Oxidative Status, Iron Plasma Levels in Venous Thrombosis Patients.

Exaggerated clot induces venous thrombosis (VTE); oxidative stress (OxS) can to be postulated as additional risk factor. This study evaluates firstly OxS by measuring surrogate biomarkers (malondialdehyde-MDA, 4-hydroxinonenal-4-HNE, superoxide desmutase enzyme (SOD)), secondly the iron (Fe) plasma level and thirdly the hepcidin protein (Hep) level in patients with VTE. A case control study was performed enrolling twenty hospitalized patients and an equal number of healthy individuals. In VTE patients, the following results were found. The MDA was 8.38 ± 0.5 µM/L, the 4-HNE measured 2.75 ± 0.03 µM/L and the SOD was 0.025 ± 0.01 U/mL. The I was 73.10 ± 10 µg/dL and the He was 4.77 ± 0.52 ng/mL. In the control group, the MDA measured 5.5 ± 0.6 µM/L, the 4-HNE 2.24 ± 0.021 µM/L and the SOD 0.08 ± 0.12 U/mL. The Hep was 2.1 ± 0.55 ng/mL and the Fe was 88.2 ± 9.19 µg/dL. Differences were statistically significant. Results suggest that in VTE there is activated OxS, Fe deregulation and over-production of Hep. Fe deregulation induces OxS, leading both to inflammation in the clot activator and stimulation of the pro-thrombotic status. The study highlights OxS and Fe and their regulation as intriguing indicators for risk of VTE.

"Crosstalk between non-coding RNAs and transcription factor LRF in non-small cell lung cancer".

Epigenetic approaches in direct correlation with assessment of critical genetic mutations in non-small cell lung cancer (NSCLC) are currently very intensive, as the epigenetic components underlying NSCLC development and progression have attained high recognition. In this level of research, established human NSCLC cell lines as well as experimental animals are widely used to detect novel biomarkers and pharmacological targets to treat NSCLC. The epigenetic background holds a great potential for the identification of epi-biomarkers for treatment response however, it is highly complex and requires precise definition as these phenomena are variable between NSCLC subtypes and systems origin. We engaged an in-depth characterization of non-coding (nc)RNAs prevalent in human KRAS-mutant NSCLC cell lines A549 and H460 and mouse KRAS-mutant NSCLC tissue by Next Generation Sequencing (NGS) and quantitative Real Time PCRs (qPCRs). Also, the transcription factor (TF) LRF, a known epigenetic silencer, was examined as a modulator of non-coding RNAs expression. Finally, interacting networks underlying epigenetic variations in NSCLC subtypes were created. Data derived from our study highlights the divergent epigenetic profiles of NSCLC of human and mouse origin, as well as the significant contribution of 12qf1: 109,709,060-109,747,960 mouse chromosomal region to micro-RNA upregulated species. Furthermore, the novel epigenetic miR-148b-3p/lncPVT1/ZBTB7A axis was identified, which differentiates human cell line of lung adenocarcinoma from large cell lung carcinoma, two characteristic NSCLC subtypes. The detailed recording of epigenetic events in NSCLC and combinational studies including networking between ncRNAs and TFs validate the identification of significant epigenetic features, prevailing in NSCLC subtypes and among experimental models. Our results enrich knowledge in the field and empower research on the epigenetic prognostic biomarkers of the disease progression, NSCLC subtypes discrimination and advancement to patient-tailored treatments.

miRNA Regulation of Cell Phenotype and Parietal Remodeling in Atherosclerotic and Non-Atherosclerotic Aortic Aneurysms: Differences and Similarities.

