proliferation and migration. ALKBH1-6mA directly and negatively regulated hypoxia inducible factor 1 α (HIF1α), which responded to angiotensin II-induced vascular remodeling. Collectively, our results demonstrate a potential epigenetic role for ALKBH1-6mA regulation in hypertension development, diagnosis and treatment.

Performance of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in diagnosis of ovarian cancer: a systematic review and meta-analysis.

BACKGROUND: To evaluate the diagnostic performance of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for ovarian cancer. PATIENTS AND METHODS: A thorough research was conducted in PubMed, Web of Science and Embase (until November 2018) to identify studies evaluating the accuracy of MALDI-TOF-MS for ovarian cancer. Using Meta-Disc1.4, Review Manager 5.3 and Stata 15.1 software to analyze the pooled results: sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and 95% confidence intervals (CI). The summary receiver operating characteristic curves (SROC) and area under the curve (AUC) show the overall performance of MALDI-TOF-MS. RESULTS: Eighteen studies were included in the meta-analysis. Methodological quality analysis of the included studies showed that these articles were at low risk of bias and applicability concerns in total. Summary estimates of the diagnostic parameters were as follows: sensitivity, 0.77 (95% CI: 0.73-0.80); specificity, 0.72 (95% CI: 0.70-0.74), PLR, 2.80 (95% CI: 2.41-3.24); NLR, 0.30 (95% CI: 0.22-0.40) and DOR, 10.71 (95% CI: 7.81-14.68). And the AUC was 0.8336. Egger's test showed no significant publication bias in this meta-analysis. CONCLUSION: In conclusion, MALDI-TOF-MS shows a good ability for diagnosing ovarian cancer. Further evaluation and optimization of standardized procedures are necessary for complete relying on MALDI-TOF-MS to diagnose ovarian cancer.

Accelerated telomere shortening independent of LRRK2 variants in Chinese patients with Parkinson's disease.

Oxidative stress and inflammation play vital roles in Parkinson's disease (PD) development. Thus, telomere length is expected to be shortened in this disease, but current data are inconclusive. We performed a case-control study of 261 patients with PD and 270 sex and age-matched healthy controls treated at the Peking Union Medical College Hospital. We found leucocyte telomere length (LTL) was significantly shortened in PD as compared with controls [1.02 (0.84-1.39) vs. 1.48 (1.08-1.94), P<0.001] and shorter LTL was associated with a dramatically increased risk of PD (lowest vs. highest quartile odds ratio (OR) =9.54, 95% CI: 5.33-17.06, P<0.001). We also investigated the roles of six LRRK2 variants in the susceptibility to PD. R1441C/G/H, G2019S, and I2020T variations were not detected in our study. No significant differences were found in the presence of variants R1398H (15.4% vs. 17.0%, P=0.619) and R1628P (2.3% vs. 0.7%, P=0.159) in PD and controls, while the G2385R variant was found to be a risk factor associated with increased PD susceptibility (OR=2.14, 95% CI: 1.12-4.10, P=0.021). No significant association was found between different LRRK2 variants and telomere length. These findings suggest that shorter LTL might be associated with PD in a manner independent of LRRK2 variants.

Differential expression of SALL4 in CTCs derived from hydatidiform moles and gestational trophoblastic neoplasms.

PROBLEM: To investigate EMT phenotype and SALL4 expression of circulating tumour cells (CTCs) in patients with gestational trophoblastic neoplasm (GTN). METHOD OF STUDY: CanPatrol CTC detection system in combination with SALL4 RNA in situ hybridization was used to investigate the profile of CTCs in different types of gestational trophoblastic disease (GTD). Circulating CTCs were phenotyped and annotated with SALL4 expression in 41 GTD patients, including 12 HM and 29 GTN, as well as 22 pregnant volunteers. RESULTS: A positive correlation between the number of CTC and serum ß-hCG concentration was found among the GTN patients. The number of E/M-CTC was positively correlated with serum ß-hCG, while M-CTC was positively correlated with prognostic score. Comparison among malignant GTD, benign GTD and healthy pregnant women revealed a significant difference in the number of total CTC, E/M-CTC, and M-CTC but not in E-CTC. ROC analysis was conducted to evaluate the performance of CTC phenotypes in distinguishing GTD patients from healthy pregnant women yielding an AUC as 0.826. Youden's index was maximal at the cutoff value of 8.5/4 mL with sensitivity and specificity at 53.66% and 100%, respectively. SALL4 expression was evaluated in GTD patients with CTC count greater than cutoff value. SALL4 high expressing CTCs (>2 signal dots) were detected in 66.67% (10/15) of malignant GTD patients but not in benign patients (0/5). CONCLUSION: Differential expression of SALL4 was seen in CTCs derived from hydatidiform moles and GTN. CTC profiling may be developed as an adjunct marker to diagnose GTN.

miR­1299/NOTCH3/TUG1 feedback loop contributes to the malignant proliferation of ovarian cancer.

