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1.  Environmental Exposures, Epigenetics and Cardiovascular Disease 
Purpose of the Review
Epigenetic modifications are heritable alterations of the genome, which can govern gene expression without altering the DNA sequence. The purpose of this review is to render an overview of the possible mechanisms of epigenetic regulation of gene expression in response to environmental pollutants leading to cardiovascular diseases (CVD).
Recent Findings
An era of cataloging epigenetic marks of the various diseased states has recently commenced, including those within the genes responsible for atherosclerosis, ischemia, hypertension and heart failure. From varied study approaches directed either towards the general understanding of the key pathway regulatory genes, or sampling population cohorts for global and gene-specific changes, it has been possible to identify several epigenetic signatures of environmental exposure relevant to CVD. Signatures of epigenetic dysregulation can be detected in peripheral blood samples, even within few hours of environmental exposure. However, the field now faces the demand for thorough, systematic, rationalized approaches to establish the relation of an exposure-driven epigenetic changes to clinical outcomes, by using sophisticated and reliable research designs and tools.
An understanding of chromatin remodeling in response to environmental stimuli conducive to CVD is emerging, with the promise of novel diagnostic and therapeutic candidates.
PMCID: PMC3742092  PMID: 22669047
Environment; Cardiovascular; Epigenetics; DNA methylation; Histone modifications; Biomarkers
2.  Twins for epigenetic studies of human aging and development 
Ageing research reviews  2012;12(1):182-187.
Most of the complex traits including aging phenotypes are caused by the interaction between genome and environmental conditions and the interface of epigenetics may be a central mechanism. Although modern technologies allow us high-throughput profiling of epigenetic patterns already at genome level, our understanding of genetic and environmental influences on the epigenetic processes remains limited. Twins are of special interest for genetic studies due to their genetic similarity and rearing-environment sharing. The classical twin design has made a great contribution in dissecting the genetic and environmental contributions to human diseases and complex traits. In the era of functional genomics, the valuable sample of twins is helping to bridge the gap between gene activity and the environments through epigenetic mechanisms unlimited by DNA sequence variations. We propose toextend the classical twin design to studythe aging–related molecular epigenetic phenotypes and link them with environmental exposures especially early life events. Different study designs and application issues will be highlighted and novel approaches introduced with aim at making uses of twins in assessing the environmental impact on epigenetic changes during development and in the aging process.
PMCID: PMC3509237  PMID: 22750314
twins; aging; epigenetics; environments; genomics
3.  Genetic and Epigenetic Changes in Human Prostate Cancer 
Acquired or inherited genetic alterations either alone or in combination with epigenetic alterations are associated with prostate carcinogenesis and its progression toward advance metastatic or castration-resistant disease. A major objective of translational cancer research in post-genome era is to discover the repertoire of genetic and epigenetic variations associated with prostate cancer. Genome-wide association studies have been at least partially successful in identifying potential germline polymorphisms and allelic imbalances such as microsatellite instability and loss of heterozygosity associated with prostate cancer susceptibility. Epigenetic mechanisms such as DNA hyper- or hypomethylation and histone modifications are reversible genetic alterations which allow stable inheritance of cellular phenotypes without any changes in the DNA sequence or quantity. Epigenetic modifications can potentially be used for the molecular classification, detection, and risk assessment in prostate cancer. Chemical inhibitors of DNA methyltransferases and histone deacetylases have been used in different clinical trials and hold promise as novel chemotherapeutics to be effective alone or in combination with other therapeutic interventions in prostate cancer.
PMCID: PMC3371912  PMID: 22737441
Genetics; Epigenetics; Genome; Somatic; Germline; Prostate Cancer
4.  Epigenetic Aspects of Posttraumatic Stress Disorder 
Disease markers  2011;30(2-3):77-87.
Development of psychiatric diseases such as posttraumatic stress disorder (PTSD) invokes, as with most complex diseases, both genetic and environmental factors. The era of genome-wide high throughput technologies has sparked the initiation of genotype screenings in large cohorts of diseased and control individuals, but had limited success in identification of disease causing genetic variants. It has become evident that these efforts at the genomic level need to be complemented with endeavours in elucidating the proteome, transcriptome and epigenetic profiles. Epigenetics is attractive in particular because there is accumulating evidence that the lasting impact of adverse life events is reflected in certain covalent modifications of the chromatin.