Aortic aneurysms are a serious health concern as their rupture leads to high morbidity and mortality. Abdominal aortic aneurysms (AAAs) and thoracic aortic aneurysms (TAAs) exhibit differences and similarities in their pathophysiological and pathogenetic features. AAA is a multifactorial disease, mainly associated with atherosclerosis, characterized by a relevant inflammatory response and calcification. TAA is rarely associated with atherosclerosis and in some cases is associated with genetic mutations such as Marfan syndrome (MFS) and bicuspid aortic valve (BAV). MFS-related and non-genetic or sporadic TAA share aortic degeneration with endothelial-to-mesenchymal transition (End-Mt) and fibrosis, whereas in BAV TAA, aortic degeneration with calcification prevails. microRNA (miRNAs) contribute to the regulation of aneurysmatic aortic remodeling. miRNAs are a class of non-coding RNAs, which post-transcriptionally regulate gene expression. In this review, we report the involvement of deregulated miRNAs in the different aortic remodeling characterizing AAAs and TAAs. In AAA, miRNA deregulation appears to be involved in parietal inflammatory response, smooth muscle cell (SMC) apoptosis and aortic wall calcification. In sporadic and MFS-related TAA, miRNA deregulation promotes End-Mt, SMC myofibroblastic phenotypic switching and fibrosis with glycosaminoglycan accumulation. In BAV TAA, miRNA deregulation sustains aortic calcification. Those differences may support the development of more personalized therapeutic approaches.

Recent advances in understanding the biology of follicular lymphoma.

Follicular lymphoma (FL), the most common indolent B-cell lymphoma, develops over decades before manifesting as overt disease. BCL2 overexpression by t(14;18) confers a survival advantage to B cells during the germinal center reaction, and abnormalities in epigenetic modifier genes lead to desynchronization of gene expression changes in germinal center B cells. Studies in mouse models have shown that BCL2 overexpression and epigenetic deregulation in B cells cooperatively promote lymphomagenesis. The immune microenvironment also plays an essential role in the biology of FL, and many molecular prognostic indicators based on the immune microenvironment have been proposed. However, high-risk gene signatures do not appear to be consistent between patients receiving different chemotherapies. FL cells frequently carry N-linked glycosylation motifs within the immunoglobulin gene, leading to chronic activation of the B-cell receptor (BCR). Recent evidence suggests that this chronic BCR signaling drives FL polarization toward a dark-zone phenotype and promotes clonal evolution. Since both epigenetic and post-transcriptional modifications of B cells have been implicated in the early stage of FL development, it may be possible to use novel non-chemotherapeutic approaches that interfere with the immunobiology in treatment or early prevention of FL.

Adaptation and Validation of the Perception of Anomie Scale in Chilean University Students.

The Perception of Anomie Scale (PAS) is a measure used to evaluate the state of society and whether it is disintegrated and deregulated. Although widely used, the psychometric properties of reliability, validity, and measurement invariance according to sex have not been studied in the Chilean university population. To explore these properties, a cross-sectional study was carried out with 383 students from public (45.7%) and private (54.3%) universities, with a mean age of 21.5 years (SD = 3.3). A CFA and ESEM were performed, which confirmed the two-factor correlated structure, achieving better goodness-of-fit indices by eliminating five items (RMSEA = 0.09; CFI = 0.98; TLI = 0.95). This also provided evidence of reliability and measurement invariance according to sex. This study provides evidence of the psychometric quality of the PAS scale, thus allowing its use in the Chilean university context.

Deregulated Transcriptome as a Platform for Adrenal Huntington's Disease-Related Pathology.

Huntington's disease (HD) is a neurodegenerative disorder that affects mainly the central nervous system (CNS) by inducing progressive deterioration in both its structure and function. In recent years, there has been growing interest in the impact of HD on peripheral tissue function. Herein, we used the R6/2 mouse model of HD to investigate the influence of the disease on adrenal gland functioning. A transcriptomic analysis conducted using a well-established quantitative method, an Affymetrix array, revealed changes in gene expression in the R6/2 model compared to genetic background controls. For the first time, we identified disruptions in cholesterol and sterol metabolism, blood coagulation, and xenobiotic metabolism in HD adrenal glands. This study showed that the disrupted expression of these genes may contribute to the underlying mechanisms of Huntington's disease. Our findings may contribute to developing a better understanding of Huntington's disease progression and aid in the development of novel diagnostic or therapeutic approaches.

A Comprehensive Bioinformatic Analysis of RNA-seq Datasets Reveals a Differential and Variable Expression of Wildtype and Variant UGT1A Transcripts in Human Tissues and Their Deregulation in Cancers.

