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Oncogenic and tumor suppressive roles of special AT-rich sequence-binding protein

Chen, Qiao Yi; Costa, Max
In recent years, research efforts have been centered on the functional roles of special AT-rich sequence-binding protein (SATB2) in cancer development. Existing studies differ in the types of tumor tissues and cell lines used, resulting in mixed results, which hinder the clear understanding of whether SATB2 acts as a tumor suppressor or promoter. Literature search for this review consisted of a basic search on PubMed using keywords "SATB2" and "special AT-rich sequence-binding protein 2." Each article was then selected for further examination based on relevance of the title. In consideration to possible missing data from a primary PubMed search, after coding for relevant information, articles listed in the references section were filtered for further review. The current literature suggests that SATB2 can act both as a tumor suppressor and as a promoter since it can be regulated by multiple factors and is able to target different downstream genes in various types of cancer cell lines as well as tissues. Future studies should focus on its contradictory roles in different types of tumors. This paper provides a comprehensive review of currently available research on the role of SATB2 in different cancer cells and tissues and may provide some insight into the contradictory roles of SATB2 in cancer development.
PMCID:6071479
PMID: 30123095
ISSN: 1477-3163
CID: 3246052

Structural comparison of human Anti-HIV-1 gp120 V3 MAbs of the same gene usage induced by vaccination and chronic infection [Meeting Abstract]

Chan, K -W; Pan, R; Costa, M; Gorny, M; Wang, S; Lu, S; Kong, X
Background: Elucidating the structural basis of antibody (Ab) gene usage and affinity maturation of vaccine-induced Abs can inform the design of immunogens for inducing desired Ab responses in HIV vaccine development. Analyses of monoclonal Abs (mAbs) encoded by the same immunoglobulin genes in different stages of maturation can help to understand the maturation process.
Method(s): We have analyzed four human anti-V3 mAbs with the same VH1-3*01 and VL3-10*01 gene usage. Two mAbs, TA6 and TA7, were developed from a vaccinee in the HIV vaccine phase I trial DP6-001 with a polyvalent DNA prime-protein boost regimen, and two others, 311-11D and 1334, were developed from HIV-infected patients.
Result(s): The somatic hypermutation (SHM) rates in VH of the vaccine-induced mAbs are lower than that of the chronic HIV infection-induced mAbs, while those in VL are comparable. Crystal structures of the antigen-binding fragments (Fabs) in complex with V3 peptides show that these mAbs bind the V3 epitope with a new cradle-binding mode, and the V3 beta hairpin lies along the antigen-binding groove, which consists of residues of both heavy and light chains. Residues conserved from the germline sequences form specific binding pockets accommodating conserved structural elements of the V3 crown hairpin, predetermining the Ab gene selection, while somatically mutated residues create additional hydrogen bonds, electrostatic interactions, and van der Waals contacts, correlating with an increased binding affinity.
Conclusion(s): Our data provide a unique example of germline sequences determining the primordial antigen-binding sites and SHMs correlating with affinity maturation of Abs induced by vaccine and natural HIV infection
EMBASE:625283355
ISSN: 1931-8405
CID: 3528242

Association between Exposure to Ambient Air Particulates and Metabolic Syndrome Components in a Saudi Arabian Population

Shamy, Magdy; Alghamdi, Mansour; Khoder, Mamdouh I; Mohorjy, Abdullah M; Alkhatim, Alser A; Alkhalaf, Abdulrahman K; Brocato, Jason; Chen, Lung Chi; Thurston, George D; Lim, Chris C; Costa, Max
Recent epidemiological evidence suggests that exposure to particulates may be a factor in the etiology of metabolic syndrome (MetS). In this novel study, we investigated the relationship between particulate levels and prevalence of MetS component abnormalities (hypertension, hyperglycemia, obesity) in a recruited cohort (N = 2025) in Jeddah, Saudi Arabia. We observed significant associations between a 10 μg/m³ increase in PM2.5 and increased risks for MetS (Risk Ratio (RR): 1.12; 95% Confidence Interval (CI): 1.06-1.19), hyperglycemia (RR: 1.08; 95% CI: 1.03-1.14), and hypertension (RR: 1.09; 95% CI: 1.04-1.14). PM2.5 from soil/road dust was found to be associated with hyperglycemia (RR: 1.12; 95% CI: 1.06-1.19) and hypertension (RR: 1.11; 95% CI: 1.05-1.18), while PM2.5 from traffic was associated with hyperglycemia (RR: 1.33; 95% CI: 1.05-1.71). We did not observe any health associations with source-specific mass exposures. Our findings suggest that exposure to specific elemental components of PM2.5, especially Ni, may contribute to the development of cardiometabolic disorders.
PMCID:5800127
PMID: 29295575
ISSN: 1660-4601
CID: 2898532

