Inhibitor of DNA Binding Protein 3 (ID3) and Nuclear Respiratory Factor 1 (NRF1) Mediated Transcriptional Gene Signatures are Associated with the Severity of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is a degenerative vasculopathy. We have previously shown that transcription regulating proteins- inhibitor of DNA binding protein 3 (ID3) and the nuclear respiratory factor 1 (NRF1) contribute to vascular dysregulation. In this study, we have identified sex specific ID3 and NRF1-mediated gene networks in CAA patients diagnosed with Alzheimer's Disease (AD).

Endocrine Disrupting Chemicals Influence Hub Genes Associated with Aggressive Prostate Cancer.

Prostate cancer (PCa) is one of the most frequently diagnosed cancers among men in the world. Its prevention has been limited because of an incomplete understanding of how environmental exposures to chemicals contribute to the molecular pathogenesis of aggressive PCa. Environmental exposures to endocrine-disrupting chemicals (EDCs) may mimic hormones involved in PCa development.

Brain infiltration of breast cancer stem cells is facilitated by paracrine signaling by inhibitor of differentiation 3 to nuclear respiratory factor 1.

Treatment options for brain metastatic breast cancer are limited because the molecular mechanism for how breast cancer cells infiltrate the brain is not fully understood. For breast tumors to metastasize to the brain first, cells need to detach from the primary tumor, enter in the blood circulation, survive within the microvascular niche, and then cross the blood-brain barrier (BBB) to colonize into the brain. It is critical to understand how breast cancer cells transmigrate through the BBB to prevent brain metastasis.

Environmental Phenol and Paraben Exposure Risks and Their Potential Influence on the Gene Expression Involved in the Prognosis of Prostate Cancer.

Prostate cancer (PCa) is one of the leading malignant tumors in US men. The lack of understanding of the molecular pathology on the risk of food supply chain exposures of environmental phenol (EP) and paraben (PB) chemicals limits the prevention, diagnosis, and treatment options. This research aims to utilize a risk assessment approach to demonstrate the association of EP and PB exposures detected in the urine samples along with PCa in US men (NHANES data 2005−2015).

Is Mycobacterium tuberculosis carcinogenic to humans?

We highlight the ability of the tuberculosis (TB) causing bacterial pathogen, Mycobacterium tuberculosis (Mtb), to induce key characteristics that are associated with established IARC classified Group 1 and Group 2A carcinogenic agents. There is sufficient evidence from epidemiological case-control, cohort and meta-analysis studies of increased lung cancer (LC) risk in pre-existing/active/old TB cases. Similar to carcinogens and other pathogenic infectious agents, exposure to aerosol-containing Mtb sprays in mice produce malignant transformation of cells that result in squamous cell carcinoma.

Computational modeling and bioinformatic analyses of functional mutations in drug target genes in .

Tuberculosis (TB) continues to be the leading cause of deaths due to its persistent drug resistance and the consequent ineffectiveness of anti-TB treatment. Recent years witnessed huge amount of sequencing data, revealing mutations responsible for drug resistance. However, the lack of an up-to-date repository remains a barrier towards utilization of these data and identifying major mutations-associated with resistance.

The Rv1523 Methyltransferase Promotes Drug Resistance Through Methylation-Mediated Cell Wall Remodeling and Modulates Macrophages Immune Responses.

The acquisition of antibiotics resistance is a major clinical challenge limiting the effective prevention and treatment of the deadliest human infectious disease tuberculosis. The molecular mechanisms by which initially () develop drug resistance remain poorly understood. In this study, we report the novel role of Rv1523 MTase in the methylation of mycobacterial cell envelope lipids and possible mechanism of its contribution in the virulence and drug resistance.

Causal Bayesian gene networks associated with bone, brain and lung metastasis of breast cancer.