The UGT1A locus generates over 60 different alternatively spliced transcripts and 30 circular RNAs. To date, v2 and v3 transcripts are the only variant UGT1A transcripts that have been functionally characterized. Both v2 and v3 transcripts encode the same inactive variant UGT1A proteins (i2s) that can negatively regulate glucuronidation activity and influence cancer cell metabolism. However, the abundance and interindividual variability in the expression of v2 and v3 transcripts in human tissues and their potential deregulation in cancers have not been comprehensively assessed. To address this knowledge gap, we quantified the expression levels of v1, v2, and v3 transcripts using RNA-seq datasets with large cohorts of normal tissues and paired normal and tumor tissues from patients with six different cancer types (liver, kidney, colon, stomach, esophagus, and bladder cancer). We found that v2 and v3 abundance varied significantly between different tissue types, and that interindividual variation was also high within the same tissue type. Moreover, the ratio of v2 to v3 variants varied between tissues, implying their differential regulation. Our results showed higher v2 abundance in gastrointestinal tissues than liver and kidney tissues, suggesting a more significant negative regulation of glucuronidation by i2 proteins in gastrointestinal tissues than in liver and kidney tissues. We further showed differential deregulation of wildtype (v1) and variant transcripts (v2, v3) in cancers that generally increased the v2/v1 and/or v3/v1 expression ratios in tumors compared to normal tissues, indicating a more significant role of the variants in tumors. Finally, we report ten novel UGT1A transcripts with novel 3' terminal exons, most of which encode variant proteins with a similar structure to UGT1A_i2 proteins. These findings further emphasize the diversity of the UGT1A transcriptome and proteome.

Prognostic significance and expression pattern of glucose related genes in breast cancer: A comprehensive computational biology approach.

Breast cancer (BC) is the most common type of malignancy globally and the main reason why women die from tumours. The Warburg effect, a characteristic of tumor, describes how most solid tumour cells acclimatize to their diverse surroundings by relying heavily on aerobic glycolysis for production of energy. In addition to producing key metabolic intermediates that are crucial for the production of macromolecules, which enable cancer cell division, invasiveness, and drug resistance, the transformed energy metabolism also supplies tumor cells with ATP for cellular energy. Here, we evaluated the expression profile, prognostic significance, and clinical relevance of glucose-related genes in BC using a bioinformatic approach. To clarify the significance of glucose-related genes in the development of breast tumours, we also performed a functional enrichment investigation of deregulated genes using the STRING and KEGG portal. The study depicted that of the 61 genes examined, 8 genes had a fold change

Whole blood transcriptional profiling reveals highly deregulated atherosclerosis genes in Philadelphia-chromosome negative myeloproliferative neoplasms.

BACKGROUND: The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are associated with a huge comorbidity burden, including an increased risk of cardiovascular diseases. Recently, chronic inflammation has been suggested to be the driving force for clonal evolution and disease progression in MPN but also potentially having an impact upon the development of accelerated (premature) atherosclerosis. OBJECTIVES: Since chronic inflammation, atherosclerosis, and atherothrombosis are prevalent in MPNs and we have previously shown oxidative stress genes to be markedly upregulated in MPNs, we hypothesized that genes linked to development of atherosclerosis might be highly deregulated as well. METHODS: Using whole blood gene expression profiling in patients with essential thrombocythemia (ET; n = 19), polycythemia vera (PV; n = 41), or primary myelofibrosis (PMF; n = 9), we herein for the first time report aberrant expression of several atherosclerosis genes. RESULTS: Of 84 atherosclerosis genes, 45, 56, and 46 genes were deregulated in patients with ET, PV, or PMF, respectively. Furthermore, BCL2L1, MMP1, PDGFA, PTGS1, and THBS4 were progressively significantly upregulated and BCL2 progressively significantly downregulated from ET over PV to PMF (all FDR <0.05). CONCLUSIONS: We have for the first time shown massive deregulation of atherosclerosis genes in MPNs, likely reflecting the inflammatory state in MPNs in association with in vivo activation of leukocytes, platelets, and endothelial cells being deeply involved in the atherosclerotic process.

A study on the emotional and attitudinal behaviors of social media users under the sudden reopening policy of the Chinese government.