Recent studies have revealed the oncogenic role of notch reporter 3 (NOTCH3) in ovarian cancer (OC). However, the possible regulators and mechanisms underlying notch receptor 3 (NOTCH3)­mediated behaviors in OC remain to be completely investigated. In the present study, we aimed to identify regulators of NOTCH3 and their interactions underlying the pathogenesis of OC. Bioinformatics analysis and luciferase reporter assay were used to identify potential regulatory miRNAs and lncRNAs of NOTCH3 in OC. Several in vivo and in vitro assays were performed to evaluate their effects on the proliferative ability mediated by NOTCH3. We identified microRNA­1299 (miR­1299) as a novel negative regulator of NOTCH3. miR­1299 was downregulated in OC and was found to be considerably correlated with tumor differentiation. Upregulation of miR­1299 inhibited cell proliferation, colony formation, and 5­ethynyl­2'­deoxyuridine (EdU) incorporation, as well as induced cell cycle arrest in the G0G1 phase in OC cells. Overexpression of miR­1299 in xenograft mouse models suppressed tumor growth in vivo. The lncRNA taurine upregulated gene 1 (TUG1), acting as a sponge of miR­1299, was found to upregulate NOTCH3 expression and promote cell proliferation in OC through the competing endogenous RNA mechanism. In addition, TUG1 was found to be a potential downstream target of NOTCH3, forming a miR­1299/NOTCH3/TUG1 feedback loop in the development of OC. Collectively, our findings improve the understanding of NOTCH3­mediated regulation in OC pathogenesis and facilitate the development of miRNA­ and lncRNA­directed diagnostics and therapeutics against this disease.

Peripheral Blood Leukocyte N6-methyladenosine is a Noninvasive Biomarker for Non-small-cell Lung Carcinoma.

BACKGROUND: N6-methyladenosine (m6A) triggers a new layer of epi-transcription. However, the potential noninvasive screening and diagnostic value of peripheral blood m6A for cancer are still unknown. Here, we intend to investigate whether leukocyte m6A can be a novel biomarker for non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Peripheral blood was collected from 119 NSCLC patients and 74 age-matched healthy controls. Total RNA was isolated from leukocytes for m6A measurement, and clinical information of participants was reviewed. The sensitivity, specificity, and area under the curve (AUC) of m6A for cancer diagnosis were evaluated by the receiver-operating characteristic (ROC) curve analysis. Flow cytometry and the Human Protein Atlas (HPA) database were used to characterize m6A in leukocyte differentials. Pearson's correlation was applied to indicate the relationship between m6A level and hematology variables. qPCR and bioinformatic analysis were used to identity the expression of m6A regulators in leukocyte. RESULTS: Leukocyte m6A was significantly elevated in 119 NSCLC patients compared with 74 healthy controls (P<0.001). We did not find significant association between m6A and age or gender. Elevated m6A level in NSCLC was associated with tumor stage (P<0.05) and tumor differentiation (P<0.05), and was significantly reduced after surgery (P<0.01). ROC curve analysis revealed that leukocyte m6A could significantly discriminate patients with lung adenocarcinoma (LUAD) (AUC=0.736, P<0.001) and lung squamous cell carcinoma (LUSC) (AUC=0.963, P<0.001) from healthy individuals. m6A displayed superior sensitivity (100%) and specificity (85.7%) for LUSC than squamous cell carcinoma (SCC) antigen and cytokeratin fragment 211 (Cyfra211). Flow cytometry analysis showed m6A modification was mainly localized on T cells and monocytes among leukocyte differentials. Leukocyte m6A was positively correlated with the number of lymphocytes and negatively correlated with monocytes in NSCLC but not in healthy controls. qPCR and bioinformatic analysis showed that elevated leukocyte m6A in NSCLC was caused by upregulated methyltransferase complex and downregulated FTO and ALKBH5. CONCLUSION: Leukocyte m6A represents a potential noninvasive biomarker for NSCLC screening, monitoring and diagnosis.

Association of N6-methyladenine DNA with plaque progression in atherosclerosis via myocardial infarction-associated transcripts.