In this review, we outline the characteristics of PTSD as a stress-related disease and survey recent developments revealing epigenetic aspects of stress-related disorders in general. There is also increasing direct evidence for gene programming and epigenetic components in PTSD. Finally, we discuss treatment options in the light of recent discoveries of epigenetic mechanisms of psychotropic drugs.
PMCID: PMC3825244  PMID: 21508512
5.  Medulloblastoma biology in the post-genomic era 
Future oncology (London, England)  2012;8(12):1597-1604.
Medulloblastomas, the most common malignant pediatric brain tumors, are comprised of four molecularly distinct subtypes. However, treatment has yet to exploit these molecular vulnerabilities. Three recent studies sequenced a total of 310 primary tumors and identified that two of the four medulloblastoma subtypes are concomitantly associated with subtype-specific mutations as previously characterized. In contrast, the overwhelming majority of mutations occurred only once in the entire cohort and just 12 genes were recurrently mutated with statistical significance. Perturbations in epigenetic regulation are emerging as a unifying theme in cancer and similarly recurring mutations in epigenetic mechanisms were distributed across all subtypes in medulloblastoma. Designing targeted therapies to such a molecularly diverse disease in the post-genomic era presents new challenges. This will require novel methods to link these nonrecurrent mutations into pathways, and preclinical models that faithfully recapitulate patient driver events. Presently, medulloblastoma reinforces epigenetic mechanisms as a tantalizing therapeutic target in cancers.
PMCID: PMC3602901  PMID: 23231521
cerebellum; chromatin; epigenetics; epigenomics; medulloblastoma; Swi/Snf; systems biology
6.  Two-dimensional electrophoretic comparison of metastatic and non-metastatic human breast tumors using in vitro cultured epithelial cells derived from the cancer tissues 
BMC Cancer  2008;8:107.
Breast carcinomas represent a heterogeneous group of tumors diverse in behavior, outcome, and response to therapy. Identification of proteins resembling the tumor biology can improve the diagnosis, prediction, treatment selection, and targeting of therapy. Since the beginning of the post-genomic era, the focus of molecular biology gradually moved from genomes to proteins and proteomes and to their functionality. Proteomics can potentially capture dynamic changes in protein expression integrating both genetic and epigenetic influences.
We prepared primary cultures of epithelial cells from 23 breast cancer tissue samples and performed comparative proteomic analysis. Seven patients developed distant metastases within three-year follow-up. These samples were included into a metastase-positive group, the others formed a metastase-negative group. Two-dimensional electrophoretical (2-DE) gels in pH range 4–7 were prepared. Spot densities in 2-DE protein maps were subjected to statistical analyses (R/maanova package) and data-mining analysis (GUHA). For identification of proteins in selected spots, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed.
Three protein spots were significantly altered between the metastatic and non-metastatic groups. The correlations were proven at the 0.05 significance level. Nucleophosmin was increased in the group with metastases. The levels of 2,3-trans-enoyl-CoA isomerase and glutathione peroxidase 1 were decreased.
We have performed an extensive proteomic study of mammary epithelial cells from breast cancer patients. We have found differentially expressed proteins between the samples from metastase-positive and metastase-negative patient groups.
PMCID: PMC2377273  PMID: 18416831
7.  Controlling Destiny through Chemistry: Small-Molecule Regulators of Cell Fate 
ACS Chemical Biology  2009;5(1):15-34.
Controlling cell fate is essential for embryonic development, tissue regeneration, and the prevention of human disease. With each cell in the human body sharing a common genome, achieving the appropriate spectrum of stem cells and their differentiated lineages requires the selective activation of developmental signaling pathways, the expression of specific target genes, and the maintenance of these cellular states through epigenetic mechanisms. Small molecules that target these regulatory processes are therefore valuable tools for probing and manipulating the molecular mechanisms by which stem cells self-renew, differentiate, and arise from somatic cell reprogramming. Pharmacological modulators of cell fate could also help remediate human diseases caused by dysregulated cell proliferation or differentiation, heralding a new era in molecular therapeutics.
