NFκB1 inhibits memory formation and supports effector function of ILC2s in memory-driven asthma.

Background: ILC2s are capable of generating memory. The mechanism of memory induction and memory-driven effector function (trained immunity) in ILC2s is unknown. Objective: NFκB1 is preferentially expressed at a high level in ILC2s. We examined the role of NFkB1 in memory induction and memory-driven effector function in a mouse model of asthma. Methods: Intranasal administration of Alternaria, flexivent, ELISA, histology, real-time PCR, western blot, flow cytometry and immunofluorescence staining. Results: NFκB1 was essential for the effector phase of memory-driven asthma. NFκB1 was critical for IL33 production, ILC2 generation, and production of type-2 cytokines, which resulted in eosinophilic inflammation and other features of asthma. NFκB1 induction of type-2 cytokines in ILC2s was independent of GATA3. NFκB1 was important for allergen induction of ILC3s and FoxP3+ Tregs. NFκB1 did not affect Th2 cells or their cytokine production. In contrast to its protagonistic role in the effector phase, NFκB1 had an antagonistic role in the memory phase. NFκB1 inhibited allergen-induced upregulation of memory-associated repressor and preparedness genes in ILC2s. NFκB1 upregulated RUNX1. NFκB1 formed a heterodimer with RUNX1 in ILC2s. Conclusions: NFκB1 positively regulated the effector phase but inhibited the induction phase of memory. The foregoing pointed to an interdependent antagonism between the memory induction and the memory effector processes. The NFκB1-RUNX1 heterodimer represented a non-canonical transcriptional activator of type-2 cytokines in ILC2s.

Role of epigenetics in innate lymphoid cells.

Epigenetics plays a crucial role in gene regulation and cell function without changing the DNA sequence. The process of differentiation in eukaryotes during cellular morphogenesis is a paradigm of epigenetic change; stem cells develop into pluripotent cell lines in the embryo, eventually becoming terminally developed cells. Recently, epigenetic changes were shown to play an important role in immune cell development, activation and differentiation, which impacts chromatin remodeling, DNA methylation, post-translational histone modifications and small or lncRNA engagement. Innate lymphoid cells (ILCs) are newly identified immune cells that lack antigen receptors. ILCs differentiate from hematopoietic stem cells via multipotent progenitor stages. In this editorial, the authors discuss the epigenetic regulation of ILC differentiation and function.

A Study to Investigate the Role of Noncoding RNA miR146 Alpha as a Potential Biomarker in Prostate Cancer.

There is a need for additional biomarkers for the diagnosis and prognosis of prostate cancer. MicroRNAs are a class of non-protein coding RNA molecules that are frequently dysregulated in different cancers including prostate cancer and show promise as diagnostic biomarkers and targets for therapy. Here we describe the role of micro RNA 146 a (miR-146a) which may serve as a diagnostic marker for prostate cancer, as indicated from the data presented in this report. Also, a pilot study indicated differential expression of miR-146a in prostate cancer cell lines and tissues from different racial groups. This report provides a novel insight into understanding the prostate carcinogenesis.

Stem Cell Therapy and Innate Lymphoid Cells.

Innate lymphoid cells have the capability to communicate with other immune cell types to coordinate the immune system functioning during homeostasis and inflammation. However, these cells behave differently at the functional level, unlike T cells, these cells do not need antigen receptors for activation because they are activated by the interaction of their receptor ligation. In hematopoietic stem cell transplantation (HSCT), T cells and NK cells have been extensively studied but very few studies are available on ILCs. In this review, an attempt has been made to provide current information related to NK and ILCs cell-based stem cell therapies and role of the stem cells in the regulation of ILCs as well. Also, the latest information on the differentiation of NK cells and ILCs from CD34+ hematopoietic stem cells is covered in the article.

Efferocytosis and the Story of "Find Me," "Eat Me," and "Don't Eat Me" Signaling in the Tumor Microenvironment.