Polycyclic aromatic hydrocarbons (PAHs) in the settled dust of automobile workshops, health and carcinogenic risk evaluation

Ali, Nadeem; Ismail, Iqbal Mohammad Ibrahim; Khoder, Mamdouh; Shamy, Magdy; Alghamdi, Mansour; Al Khalaf, Abdulrahman; Costa, Max
There are studies available on the occurrence of PAHs in indoor settled dust from residential and different occupational settings in literature but limited data is available on their occurrence and potential health risk assessment in automobile workshops. In recent decades Saudi Arabia has experienced tremendous growth in the petroleum industry and as a result, the automobile industry is booming. People working in automobile workshops are at a greater risk of exposure to chemicals releasing from the petroleum products. The main objective of this study was to report PAHs in settled dust from different automobile workshops of Jeddah, Saudi Arabia, and evaluate health risk for workers through dust exposure. Pyrene (1585-13500ng/g), Benz[a]anthracene (
PMID: 28575826
ISSN: 1879-1026
CID: 2591902

Transcription factors and stress response gene alterations in human keratinocytes following Solar Simulated Ultra Violet Radiation

Marais, Thomas L Des; Kluz, Thomas; Xu, Dazhong; Zhang, Xiaoru; Gesumaria, Lisa; Matsui, Mary S; Costa, Max; Sun, Hong
Ultraviolet radiation (UVR) from sunlight is the major effector for skin aging and carcinogenesis. However, genes and pathways altered by solar-simulated UVR (ssUVR), a mixture of UVA and UVB, are not well characterized. Here we report global changes in gene expression as well as associated pathways and upstream transcription factors in human keratinocytes exposed to ssUVR. Human HaCaT keratinocytes were exposed to either a single dose or 5 repetitive doses of ssUVR. Comprehensive analyses of gene expression profiles as well as functional annotation were performed at 24 hours post irradiation. Our results revealed that ssUVR modulated genes with diverse cellular functions changed in a dose-dependent manner. Gene expression in cells exposed to a single dose of ssUVR differed significantly from those that underwent repetitive exposures. While single ssUVR caused a significant inhibition in genes involved in cell cycle progression, especially G2/M checkpoint and mitotic regulation, repetitive ssUVR led to extensive changes in genes related to cell signaling and metabolism. We have also identified a panel of ssUVR target genes that exhibited persistent changes in gene expression even at 1 week after irradiation. These results revealed a complex network of transcriptional regulators and pathways that orchestrate the cellular response to ssUVR.
PMCID:5648893
PMID: 29051608
ISSN: 2045-2322
CID: 3065952

A comprehensive review of metal-induced cellular transformation studies

Chen, Qiao Yi; Costa, Max
In vitro transformation assays not only serve practical purposes in screening for potential carcinogenic substances in food, drug, and cosmetic industries, but more importantly, they provide a means of understanding the critical biological processes behind in vivo cancer development. In resemblance to cancer cells in vivo, successfully transformed cells display loss of contact inhibition, gain of anchorage independent growth, resistant to proper cell cycle regulation such as apoptosis, faster proliferation rate, potential for cellular invasion, and ability to form tumors in experimental animals. Cells purposely transformed using metal exposures enable researchers to examine molecular changes, dissect various stages of tumor formation, and ultimately elucidate metal induced cancer mode of action. For practical purposes, this review specifically focuses on studies incorporating As-, Cd-, Cr-, and Ni-induced cell transformation. Through investigating and comparing an extensive list of studies using various methods of metal-induced transformation, this review serves to bridge an information gap and provide a guide for avoiding procedural discrepancies as well as maximizing experimental efficiency.
PMID: 28506836
ISSN: 1096-0333
CID: 2562762

Health risk associated with airborne particulate matter and its components in Jeddah, Saudi Arabia