PMCID: PMC2807212  PMID: 20000447
Differentiation: The process by which unspecialized cells acquire specific functions, allowing the generation of complex tissues and organs. Differentiation is frequently controlled by cell signaling pathways and maintained through epigenetic mechanisms.; Ectoderm: The outer germ layer that gives rise to skin, the nervous system, and sensory organs.; Endoderm: The inner germ layer that gives rise to respiratory and digestive organs.; Embryonic stem cells: Pluripotent cells derived from embryos that can be propagated in culture.; Feeder cells: Cells co-cultured with pluripotent cells to prevent their differentiation. Feeder cells are typically mouse or human embryonic fibroblasts.; Induced pluripotent stem cells: Pluripotent cells obtained through the reprogramming of differentiated cells. Induced pluripotent stem cells are functionally similar to embryonic stem cells.; Mesoderm: The middle germ layer that gives rise to muscle, bone, connective tissues, and blood cells.; Multipotent cells: Cells that can give rise to more than one cell type of the body.; Pluripotent cells: Cells that can give rise to all differentiated cell types of the body but not extraembryonic tissues.; Totipotent cells: Cells that give rise to all differentiated cell types of the body and extraembryonic tissues such as the placenta.
8.  Genome-scale approaches to the epigenetics of common human disease 
Traditionally, the pathology of human disease has been focused on microscopic examination of affected tissues, chemical and biochemical analysis of biopsy samples, other available samples of convenience, such as blood, and noninvasive or invasive imaging of varying complexity, in order to classify disease and illuminate its mechanistic basis. The molecular age has complemented this armamentarium with gene expression arrays and selective analysis of individual genes. However, we are entering a new era of epigenomic profiling, i.e., genome-scale analysis of cell-heritable nonsequence genetic change, such as DNA methylation. The epigenome offers access to stable measurements of cellular state and to biobanked material for large-scale epidemiological studies. Some of these genome-scale technologies are beginning to be applied to create the new field of epigenetic epidemiology.
PMCID: PMC3107986  PMID: 19844740
Epigenetics; Epidemiology; DNA methylation
9.  Aberrant DNA Methylation Is Associated with Disease Progression, Resistance to Imatinib and Shortened Survival in Chronic Myelogenous Leukemia 
PLoS ONE  2011;6(7):e22110.
The epigenetic impact of DNA methylation in chronic myelogenous leukemia (CML) is not completely understood. To elucidate its role we analyzed 120 patients with CML for methylation of promoter-associated CpG islands of 10 genes. Five genes were identified by DNA methylation screening in the K562 cell line and 3 genes in patients with myeloproliferative neoplasms. The CDKN2B gene was selected for its frequent methylation in myeloid malignancies and ABL1 as the target of BCR-ABL translocation. Thirty patients were imatinib-naïve (mostly treated by interferon-alpha before the imatinib era), 30 were imatinib-responsive, 50 were imatinib-resistant, and 10 were imatinib-intolerant. We quantified DNA methylation by bisulfite pyrosequencing. The average number of methylated genes was 4.5 per patient in the chronic phase, increasing significantly to 6.2 in the accelerated and 6.4 in the blastic phase. Higher numbers of methylated genes were also observed in patients resistant or intolerant to imatinib. These patients also showed almost exclusive methylation of a putative transporter OSCP1. Abnormal methylation of a Src suppressor gene PDLIM4 was associated with shortened survival independently of CML stage and imatinib responsiveness. We conclude that aberrant DNA methylation is associated with CML progression and that DNA methylation could be a marker associated with imatinib resistance. Finally, DNA methylation of PDLIM4 may help identify a subset of CML patients that would benefit from treatment with Src/Abl inhibitors.
PMCID: PMC3132778  PMID: 21760961
10.  The quest for genetic risk factors for Crohn's disease in the post-GWAS era 
Genome Medicine  2011;3(2):13.
Multiple genome-wide association studies (GWASs) and two large scale meta-analyses have been performed for Crohn's disease and have identified 71 susceptibility loci. These findings have contributed greatly to our current understanding of the disease pathogenesis. Yet, these loci only explain approximately 23% of the disease heritability. One of the future challenges in this post-GWAS era is to identify potential sources of the remaining heritability. Such sources may include common variants with limited effect size, rare variants with higher effect sizes, structural variations, or even more complicated mechanisms such as epistatic, gene-environment and epigenetic interactions. Here, we outline potential sources of this hidden heritability, focusing on Crohn's disease and the currently available data. We also discuss future strategies to determine more about the heritability; these strategies include expanding current GWAS, fine-mapping, whole genome sequencing or exome sequencing, and using family-based approaches. Despite the current limitations, such strategies may help to transfer research achievements into clinical practice and guide the improvement of preventive and therapeutic measures.