Using a machine learning method, this study aimed to identify unique causal networks of genes associated with bone, brain, and lung metastasis of breast cancer. Bayesian network analysis identified differentially expressed genes in primary breast cancer tissues, in bone, brain, and lung breast cancer metastatic tissues, and the clinicopathological features of patients obtained from the Gene Expression Omnibus microarray datasets. We evaluated the causal Bayesian networks of breast metastasis to distant sites (bone, brain, or lung) by (i) measuring how well the structures of each specific type of breast cancer metastasis fit the data, (ii) comparing the structures with known experimental evidence, and (iii) reporting predictive capabilities of the structures.

Environmental DNA and RNA as Records of Human Exposome, Including Biotic/Abiotic Exposures and Its Implications in the Assessment of the Role of Environment in Chronic Diseases.

Most of environment-related diseases often result from multiple exposures of abiotic and/or biotic stressors across various life stages. The application of environmental DNA/RNA (eDNA/eRNA) to advance ecological understanding has been very successfully used. However, the eminent extension of eDNA/eRNA-based approaches to estimate human exposure to biotic and/or abiotic environmental stressors to understand the environmental causes of chronic diseases has yet to start.

Nuclear Respiratory Factor 1 (NRF1) Transcriptional Activity-Driven Gene Signature Association with Severity of Astrocytoma and Poor Prognosis of Glioblastoma.

Despite tremendous progress in understanding the pathobiology of astrocytoma, major gaps remain in our knowledge of the molecular basis underlying the aggressiveness of high-grade astrocytoma (glioblastoma - GBM). Recently, we and others have shown nuclear respiratory factor 1 (NRF1) transcription factor being highly active in human cancers, but its role in astrocytoma remains unknown. Therefore, the purpose of this study was to uncover the role of NRF1 in the progression of GBM.

Integrated Chip-Seq and RNA-Seq Data Analysis Coupled with Bioinformatics Approaches to Investigate Regulatory Landscape of Transcription Modulators in Breast Cancer Cells.

The objective of this chapter is to describe step-by-step bioinformatics and functional genomics solutions for analyzing ChIP-Seq and RNA-Seq data for understanding the regulatory mechanisms of chromatin modifiers and transcription factors that can drive pathogenesis of chronic complex human diseases, such as cancer. Here we have used two transcription regulatory proteins: nuclear respiratory factor 1 (NRF1) and inhibitor of differentiation protein 3 (ID3) for ChIP-Seq and RNA-Seq data as examples for discussing the importance of selecting the appropriate computational analysis methods, software, and parameters for the processing of raw data as well as their integrative regulatory landscape analysis to obtain accurate and reliable results. Both ChIP-Seq and RNA-Seq analytic methodologies are used as instructional examples to identify NRF1 or ID3 binding to the promoters and enhancers in the genome and their effects on the activity as well as to discover target genes that can drive breast cancer.

Nuclear Respiratory Factor 1 Acting as an Oncoprotein Drives Estrogen-Induced Breast Carcinogenesis.

We have previously shown nuclear respiratory factor 1 (NRF1)-mediated transcriptional programming of mitobiogenesis contributes to estrogen-induced breast cancer through modulating cell cycle progression. In this study, we report a new role of NRF1 that goes beyond that of programming mitobiogenesis. Specifically, we report a novel oncogenic function of NRF1 supporting its causative role in breast cancer development and progression.

NRF1 motif sequence-enriched genes involved in ER/PR -ve HER2 +ve breast cancer signaling pathways.

Nuclear respiratory factor 1 (NRF1) transcription factor has recently been shown to control breast cancer progression. However, mechanistic aspects by which NRF1 may contribute to susceptibility to different breast tumor subtypes are still not fully understood. Since transcriptional control of NRF1 seems to be dependent on epidermal growth factor receptor signaling, herein, we investigated the role of NRF1 in estrogen receptor/progesterone receptor negative, but human epidermal growth factor receptor 2-positive (ER/PR -ve HER2 +ve) breast cancer.

Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression.