Harrison, Roy M; Bousiotis, Dimitrios; Mohorjy, A M; Alkhalaf, A K; Shamy, M; Alghamdi, M; Khoder, M; Costa, M
Samples of PM2.5 and PM10 have been collected in all of four seasons at seven sites within the city of Jeddah, Saudi Arabia. The samples have been analysed for a range of trace elements. There is a large loading of wind-blown dust and the majority of elements are predominantly associated with coarse particles. Enrichment factors, however, show that some elements are markedly enriched above crustal abundance. Using mean data for the PM2.5 and PM10 fractions from each of the seven sampling sites, health risks have been estimated for particulate matter mass, the elements Cr, Mn, Ni, Pb, As, Cd and V measured in this study, and polycyclic aromatic hydrocarbons using data from an earlier study within Jeddah. Cancer risks are calculated from mean airborne concentrations and cancer slope factors for the carcinogenic metals and PAH, but the cancer risks are relatively modest compared to the lifetime risk of mortality due to PM2.5 exposure. The risks associated with exposure to V and Mn are considered to be small, while concentrations of cadmium far exceed the European Union Limit Value and World Health Organisation guideline. Cadmium shows a very high crustal enrichment factor but is present predominantly in the coarse particle fraction suggesting that local soils and surface dusts are unusually enriched in Cd relative to the global average. Using national data for mortality rates, the excess mortality due to PM2.5 exposure has been calculated and amounts to over 1100 deaths annually for the city of Jeddah.
PMID: 28285859
ISSN: 1879-1026
CID: 2489812

Tungsten exposure causes a selective loss of histone demethylase protein

Laulicht Glick, Freda; Wu, Feng; Zhang, Xiaoru; Jordan, Ashley; Brocato, Jason; Kluz, Thomas; Sun, Hong; Costa, Max
In the course of our investigations into the toxicity of tungstate, we discovered that cellular exposure resulted in the loss of the histone demethylase protein. We specifically investigated the loss of two histone demethylase dioxygenases, JARID1A and JMJD1A. Both of these proteins were degraded in the presence of tungstate and this resulted in increased global levels of H3K4me3 and H3K9me2, the substrates of JARID1A and JMJD1A respectively. Treatment with MG132 completely inhibited the loss of the demethylase proteins induced by tungstate treatment, suggesting that tungstate activated the proteasomal degradation of these proteins. The changes in global histone marks and loss of histone demethylase protein persisted for at least 48 hours after removing sodium tungstate from the culture. The increase in global histone methylation remained when cells were cultured in methionine-free media, indicating that the increased histone methylation did not depend upon any de novo methylation process, but rather was due to the loss of the demethylase protein. Similar increases of H3K4me3 and H3K9me2 were observed in the livers of the mice that were acutely exposed to tungstate via their drinking water. Taken together, our results indicated that tungstate exposure specifically reduced histone demethylase JARID1A and JMJD1A via proteasomal degradation, leading to increased histone methylation
PMCID:5708117
PMID: 28218462
ISSN: 1098-2744
CID: 2460152

Nickel ions inhibit histone demethylase JMJD1A and DNA repair enzyme ABH2 by replacing the ferrous iron in the catalytic centers

Chen, Haobin; Giri, Nitai Charan; Zhang, Ronghe; Yamane, Kenichi; Zhang, Yi; Maroney, Michael; Costa, Max
PMCID:5481578
PMID: 28646124
ISSN: 1083-351x
CID: 3073962

Evaluation of the Effects of Airborne Particulate Matter on Bone Marrow-Mesenchymal Stem Cells (BM-MSCs): Cellular, Molecular and Systems Biological Approaches

Abu-Elmagd, Muhammad; Alghamdi, Mansour A; Shamy, Magdy; Khoder, Mamdouh I; Costa, Max; Assidi, Mourad; Kadam, Roaa; Alsehli, Haneen; Gari, Mamdooh; Pushparaj, Peter Natesan; Kalamegam, Gauthaman; Al-Qahtani, Mohammed H
Particulate matter (PM) contains heavy metals that affect various cellular functions and gene expression associated with a range of acute and chronic diseases in humans. However, the specific effects they exert on the stem cells remain unclear. Here, we report the effects of PM collected from the city of Jeddah on proliferation, cell death, related gene expression and systems of biological analysis in bone marrow mesenchymal stem cells (BM-MSCs), with the aim of understanding the underlying mechanisms. PM2.5 and PM10 were tested in vitro at various concentrations (15 to 300 microg/mL) and durations (24 to 72 h). PMs induced cellular stress including membrane damage, shrinkage and death. Lower concentrations of PM2.5 increased proliferation of BM-MSCs, while higher concentrations served to decrease it. PM10 decreased BM-MSCs proliferation in a concentration-dependent manner. The X-ray fluorescence spectrometric analysis showed that PM contains high levels of heavy metals. Ingenuity Pathway Analysis (IPA) and hierarchical clustering analyses demonstrated that heavy metals were associated with signaling pathways involving cell stress/death, cancer and chronic diseases. qRT-PCR results showed differential expression of the apoptosis genes (BCL2, BAX); inflammation associated genes (TNF-alpha and IL-6) and the cell cycle regulation gene (p53). We conclude that PM causes inflammation and cell death, and thereby predisposes to chronic debilitating diseases.
PMCID:5409640
PMID: 28425934
ISSN: 1660-4601
CID: 2532352