PMCID: PMC3092098  PMID: 21392414
11.  Next-Generation Genomics: an Integrative Approach 
Nature Reviews. Genetics  2010;11(7):476-486.
Integrating results from diverse experiments is an essential process in our effort to understand the logic of complex systems, such as development, homeostasis and responses to the environment. With the advent of high-throughput methods - including genome-wide association studies (GWAS), ChIP-Seq, and RNA-Seq, etc., - acquisition of genome-scale data has never been easier. Epigenetics, transcriptomics, proteomics and genomics each provide an insightful, and yet single-dimensional, view of genome function; integrative analysis promises a unified, global view. However, the large amount of information and diverse technology platforms pose multiple challenges for data access and processing. This Review discusses emerging issues and strategies related to data integration in the era of next-generation genomics.
PMCID: PMC3321268  PMID: 20531367
12.  MAOA promoter methylation and susceptibility to carotid atherosclerosis: role of familial factors in a monozygotic twin sample 
BMC Medical Genetics  2012;13:100.
Atherosclerosis is a complex process involving both genetic and epigenetic factors. The monoamine oxidase A (MAOA) gene regulates the metabolism of key neurotransmitters and has been associated with cardiovascular risk factors. This study investigates whether MAOA promoter methylation is associated with atherosclerosis, and whether this association is confounded by familial factors in a monozygotic (MZ) twin sample.
We studied 84 monozygotic (MZ) twin pairs drawn from the Vietnam Era Twin Registry. Carotid intima-media thickness (IMT) was measured by ultrasound. DNA methylation in the MAOA promoter region was quantified by bisulfite pyrosequencing using genomic DNA isolated from peripheral blood leukocytes. The association between DNA methylation and IMT was first examined by generalized estimating equation, followed by matched pair analyses to determine whether the association was confounded by familial factors.
When twins were analyzed as individuals, increased methylation level was associated with decreased IMT at four of the seven studied CpG sites. However, this association substantially reduced in the matched pair analyses. Further adjustment for MAOA genotype also considerably attenuated this association.
The association between MAOA promoter methylation and carotid IMT is largely explained by familial factors shared by the twins. Because twins reared together share early life experience, which may leave a long-lasting epigenetic mark, aberrant MAOA methylation may represent an early biomarker for unhealthy familial environment. Clarification of familial factors associated with DNA methylation and early atherosclerosis will provide important information to uncover clinical correlates of disease.
PMCID: PMC3532355  PMID: 23116433
DNA methylation; MAOA; Carotid atherosclerosis; Monozygotic twins; Familial factors
13.  Promoter methylation of serotonin transporter gene is associated with obesity measures: a monozygotic twin study 
Epigenetic mechanisms are increasingly being recognized as an important factor for obesity. The serotonin transporter gene (SLC6A4) has a critical role in regulating food intake, body weight and energy balance. This study examines the potential association between SLC6A4 promoter methylation and obesity measures in a monozygotic (MZ) twin sample.
We studied 84 MZ twin pairs drawn from the Vietnam Era Twin Registry. Obesity measures include body mass index (BMI), body weight, waist circumference (WC) and waist-hip ratio (WHR). The SLC6A4 promoter methylation profile in peripheral blood leukocytes was quantified by bisulfite pyrosequencing. The association between methylation variation and obesity parameters was examined by mixed-model regression and matched pair analysis, adjusting for age, smoking, alcohol consumption, physical activity and total daily energy intake. Multiple testing was controlled using the adjusted false discovery rate (q-value).
Mean methylation level was positively correlated with BMI (r=0.29; P=0.0002), body weight (r=0.31; P<0.0001) and WC (r=0.20; P=0.009), but not WHR. Intra-pair differences in mean methylation were significantly correlated with intra-pair differences in BMI, body weight and WC, but not WHR. On average, a 1% increase in mean methylation was associated with 0.33 kg m−2 increase in BMI (95% CI: 0.02–0.65; P=0.03), 1.16 kg increase in body weight (95% CI, 0.16–2.16; P=0.02) and 0.78 cm increase in WC (95% CI, 0.05–1.50; P=0.03) after controlling for potential confounders.