Introduction: Since the outbreak of the COVID-19 pandemic, the Chinese government has implemented a series of strict prevention and control policies to prevent the spread of the virus. Recently, the Chinese government suddenly changed its approach and lifted all prevention and control measures. This sudden change in policy is expected to lead to a widespread outbreak of COVID-19 in China, and the public and local governments are not adequately prepared for the unknown impact on society. The change in the "emergency" prevention and control policy provides a unique research perspective for this study. Methods: The purpose of this study is to analyze the public's attitudes and emotional responses to COVID-19 under the sudden opening policy, identify the key factors that contribute to these attitudes and emotions, and propose solutions. In response to this sudden situation, we conducted data mining on topics and discussions related to the opening of the epidemic on Sina Weibo, collecting 125,686 interactive comments. We used artificial intelligence technology to analyze the attitudes and emotions reflected in each data point, identify the key factors that contribute to these attitudes and emotions, explore the underlying reasons, and find corresponding solutions. Results: The results of the study show that in the face of the sudden release of the epidemic, the public mostly exhibited negative emotions and behaviors, with many people experiencing anxiety and panic. However, the gradual resumption of daily life and work has also led some people to exhibit positive attitudes. Conclusion: The significance of this study is to help the government and institutions understand the impact of policy implementation on users, and to enable them to adjust policies in a timely manner to respond to potential social risks. The government, emergency departments, and the public can all prepare for similar situations based on the conclusions of this study.

Insight into de-regulation of amino acid feedback inhibition: a focus on structure analysis method.

Regulation of amino acid's biosynthetic pathway is of significant importance to maintain homeostasis and cell functions. Amino acids regulate their biosynthetic pathway by end-product feedback inhibition of enzymes catalyzing committed steps of a pathway. Discovery of new feedback resistant enzyme variants to enhance industrial production of amino acids is a key objective in industrial biotechnology. Deregulation of feedback inhibition has been achieved for various enzymes using in vitro and in silico mutagenesis techniques. As enzyme's function, its substrate binding capacity, catalysis activity, regulation and stability are dependent on its structural characteristics, here, we provide detailed structural analysis of all feedback sensitive enzyme targets in amino acid biosynthetic pathways. Current review summarizes information regarding structural characteristics of various enzyme targets and effect of mutations on their structures and functions especially in terms of deregulation of feedback inhibition. Furthermore, applicability of various experimental as well as computational mutagenesis techniques to accomplish feedback resistance has also been discussed in detail to have an insight into various aspects of research work reported in this particular field of study.

Implications of Toll-like receptors (TLRs) and their signaling mechanisms in human cancers.

Most essential pattern-recognition receptors regulating innate immune functions are toll-like receptors (TLRs). TLRs are characterized by lack of concurrent epithelial markers and are typically identified by their gene expressions. One major mechanism by which TLRs generate their effector functions is by triggering inflammatory responses. Activation of TLRs can impact initiation, advancement, and control of cancers by regulating the inflammatory microenvironment. Several TLRs have been implicated in human cancers and some of them are identified as cancer biomarkers as well; for example, TLRs 2, 3, 5 are expressed more frequently in most cancers. Knowing the upregulation and downregulation of the TLR genes in human cancers will be useful for the development of newer therapeutic targets which can disrupt the pathways associated with such deregulation. We present here the various TLRs and their functions in human lung, gastric, breast, prostate, oral, ovarian, colorectal, cervical, esophageal, bladder and hepatic cancers.

Using Sister Chromatid Exchange Assay to Detect Homologous Recombination Deficiency in Epigenetically Deregulated Urothelial Carcinoma Cells.

Sister chromatid exchange (SCE) is the process of exchanging regions between two sister chromatids during DNA replication. Exchanges between replicated chromatids and their sisters can be visualized in cells when DNA synthesis in one chromatid is labelled by 5-bromo-2'-deoxyuridine (BrdU). Homologous recombination (HR) is considered as the principal mechanism responsible for the sister chromatid exchange (SCE) upon replication fork collapse, and therefore SCE frequency upon genotoxic conditions reflects the capacity of HR repair to respond to replication stress. During tumorigenesis, inactivating mutations or altered transcriptome can affect a plethora of epigenetic factors that participate in DNA repair processes, and there are an increasing number of reports which demonstrate a link between epigenetic deregulation in cancer and homologous recombination deficiency (HRD). Therefore, the SCE assay can provide valuable information regarding the HR functionality in tumors with epigenetic deficiencies. In this chapter, we provide a method to visualize SCEs. The technique outlined below is characterized by high sensitivity and specificity and has been successfully applied to human bladder cancer cell lines. In this context, this technique could be used to characterize the dynamics of HR repair in tumors with deregulated epigenome.