The process of efferocytosis involves removal of dying or dead cells by phagocytosis. Another term "efferosome" is used which means a fluid-filled membrane vesicle which engulfs dead cells. The process of efferocytosis works in coordination with apoptosis because before the contents of apoptotic cells are bleached out, they are engulfed by efferosomes. Thus, the microenvironment is not polluted with toxic enzymes and oxidants. A defect in the apoptotic cell clearance may participate in autoimmunity and chronic inflammation for homeostasis and proper tissue development, for which removal of dead cells is essential. This also protects from chronic inflammation and autoimmunity. In different tumor types and other diseases, efferocytosis has been studied extensively and potential pathways identified. A few of the intermediates in different pathways, which create aggressive and tolerogenic tumor microenvironment, might be considered for therapeutic or interventional purposes. Since the key players in efferocytosis are macrophages and dendritic cells, development of antigen-dependent antitumor immunity is affected by efferocytosis. The literature analysis suggests that efferocytosis is an underappreciated immune checkpoint, perhaps one that might be therapeutically targeted in the setting of cancer. The current status of efferocytosis and its role in tumor microenvironment is discussed in this article.

Epidemiologic Research of Rare Cancers: Trends, Resources, and Challenges.

BACKGROUND: The goals of this project were to assess the status of NCI's rare cancer-focused population science research managed by the Division of Cancer Control and Population Sciences (DCCPS), to develop a framework for evaluation of rare cancer research activities, and to review available resources to study rare cancers. METHODS: Cancer types with an overall age-adjusted incidence rate of less than 20 cases per 100,000 individuals were identified using NCI Surveillance, Epidemiology and End Results (SEER) Program data. SEER data were utilized to develop a framework based on statistical commonalities. A portfolio analysis of DCCPS-supported active grants and a review of three genomic databases were conducted. RESULTS: For the 45 rare cancer types included in the analysis, 123 active DCCPS-supported rare cancer-focused grants were identified, of which the highest percentage (18.7%) focused on ovarian cancer. The developed framework revealed five clusters of rare cancer types. The cluster with the highest number of grants (n = 43) and grants per cancer type (10.8) was the cluster that included cancer types of higher incidence, average to better survival, and high prevalence (in comparison with other rare cancers). Resource review revealed rare cancers are represented in available genomic resources, but to a lesser extent compared with more common cancers. CONCLUSIONS: This article provides an overview of the rare cancer-focused population sciences research landscape as well as information on gaps and opportunities. IMPACT: The findings of this article can be used to develop efficient and comprehensive strategies to accelerate rare cancer research.See related commentary by James V. Lacey Jr, p. 1300.

Sprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases.

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4+ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1-bound CSK restored ERK1/2 activation in Spry2-/- T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.

A health disparities study of MicroRNA-146a expression in prostate cancer samples derived from African American and European American patients.

Considering the prevalence of prostate cancer all over the world, it is desired to have tools, technologies, and biomarkers which help in early detection of the disease and discriminate different races and ethnic groups. Genetic information from the single gene analysis and genome-wide association studies have identified few biomarkers, however, the drivers of prostate cancer remain unknown in the majority of prostate cancer patients. In those cases where genetic association has been identified, the genes confer only a modest risk of this cancer, hence, making them less relevant for risk counseling and disease management. There is a need for additional biomarkers for diagnosis and prognosis of prostate cancer. MicroRNAs are a class of non-protein coding RNA molecules that are frequently dysregulated in different cancers including prostate cancer and show promise as diagnostic biomarkers and targets for therapy. Here we describe the role of micro RNA 146a (miR-146a) which may serve as a diagnostic and prognostic marker for prostate cancer, as indicated from the data presented in this report. Also, a pilot study indicated differential expression of miR-146a in prostate cancer cell lines and tissues from different racial groups. Reduced expression of miR-146a was observed in African American tumor tissues compared to those from European Whites This report provides a novel insight into understanding the prostate carcinogenesis.

Optimal identification of human conventional and nonconventional (CRTH2-IL7Rα-) ILC2s using additional surface markers.