SLC6A4 promoter hypermethylation is significantly associated with an increased prevalence of obesity within a MZ twin study.
PMCID: PMC3539149  PMID: 22290534
DNA methylation; serotonin transporter gene; SLC6A4; monozygotic twins
14.  Novel Approaches for Treating Musculoskeletal Diseases: Molecular Orthopedics and Systems Medicine 
Molecular medicine uses knowledge about cell structure and function for disease, diagnostics, stage characterisation and treatment. The advent of genomic technologies is considerably leading to developments in the field of molecular medicine. The accumulation of detailed information about gene expression, epigenetic variability, protein transcription and functional modulation is contributing to a new era in medicine. Rapid and early diagnostic procedures, molecular characterisation of degenerative and proliferative diseases and personalized therapies are predicted to lead to advancements in health prevention and treatment of disease. Diagnostic tools and therapies based on local and /or general modulation of cellular processes for traumatic or degenerative musculoskeletal conditions are becoming available. A logical consequence of the information derived from extensive data gathering, systems biology and systemic medicine has lead to significant improvements in understanding biological structure and function in a simultaneous bottom top and integrative, holistic manner. The description of disease mechanism at an intimate, subcellular level has a dual benefit. A thorough understanding of the crosstalk involved in molecular pathways both in the normal and the diseased state are expanding scientific knowledge and simultaneously are enabling design cell-targeted and individualized therapies. This paper presents a brief overview of current molecular based treatments available to the orthopedic surgeon and introduces the concept of systemic medicine from the perspective of musculoskeletal pathology.
PMCID: PMC3664448  PMID: 23798982
Systems biology; systems medicine; molecular biomarkers; gene therapy.
15.  The landscape for epigenetic/epigenomic biomedical resources 
Epigenetics  2012;7(9):982-986.
Recent advances in molecular biology and computational power have seen the biomedical sector enter a new era, with corresponding development of Bioinformatics as a major discipline. Generation of enormous amounts of data has driven the need for more advanced storage solutions and shared access through a range of public repositories. The number of such biomedical resources is increasing constantly and mining these large and diverse data sets continues to present real challenges. This paper attempts a general overview of currently available resources, together with remarks on their data mining and analysis capabilities. Of interest here is the recent shift in focus from genetic to epigenetic/epigenomic research and the emergence and extension of resource provision to support this both at local and global scale. Biomedical text and numerical data mining are both considered, the first dealing with automated methods for analyzing research content and information extraction, and the second (broadly) with pattern recognition and prediction. Any summary and selection of resources is inherently limited, given the spectrum available, but the aim is to provide a guideline for the assessment and comparison of currently available provision, particularly as this relates to epigenetics/epigenomics.
PMCID: PMC3515018  PMID: 22874136
biomedical resource; data mining; epigenetics; epigenomics; methylation; primary database; secondary database
16.  Synthetic Genetic Targeting of Genome Instability in Cancer 
Cancers  2013;5(3):739-761.
Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently needed to better target cancer cells. As we approach the era of personalized medicine, targeting the specific molecular defect(s) within a given patient’s tumor will become a more effective treatment strategy than traditional approaches that often target a given cancer type or sub-type. Synthetic genetic interactions are now being examined for their therapeutic potential and are designed to target the specific genetic and epigenetic phenomena associated with tumor formation, and thus are predicted to be highly selective. In general, two complementary approaches have been employed, including synthetic lethality and synthetic dosage lethality, to target aberrant expression and/or function associated with tumor suppressor genes and oncogenes, respectively. Here we discuss the concepts of synthetic lethality and synthetic dosage lethality, and explain three general experimental approaches designed to identify novel genetic interactors. We present examples and discuss the merits and caveats of each approach. Finally, we provide insight into the subsequent pre-clinical work required to validate novel candidate drug targets.
PMCID: PMC3795363  PMID: 24202319
cancer; genome instability; tumor suppressor gene; oncogene; synthetic genetic approach; synthetic lethality; synthetic dosage lethality; cancer therapy
17.  Nonhuman Primate Models in the Genomic Era: A Paradigm Shift 
ILAR Journal  2013;54(2):154-165.