MicroRNA-765 is upregulated in myelodysplastic syndromes and induces apoptosis via PLP2 inhibition in leukemia cells.

Background: Epigenetic studies, particularly research on microRNA (miRNA), have flourished. The abnormal expression of miRNA contributes to the development of hematologic malignancies. miR-765 has been reported to inhibit cell proliferation by downregulating proteolipid protein 2 (PLP2), which causes apoptosis. We investigated miR-765 dysregulation in myelodysplastic syndromes (MDS). Methods: We compared the expression profiles of miR-765 in 65 patients with MDS and 11 controls. Cell proliferation and apoptosis assays were performed to determine the in vitro effects of miR-765 on leukemia cells transfected with the miR-765 mimic. Reverse transcription quantitative PCR (RT-qPCR) and western blotting were performed to examine the targets of miR-765. Results: We found that miR-765 levels were upregulated 10.2-fold in patients with MDS compared to controls. In refractory cytopenia with multilineage dysplasia, the percentage of patients with elevated miR-765 levels was significantly higher than in other forms of MDS. Experiments with leukemia cells revealed that transfection with a miR-765 mimic inhibited cell proliferation and induced apoptosis. RT-qPCR and western blotting demonstrated that the target of miR-765 was PLP2. Conclusion: These findings imply that upregulation of miR-765 induces apoptosis via downregulation of PLP2 and may have a role in MDS pathogenesis.

Rewired Metabolism Caused by the Oncogenic Deregulation of MYC as an Attractive Therapeutic Target in Cancers.

MYC is one of the most deregulated oncogenes on multiple levels in cancer. As a node transcription factor, MYC plays a diverse regulatory role in many cellular processes, including cell cycle and metabolism, both in physiological and pathological conditions. The relentless growth and proliferation of tumor cells lead to an insatiable demand for energy and nutrients, which requires the rewiring of cellular metabolism. As MYC can orchestrate all aspects of cellular metabolism, its altered regulation plays a central role in these processes, such as the Warburg effect, and is a well-established hallmark of cancer development. However, our current knowledge of MYC suggests that its spatial- and concentration-dependent contribution to tumorigenesis depends more on changes in the global or relative expression of target genes. As the direct targeting of MYC is proven to be challenging due to its relatively high toxicity, understanding its underlying regulatory mechanisms is essential for the development of tumor-selective targeted therapies. The aim of this review is to comprehensively summarize the diverse forms of MYC oncogenic deregulation, including DNA-, transcriptional- and post-translational level alterations, and their consequences for cellular metabolism. Furthermore, we also review the currently available and potentially attractive therapeutic options that exploit the vulnerability arising from the metabolic rearrangement of MYC-driven tumors.

ZNF692 promote proliferation through transcriptional repression of essential genes in clear cell renal carcinoma.

Transcription deregulation is recognized as a prominent hallmark of carcinogenesis. However, our understanding of the transcription factors implicated in the dysregulated transcription network of clear cell renal carcinoma (ccRCC) remains incomplete. In this study, we present evidence that ZNF692 drives tumorigenesis in ccRCC through the transcriptional repression of essential genes. We observed overexpression of ZNF692 in various cancers, including ccRCC, and found that the knockdown or knockout of ZNF692 suppressed the growth of ccRCC. Genome-wide binding site analysis using ChIP-seq revealed that ZNF692 regulates genes associated with cell growth, Wnt signaling, and immune response in ccRCC. Furthermore, motif enrichment analysis identified a specific motif (5'-GCRAGKGGAKAY-3') that is recognized and bound by ZNF692. Subsequent luciferase reporter assays demonstrated that ZNF692 transcriptionally represses the expression of IRF4 and FLT4 in a ZNF692 binding motif-dependent manner. Additionally, we observed MYC binding to the promoter regions of ZNF692 in most cancer types, driving ZNF692 overexpression specifically in ccRCC. Overall, our study sheds light on the functional significance of ZNF692 in ccRCC and provides valuable insights into its therapeutic potential as a target in cancer treatment.