BACKGROUND: Human type 2 innate lymphoid cells (ILC2s) are identified by coupled detection of CRTH2 and IL7Rα on lineage negative (Lin-) cells. Type 2 cytokine production by CRTH2-IL7Rα- innate lymphoid cells (ILCs) is unknown. OBJECTIVE: We sought to identify CRTH2-IL7Rα- type 2 cytokine-producing ILCs and their disease relevance. METHODS: We studied human blood and lung ILCs from asthmatic and control subjects by flow cytometry, ELISA, RNA sequencing, quantitative PCR, adoptive transfer to mice, and measurement of airway hyperreactivity by Flexivent. RESULTS: We found that IL-5 and IL-13 were expressed not only by CRTH2+ but also by CRTH2-IL7Rα+ and CRTH2-IL7Rα- (double-negative [DN]) human blood and lung cells. All 3 ILC populations expressed type 2 genes and induced airway hyperreactivity when adoptively transferred to mice. The frequency of type 2 cytokine-positive IL7Rα and DN ILCs were similar to that of CRTH2 ILCs in the blood and lung. Their frequency was higher in asthmatic patients than in disease controls. Transcriptomic analysis of CRTH2, IL7Rα, and DN ILCs confirmed the expression of mRNA for type 2 transcription factors in all 3 populations. Unexpectedly, the mRNA for GATA3 and IL-5 correlated better with mRNA for CD30, TNFR2, ICOS, CCR4, and CD200R1 than for CRTH2. By using a combination of these surface markers, especially CD30/TNFR2, we identified a previously unrecognized ILC2 population. CONCLUSIONS: The commonly used surface markers for human ILC2s leave a majority of type 2 cytokine-producing ILC2s unaccounted for. We identified top GATA3-correlated cell surface-expressed genes in human ILCs by RNA sequencing. These new surface markers, such as CD30 and TNFR2, identified a previously unrecognized human ILC2 population. This ILC2 population is likely to contribute to asthma.

Role of Oral Microbiome Signatures in Diagnosis and Prognosis of Oral Cancer.

Despite advancement in cancer treatment, oral cancer has a poor prognosis and is often detected at late stage. To overcome these challenges, investigators should search for early diagnostic and prognostic biomarkers. More than 700 bacterial species reside in the oral cavity. The oral microbiome population varies by saliva and different habitats of oral cavity. Tobacco, alcohol, and betel nut, which are causative factors of oral cancer, may alter the oral microbiome composition. Both pathogenic and commensal strains of bacteria have significantly contributed to oral cancer. Numerous bacterial species in the oral cavity are involved in chronic inflammation that lead to development of oral carcinogenesis. Bacterial products and its metabolic by-products may induce permanent genetic alterations in epithelial cells of the host that drive proliferation and/or survival of epithelial cells. Porphyromonas gingivalis and Fusobacterium nucleatum induce production of inflammatory cytokines, cell proliferation, and inhibition of apoptosis, cellular invasion, and migration thorough host cell genomic alterations. Recent advancement in metagenomic technologies may be useful in identifying oral cancer-related microbiome, their genomes, virulence properties, and their interaction with host immunity. It is very important to address which bacterial species is responsible for driving oral carcinogenesis. Alteration in the oral commensal microbial communities have potential application as a diagnostic tool to predict oral squamous cell carcinoma. Clinicians should be aware that the protective properties of the resident microflora are beneficial to define treatment strategies. To develop highly precise and effective therapeutic approaches, identification of specific oral microbiomes may be required. In this review, we narrate the role of microbiome in the progression of oral cancer and its role as an early diagnostic and prognostic biomarker for oral cancer.

Towards quality assurance and quality control in untargeted metabolomics studies.

We describe here the agreed upon first development steps and priority objectives of a community engagement effort to address current challenges in quality assurance (QA) and quality control (QC) in untargeted metabolomic studies. This has included (1) a QA and QC questionnaire responded to by the metabolomics community in 2015 which recommended education of the metabolomics community, development of appropriate standard reference materials and providing incentives for laboratories to apply QA and QC; (2) a 2-day 'Think Tank on Quality Assurance and Quality Control for Untargeted Metabolomic Studies' held at the National Cancer Institute's Shady Grove Campus and (3) establishment of the Metabolomics Quality Assurance and Quality Control Consortium (mQACC) to drive forward developments in a coordinated manner.