Because of their strong similarities to humans across physiologic, developmental, behavioral, immunologic, and genetic levels, nonhuman primates are essential models for a wide spectrum of biomedical research. But unlike other animal models, nonhuman primates possess substantial outbred genetic variation, reducing statistical power and potentially confounding interpretation of results in research studies. Although unknown genetic variation is a hindrance in studies that allocate animals randomly, taking genetic variation into account in study design affords an opportunity to transform the way that nonhuman primates are used in biomedical research. New understandings of how the function of individual genes in rhesus macaques mimics that seen in humans are greatly advancing the rhesus macaques utility as research models, but epistatic interaction, epigenetic regulatory mechanisms, and the intricacies of gene networks limit model development. We are now entering a new era of nonhuman primate research, brought on by the proliferation and rapid expansion of genomic data. Already the cost of a rhesus macaque genome is dwarfed by its purchase and husbandry costs, and complete genomic datasets will inevitably encompass each rhesus macaque used in biomedical research. Advancing this outcome is paramount. It represents an opportunity to transform the way animals are assigned and used in biomedical research and to develop new models of human disease. The genetic and genomic revolution brings with it a paradigm shift for nonhuman primates and new mandates on how nonhuman primates are used in biomedical research.
PMCID: PMC3814397  PMID: 24174439
candidate gene; drug development; macaque; personalized medicine; pharmacogenomics; physiogenetics; polymorphism; stress
18.  Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms 
Oncotarget  2013;4(12):2186-2207.
In the era of new and mostly effective therapeutic protocols, multiple myeloma still tends to be a hard-to-treat hematologic cancer. This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment. Furthermore, the heterogeneous nature of multiple myeloma makes treating patients with the same drug challenging because finding a drugable oncogenic process common to all patients is not yet feasible, while our current knowledge of genetic/epigenetic basis of multiple myeloma pathogenesis is outstanding. Nonetheless, bone marrow microenvironment components are well known as playing critical roles in myeloma tumor cell survival and environment-mediated drug resistance happening most possibly in all myeloma patients. Generally speaking, however; real mechanisms underlying drug resistance in multiple myeloma are not completely understood. The present review will discuss the latest findings and concepts in this regard. It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations. It will also highlight how bone marrow microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could contribute to drug resistance in multiple myeloma.
PMCID: PMC3926819  PMID: 24327604
multiple myeloma; drug resistance; signaling pathways; oncogenes
19.  Length of Stay: An Inappropriate Readout of the Success of Enhanced Recovery Programs 
World Journal of Surgery  2008;32(6):971-975.
Enhanced recovery after surgery (ERAS) programs are designed to reduce hospital length of stay by shortening the postoperative recovery period. The intended effect of an accelerated recovery on the length of stay may be frustrated by a delayed discharge. This study was designed to assess the influence of an ERAS program on the proportion, appropriateness, and extent of delay in discharge.
Patients who enrolled in the ERAS program (n = 121) between 2003 and 2006 were compared with 52 patients who were managed traditionally in 2001.
Ninety percent of the pre-ERAS patients and 87% of the ERAS patients were not discharged on the day that discharge criteria were fulfilled. The additional stay of 59% of the pre-ERAS patients and 69% of the ERAS patients was inappropriate. Wound care (15% in the pre-ERAS and 3% of the ERAS group) and observation of any symptoms pointing to an anastomotic leakage (10% in both groups) were the most important reasons for a medical appropriate delay of discharge. The extent of delay in discharge decreased significantly from a median of two days in the pre-ERAS group to a median of 1 day in the ERAS group (p = 0.004).
Reductions in length of stay up to a median of 2 days after start of an enhanced recovery program may relate to changes in organization of care and not to a shorter recovery period. Recovery statistics should replace or at least be added to the length of stay as outcome of enhanced recovery programs.
PMCID: PMC2386846  PMID: 18224480
20.  Role of the ERas gene in gastric cancer cells 
Oncology Reports  2013;30(1):50-56.