Integrating differential expression, co-expression and gene network analysis for the identification of common genes associated with tumor angiogenesis deregulation.

Angiogenesis is essential for tumor growth and cancer metastasis. Identifying the molecular pathways involved in this process is the first step in the rational design of new therapeutic strategies to improve cancer treatment. In recent years, RNA-seq data analysis has helped to determine the genetic and molecular factors associated with different types of cancer. In this work we performed integrative analysis using RNA-seq data from human umbilical vein endothelial cells (HUVEC) and patients with angiogenesis-dependent diseases to find genes that serve as potential candidates to improve the prognosis of tumor angiogenesis deregulation and understand how this process is orchestrated at the genetic and molecular level. We downloaded four RNA-seq datasets (including cellular models of tumor angiogenesis and ischaemic heart disease) from the Sequence Read Archive. Our integrative analysis includes a first step to determine differentially and co-expressed genes. For this, we used the ExpHunter Suite, an R package that performs differential expression, co-expression and functional analysis of RNA-seq data. We used both differentially and co-expressed genes to explore the human gene interaction network and determine which genes were found in the different datasets that may be key for the angiogenesis deregulation. Finally, we performed drug repositioning analysis to find potential targets related to angiogenesis inhibition. We found that that among the transcriptional alterations identified, SEMA3D and IL33 genes are deregulated in all datasets. Microenvironment remodeling, cell cycle, lipid metabolism and vesicular transport are the main molecular pathways affected. In addition to this, interacting genes are involved in intracellular signaling pathways, especially in immune system and semaphorins, respiratory electron transport and fatty acid metabolism. The methodology presented here can be used for finding common transcriptional alterations in other genetically-based diseases.

Plantamajoside modulates immune dysregulation and hepatic lipid metabolism in rats with nonalcoholic fatty liver disease via AMPK/Nrf2 elevation.

Nonalcoholic fatty liver disease (NAFLD) is a hepatic metabolic syndrome with a rapidly increasing prevalence globally. Plantamajoside (PMS), a phenylethanoid glycoside component extracted from Plantago asiatica, has various biological properties. However, its effect on NAFLD remains unknown. The study aimed to explore the effect and mechanism of PMS on NAFLD in the high-fat diet (HFD)-feeding rats. PMS induced a decrease in body and liver weight, and the amelioration in the blood lipid parameters and pathological symptoms in HFD-feeding rats. The increase in the serum concentrations and the relative protein expressions of proinflammatory factors was decreased by the PMS treatment in HFD-induced NAFLD rats. Additionally, PMS reduced the excessive lipid vacuoles, and modified the relative expressions of proteins involved in the fatty acid synthesis and uptake in HFD-feeding rats. Mechanically, the downregulation of AMPK/Nrf2 pathway in HFD-feeding rats was restored by the PMS treatment. Inhibition of AMPK pathway reversed the PMS-induced the increase in the level of inflammatory factors, pathological symptoms, excessive lipid vacuoles, and the relative expression of proteins involved in the fatty acid synthesis and uptake. Collectively, PMS ameliorated immune dysregulation and abnormal hepatic lipid metabolism by activating AMPK/Nrf2 pathway in rats with NAFLD.

Employment Protection Legislation, Labour Market Dualism, and Fertility in Europe.

Theoretically, whether a more loosely regulated labour market inhibits or fosters fertility in a society is ambiguous. Empirically, the few studies analysing the relationship between the strictness of employment protection legislation-the norms and procedures regulating labour markets' hiring and firing processes-and fertility have found mixed evidence. This paper reconciles the ambivalent conclusions of previous studies by analysing the impact of employment protection legislation and labour market dualism on total fertility across 19 European countries between 1990 and 2019. Our results indicate that an increase in employment protection for regular workers positively affects total fertility. Nonetheless, an increasing gap between the regulation of regular and temporary employment-that is, labour market dualism-negatively impacts total fertility. These effects, of small-to-moderate intensity, are relatively homogeneous across age groups and geographical areas and are especially pronounced among the lower educated. We conclude that labour market dualism, rather than a "rigid" employment protection legislation, discourages fertility.