Next steps in studying the human microbiome and health in prospective studies, Bethesda, MD, May 16-17, 2017.

The National Cancer Institute (NCI) sponsored a 2-day workshop, "Next Steps in Studying the Human Microbiome and Health in Prospective Studies," in Bethesda, Maryland, May 16-17, 2017. The workshop brought together researchers in the field to discuss the challenges of conducting microbiome studies, including study design, collection and processing of samples, bioinformatics and statistical methods, publishing results, and ensuring reproducibility of published results. The presenters emphasized the great potential of microbiome research in understanding the etiology of cancer. This report summarizes the workshop and presents practical suggestions for conducting microbiome studies, from workshop presenters, moderators, and participants.

Role of Microbiome in Carcinogenesis Process and Epigenetic Regulation of Colorectal Cancer.

Epigenetic changes during the development of colorectal cancer (CRC) play a significant role. Along with factors such as diet, lifestyle, and genetics, oncogenic infection, bacteria alone or whole microbiome, has been associated with this tumor type. How gut microbiome contributes to CRC pathogenesis in the host is not fully understood. Most of the epigenetic studies in CRC have been conducted in populations infected with Helicobacter pylori. In the current review, we summarize how the gut microbiota contributes in colon carcinogenesis and the potential role of epigenetic mechanism in gene regulation. We discuss microbiota-mediated initiation and progression of colon tumorigenesis and have also touched upon the role of microbial metabolites as an initiator or an inhibitor for procarcinogenic or antioncogenic activities. The hypothesis of gut microbiota associated CRC revealed the dynamic and complexity of microbial interaction in initiating the development of CRC. In the multifaceted processes of colonic carcinogenesis, gradual alteration of microbiota along with their microenvironment and the potential oncopathogenic microbes mediated modulation of cancer therapy and other factors involved in microbiome dysbiosis leading to the CRC have also been discussed. This review provides a comprehensive summary of the mechanisms of CRC development, the role of microbiome or single bacterial infection in regulating the processes of carcinogenesis, and the intervention by novel therapeutics. Epigenetic mechanism involved in CRC is also discussed.

Challenges and Opportunities in Social Epigenomics and Cancer.

Social epigenomics is an area of science that evaluates why and how different social factors and processes affect different components of the epigenome. As it happens with most of the new areas in science, social epigenetics being a relatively new area, only limited progress has been made. However, the potential of implicating social epigenomics in improving health and health related policies is tremendous. Epidemiologic studies evaluating social, behavior, family, and environmental factors have helped understand social inequality and develop the area of social epigenomics. Most of the information in social epidemiology has been gathered from genetic studies. Now the time has come that we may apply similar approaches in social epigenomics because technologies of determining methylation, histone, and noncoding RNA profiling are well developed. The focus of this chapter is to understand the role of epigenetic regulation in social experiences at various stages in life due to altered function of genes and affecting health in populations with different races/ethnicity. Here we discuss the current challenges and opportunities in the field.

Epigenetic and Genetic Regulation of PDCD1 Gene in Cancer Immunology.

Utilizing biology of PD-1: PD-L1 interaction related pathways for cancer immunotherapy is an emerging concept in cancer research. However, there is limited literature on epigenetic regulation of PD1 gene (PDCD1). Promising data from clinical trials of PD/PDl-1 immunotherapy in melanoma, renal cancers, colorectal and lung cancers has generated a lot of hope for successful treatment of patients. Immunotherapy in cancers has a significant role in strategizing NCI's Cancer Moonshot Program of US NIH and FDA policies. The cost of the treatment by immunotherapy is extremely high. This preview presents a concise compilation of current knowledge on how the PD-1 gene is regulated in different cancers and infections. We have also discussed about epigenetic regulation of PDCD1 gene, especially the effect of different epigenetic inhibitors of DNA methylation and histone modifications at different steps in PD-1 regulation.

Methylation and MicroRNA Profiling to Understand Racial Disparities of Prostate Cancer.