As a novel member of the Ras family, ERas, found in murine embryonic stem (ES) cells in 2003, was considered a pseudogene. To date, there are a few reports on the relationship between ERas and tumors. It was recently suggested that ERas could affect gastric carcinoma (GC) metastasis, but no significant relationship was found with tumor proliferation. Since ERas plays an important role in tumor-like growth of ES cells subcutaneously injected into nude mice, we hypothesized that ERas plays a role in tumor proliferation. In this experiment, we selected 7 GC strains from different sources with different differentiation degrees, we detected the expression of full length ERas transcript, and selected two ERas highly expressing GC strains, MKN-28 and BGC-823. After knocking down the ERas gene by siRNA, we observed that there was a significant decrease in proliferation, metastasis as well as clonality. Therefore, ERas is confirmed to be an important gene in affecting tumor proliferation and metastasis. Furthermore, the significance of the ERas mechanism and signaling pathway is shown.
PMCID: PMC3729207  PMID: 23612786
ERas; embryonic stem cell; gastric carcinoma; siRNA interference
21.  Identification of an estrogen-regulated circadian mechanism necessary for breast acinar morphogenesis 
Cell Cycle  2012;11(19):3691-3700.
Altered estrogen receptor α (ERA) signaling and altered circadian rhythms are both features of breast cancer. By using a method to entrain circadian oscillations in human cultured cells, we recently reported that the expression of key clock genes oscillates in a circadian fashion in ERA-positive breast epithelial cells but not in breast cancer cells, regardless of their ERA status. Moreover, we reported that ERA mRNA oscillates in a circadian fashion in ERA-positive breast epithelial cells, but not in ERA-positive breast cancer cells. By using ERA-positive HME1 breast epithelial cells, which can be both entrained in vitro and can form mammary gland-like acinar structures in three-dimensional (3D) culture, first we identified a circuit encompassing ERA and an estrogen-regulated loop consisting of two circadian clock genes, PER2 and BMAL1. Further, we demonstrated that this estrogen-regulated circuit is necessary for breast epithelial acinar morphogenesis. Disruption of this circuit due to ERA-knockdown, negatively affects the estrogen-sustained circadian PER2-BMAL1 mechanism as well as the formation of 3D HME1 acini. Conversely, knockdown of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects ERA circadian oscillations and 3D breast acinar morphogenesis. To our knowledge, this study provides the first evidence of the implication of an ERA-circadian clock mechanism in the breast acinar morphogenetic process.
PMCID: PMC3478319  PMID: 22935699
3D acinar morphogenesis; BMAL1; PER2; breast epithelial cells; circadian clock; estrogen receptor alpha (ERA); estrogen
22.  16S rRNA Is Bound to Era of Streptococcus pneumoniae 
Journal of Bacteriology  1999;181(17):5242-5249.
Era is an essential membrane-associated GTPase that is present in bacteria and mycoplasmas. Era appears to play an important role in the regulation of the bacterial cell cycle. In this study, we expressed the native and glutathione S-transferase (GST) fusion forms of Streptococcus pneumoniae Era in Escherichia coli and purified both proteins to homogeneity. We showed that RNA was copurified with the GST-Era protein of S. pneumoniae during affinity purification and remained associated with the protein after removal of the GST tag by thrombin cleavage. The thrombin-treated and untreated GST-Era proteins could bind and hydrolyze GTP and exhibited similar kinetic properties (dissociation constant [kD], Km, and Vmax). However, the native Era protein purified by using different chromatographic columns had a much lower GTPase activity than did GST-Era, although it had a similar kD. In addition, RNA was not associated with the protein. Purified GST-Era protein was shown to be present as high (600-kDa)- and low (120-kDa)-molecular-mass forms. The high-molecular-mass form of GST-Era was associated with RNA and exhibited a very high GTPase activity. Approximately 40% of purified GST-Era protein was associated with RNA, and removal of the RNA resulted in a significant reduction in GTPase activity. The RNA associated with GST-Era was shown to be predominantly 16S rRNA. The native Era protein isolated directly from S. pneumoniae was also present as a high-molecular-mass species (600 kDa) complexed with RNA. Together, our results suggest that 16S rRNA is associated with Era and might stimulate its GTPase activity.
PMCID: PMC94028  PMID: 10464193
23.  GTPase-dependent signaling in bacteria: characterization of a membrane-binding site for era in Escherichia coli. 
Journal of Bacteriology  1994;176(1):44-49.