Modification of the novel N6-methyladenine (m6A) DNA implicates this epigenetic mark in human malignant disease, but its role in atherosclerosis (AS) is largely unknown. Here, we found that the leukocyte level of m6A but not 5mC DNA modification was decreased with increasing of carotid plaque size and thickness in 207 AS patients as compared with 142 sex- and age-matched controls. Serum low-density lipoprotein (LDL) and leukocyte m6A levels were associated with the progression of carotid plaque size and thickness. Both LDL level and plaque thickness were also independently and negatively related to m6A level. Reduced m6A level was further confirmed in leukocytes and endothelium in western diet-induced AS mice and in oxidized-LDL (ox-LDL)-treated human endothelium and monocyte cells. Decreased m6A level was closely related to the upregulation of AlkB homolog 1 (ALKBH1), the demethylase of m6A. Silencing of ALKBH1 or hypoxia-inducible factor 1α (HIF1α) could rescue the ox-LDL-increased level of MIAT, a hypoxia-response gene. Mechanically, ox-LDL induced HIF1α for transfer into the nucleus. Nuclear HIF1α bound to the ALKBH1-demethylated MIAT promoter and transcriptionally upregulated its expression. Therefore, elevated ALKBH1 level in endothelium and leukocytes reduced m6A level, which is a novel and sensitive biomarker for AS progression.

FUN14 domain-containing 1 promotes breast cancer proliferation and migration by activating calcium-NFATC1-BMI1 axis.

BACKGROUND: FUN14 domain-containing 1 (FUNDC1), as a novel member of mitochondria-associated endoplasmic reticulum (ER) membranes associates with mitochondrial division and mitophagy. However, the expression profile and functional roles of FUNDC1 remain largely unclear in human cancer biology, including breast cancer (BC). METHODS: Immunohistochemistry and western blot analysis were used to determine the expression of FUNDC1 and BMI1 polycomb ring finger oncogene (BMI1). CCK8, cell counting and transwell assays were used to analyze cell proliferation, migration and invasion, respectively. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to detect the transcriptional regulation of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1). The prognostic merit of NFATC1 expression was assessed by Kaplan-Meier assay. FINDINGS: Immunohistochemistry revealed strong immunostaining for FUNDC1 in cytoplasmic and nuclear membrane distribution in BC tissues as compared with normal breast epithelium. Kaplan-Meier survival analysis showed worse outcome for BC patients with high FUNDC1 expression. In vitro assay of gain- and loss-of-function of FUNDC1 suggested that FUNDC1 could stimulate BC cell proliferation, migration and invasion. Furthermore, elevated FUNDC1 level promoted Ca2+ cytosol influx from ER and extracellular, as well as NFATC1 nuclear translocation and activity. Nuclear NFATC1 bound to the BMI1 gene promoter and transcriptionally upregulated its expression. Notably, BMI1 overexpression could rescue the loss of function of FUNDC1. Co-expression of FUNDC1 and BMI1 in BC patients predicted worse prognosis than without either expression. INTERPRETATION: FUNDC1 might promote BC progression by activating the Ca2+-NFATC1-BMI1 axis. This pathway may be promising for developing multiple targets for BC therapy.

Higher FT4 or TSH below the normal range are associated with increased risk of dementia: a meta-analysis of 11 studies.

Observational studies of thyroid function and dementia have reported conflicting results. We reviewed cohort and case-control studies from MEDLINE, EMBASE, Web of Science and the Cochrane Library that focused on the association between serum thyroxine, thyrotropin and dementia. A total of 24,952 participants from three case-control and eight cohort studies were included. The relationships between dementia and the per standard deviation (SD) increment of free thyroxine (FT4) (random relative ratio (RR) = 1.08, 95% confidence interval (CI) 1.00-1.17) and thyroid-stimulating hormone (TSH) (fixed RR = 0.91, 95% CI 0.84-0.99) were well established. TSH levels in the low category were associated with an increased risk of dementia (fixed RR = 1.60, 95% CI 1.27-2.00). However, the positive association was confined to TSH levels below the normal range (fixed RR = 1.77, 95% CI 1.31-2.39), not those in the lower tertile of the normal range (fixed RR = 1.39, 95% CI 0.98-1.97). Additionally, dementia was not significantly associated with high TSH levels (fixed RR = 0.99, 95% CI 0.76-1.29). Furthermore, there was no positive association between dementia and the low or high categories of TSH in men. Thus, individuals with higher FT4 levels or those with TSH levels below the normal range have an increased risk of dementia.