Prostate cancer is a serious disease in terms of its high incidence and mortality rate in the USA and around the world. The prostate specific antigen (PSA) has been used for prostate cancer diagnosis and follow-up of treatment but a number of challenges remain. Epigenetic biomarkers, especially methylation and microRNA (miR) biomarkers provide an opportunity for diagnosis, prognosis, and recurrence of prostate cancer. Differential global methylation has shown some promising results. In this chapter, the emphasis is given on those biomarkers which can be assayed noninvasively in a prospective study and in a clinic. Challenges in the field, especially the validation of potential biomarkers, and their potential solutions are provided in this chapter.

Metatranscriptome Analysis Deciphers Multifunctional Genes and Enzymes Linked With the Degradation of Aromatic Compounds and Pesticides in the Wheat Rhizosphere.

Agricultural soils are becoming contaminated with synthetic chemicals like polyaromatic compounds, petroleum hydrocarbons, polychlorinated biphenyls (PCBs), phenols, herbicides, insecticides and fungicides due to excessive dependency of crop production systems on the chemical inputs. Microbial degradation of organic pollutants in the agricultural soils is a continuous process due to the metabolic multifunctionalities and enzymatic capabilities of the soil associated communities. The plant rhizosphere with its complex microbial inhabitants and their multiple functions, is amongst the most live and dynamic component of agricultural soils. We analyzed the metatranscriptome data of 20 wheat rhizosphere samples to decipher the taxonomic microbial communities and their multifunctionalities linked with the degradation of organic soil contaminants. The analysis revealed a total of 21 different metabolic pathways for the degradation of aromatic compounds and 06 for the xenobiotics degradation. Taxonomic annotation of wheat rhizosphere revealed bacteria, especially the Proteobacteria, actinobacteria, firmicutes, bacteroidetes, and cyanobacteria, which are shown to be linked with the degradation of aromatic compounds as the dominant communities. Abundance of the transcripts related to the degradation of aromatic amin compounds, carbazoles, benzoates, naphthalene, ketoadipate pathway, phenols, biphenyls and xenobiotics indicated abundant degradation capabilities in the soils. The results highlighted a potentially dominant role of crop rhizosphere associated microbial communities in the remediation of contaminant aromatic compounds.

Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin-driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations.

BACKGROUND: IL-33 plays an important role in the development of experimental asthma. OBJECTIVE: We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of asthma in a mouse model. METHODS: We studied allergen-induced experimental asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. RESULTS: Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of experimental asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13+ CD4 T cells, forkhead box P3-positive regulatory T cells, and IL-5+ ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45+lin-CD25+ cells) and IL-13+ ILC2s, emergence of a TSLP receptor-positive IL-9+ ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9+ and IL-13+ ILC2 numbers in the lung. CONCLUSIONS: Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9+ and IL-13+ ILC2s and mast cells and leads to development of chronic experimental asthma. An anti-TSLP antibody abrogates all pathologic features of asthma in this model.

Respiratory cancer database: An open access database of respiratory cancer gene and miRNA.

AIMS: Respiratory cancer database (RespCanDB) is a genomic and proteomic database of cancer of respiratory organ. It also includes the information of medicinal plants used for the treatment of various respiratory cancers with structure of its active constituents as well as pharmacological and chemical information of drug associated with various respiratory cancers. MATERIALS AND METHODS: Data in RespCanDB has been manually collected from published research article and from other databases. Data has been integrated using MySQL an object-relational database management system. MySQL manages all data in the back-end and provides commands to retrieve and store the data into the database. The web interface of database has been built in ASP. RESULTS AND CONCLUSIONS: RespCanDB is expected to contribute to the understanding of scientific community regarding respiratory cancer biology as well as developments of new way of diagnosing and treating respiratory cancer. Currently, the database consist the oncogenomic information of lung cancer, laryngeal cancer, and nasopharyngeal cancer. Data for other cancers, such as oral and tracheal cancers, will be added in the near future. The URL of RespCanDB is http://ridb.subdic-bioinformatics-nitrr.in/.