Era is an Escherichia coli GTPase that is essential for cell viability and is peripherally associated with the cytoplasmic membrane. Both immunoelectron microscopy and subcellular-fractionation experiments have shown that Era is present in cytoplasmic as well as membrane-associated pools. These data led to speculation that the mechanism of action of Era may require cycling between membrane and cytoplasmic sites. In order to investigate this possibility, an in vitro binding assay was developed to characterize the binding of Era to membrane fractions. Competition and saturation binding experiments suggest that a site that is specific for Era and capable of binding up to 5 ng of Era per microgram of membrane protein is present in membrane preparations. The binding curve is complex, indicating that multiple equilibria describe the interaction. The binding of Era to this putative receptor is dependent on guanine nucleotides; binding cannot be measured in the absence of nucleotide, and neither ATP nor UTP can substitute. Subfractionation of cell walls showed that the guanine nucleotide-dependent binding site was present in fractions enriched in cytoplasmic membrane. These data provide evidence that Era may be involved in a GTPase-receptor-coupled membrane-signaling pathway that is essential for growth in E. coli.
PMCID: PMC205012  PMID: 8282709
24.  The Changing Epidemiology of Pediatric Endocarditis at a Children's Hospital Over Seven Decades 
Pediatric cardiology  2010;31(6):813-820.
This study sought to determine whether improvements in the care of children with congenital heart disease (CHD) have changed the epidemiology of infective endocarditis (IE). A retrospective study of patients 18 years of age and younger treated for IE from 1992 to 2004 (era 3) was conducted at the authors' children's hospital in New York City. This study was compared with two previous studies conducted at the same hospital from 1930 to 1959 (era 1) and from 1977 to 1992 (era 2). During the three eras, IE was diagnosed for 205 children with a median age of 8 years during eras 1 and 2, which decreased to 1.5 years during era 3, partly because of IE after cardiac surgery for young infants. In era 3, nonstreptococcal and nonstaphylococcal pathogens associated with hospital-acquired IE increased. Complications from IE declined during era 3, but after the widespread availability of antibiotics in 1944, crude mortality rates were similar in eras 1 (32%), 2 (21%), and 3 (24%). However, in era 3, mortality occurred only among subjects with hospital-acquired IE. The epidemiology of pediatric IE has changed in the modern era. Currently, IE is most likely to occur among young children with complex congenital heart disease. Pediatric IE remains associated with high crude mortality rates when it is acquired in the hospital.
PMCID: PMC2997359  PMID: 20414646
Congenital heart disease; Endocarditis; Pediatrics
25.  Population-based outcomes after brain radiotherapy in patients with brain metastases from breast cancer in the Pre-Trastuzumab and Trastuzumab eras 
To evaluate the survival of patients with human epidermal growth factor receptor 2 (HER2) positive and negative metastatic breast cancer irradiated for brain metastases before and after the availability of trastuzumab (T).
Materials and methods
Women diagnosed with brain metastasis from breast cancer in two eras between 2000 and 2007 (T-era, n = 441) and 1986 to 1992 (PreT-era, n = 307), treated with whole brain radiotherapy (RT) were identified. In the T-era, HER2 testing was part of routine clinical practice, and in the preT-era 128/307 (42%) cases had HER2 testing performed retrospectively on tissue microarrays. Overall survival (OS) was estimated using the Kaplan-Meier method and comparisons between eras used log-rank tests.
In the preT- and T-era cohorts, the rate of HER2 positivity was 40% (176/441) and 26% (33/128) (p < 0.001). The median time from diagnosis to brain RT was longer in the preT-era (3.3 years versus 2.3 years, p < 0.001). Survival after brain RT was improved in the T-era compared to the preT-era (1-year OS 26% versus 12%, p < 0.001). The 1-year OS rate for HER2 negative patients was 20% in both eras (p = 0.97). Among HER2 positive patients, the 1-year OS in the preT-era was 5% compared to 40% in the T-era (p < 0.001).
Distinct from patients with HER2 negative disease in whom no difference in survival after brain RT was observed over time, patients with HER2 positive brain metastases experienced significantly improved survival subsequent to the availability of trastuzumab.
PMCID: PMC3582534  PMID: 23302543
Breast cancer; Brain metastasis; Brain irradiation; Trastuzumab; HER2 status

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