Background: Nuclear respiratory factor 1 (NRF1), historically perceived as a protein regulating genes controlling mitochondrial biogenesis, is now widely recognized as a multifunctional protein and as a key player in the transcriptional modulation of genes implicated in various cellular functions. Here, we present emerging data supporting novel roles of NRF1 in cancer development and progression through its interplay with the transcription factors E2F4 and MYC. To identify common human NRF1, E2F4 and MYC target genes, we analyzed the Encyclopedia of DNA Elements (ENCODE) NRF1 ChIP-Seq data.

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases.

During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese.

Environmental estrogen-like endocrine disrupting chemicals and breast cancer.

Background: Estrogen-mimicking endocrine disruptors (EEDs) such as polychlorinated biphenyls (PCBs), bisphenol A (BPA), and phthalates have been found ubiquitously throughout our environment. Although exposure to EEDs has the ability to interfere with endocrine control of reproductive function and development in both humans and wildlife, inconsistent reports have made it difficult to draw conclusions concerning the hypothesized increased risk of breast cancer associated with EEDs.

Objectives: The purpose of this study was to examine the cross-sectional relationship between exposure to PCBs, BPA or phthalates; and risk of breast cancer in U.

Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer.

We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis.

Proteomic and Mitochondrial Genomic Analyses of Pediatric Brain Tumors.

The molecular mechanism unraveling why a particular type of pediatric brain tumor (pBT) behaves so differently from child to child or genetic/epigenetic changes in the mitochondrial genome vary from tumor to tumor is not clearly understood. Despite the identification of mitochondrial DNA (mtDNA) mutations in different types of pBT, the contribution of mitochondrial dysfunction-related genes or proteins that are selectively up- or down-regulated in pBT of different types has not been comprehensively examined. In the present study, we combined a 2D DIGE approach with protein identification using MALDI-TOF MS and LC-MS/MS, coupled with mtDNA genomics to screen brain samples for discovering changes in protein expression, and mtDNA sequence variation and mtDNA copy number in the disease states.

Bayesian network and mechanistic hierarchical structure modeling of increased likelihood of developing intractable childhood epilepsy from the combined effect of mtDNA variants, oxidative damage, and copy number.

Despite that mutations in mitochondrial DNA (mtDNA) have been associated with major epilepsy syndromes, the role of mtDNA instability and mitochondrial dysfunction in epileptogenesis has not been comprehensively examined. In the present study, we investigated the role of mtDNA copy number, oxidative damage, and mtDNA variants as independent or combined risk factors for the development of intractable childhood epilepsy. We analyzed mtDNA copy number and oxidative damage by quantitative polymerase chain reaction (PCR), and mtDNA variants by dot blot in brain tissue specimens collected from 21 pediatric intractable epilepsy patients and 11 non-epileptic patients.

Reverse engineering of modified genes by Bayesian network analysis defines molecular determinants critical to the development of glioblastoma.

In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV), and 'key genes' within each grade were identified.

Thioredoxin-mediated redox regulation of resistance to endocrine therapy in breast cancer.

Resistance to endocrine therapy in breast carcinogenesis due to the redox regulation of the signal transduction system by reactive oxygen species (ROS) is the subject of this review article. Both antiestrogens and aromatase inhibitors are thought to prevent cancer through modulating the estrogen receptor function, but other mechanisms cannot be ruled out as these compounds also block metabolism and redox cycling of estrogen and are free radical scavengers. Endocrine therapeutic agents, such as, tamoxifen and other antiestrogens, and the aromatase inhibitor, exemestane, are capable of producing ROS.

Reactive oxygen species via redox signaling to PI3K/AKT pathway contribute to the malignant growth of 4-hydroxy estradiol-transformed mammary epithelial cells.

The purpose of this study was to investigate the effects of 17-β-estradiol (E2)-induced reactive oxygen species (ROS) on the induction of mammary tumorigenesis. We found that ROS-induced by repeated exposures to 4-hydroxy-estradiol (4-OH-E2), a predominant catechol metabolite of E2, caused transformation of normal human mammary epithelial MCF-10A cells with malignant growth in nude mice. This was evident from inhibition of estrogen-induced breast tumor formation in the xenograft model by both overexpression of catalase as well as by co-treatment with Ebselen.