Changes In DNA Sequence Research Articles

Computational Simulation and Biophysical Study on Cerium Chloride-Induced B-to-Z Transition in (CG) n DNA.

Rare earth elements have been shown to trigger the B-to-Z DNA transition in diverse self-assembled branched DNA architectures. Herein, we investigated the influence of cerium chloride on the conformational changes of DNA sequences containing repeated cytosine-guanine (CG)6-12 or guanine-cytosine (GC)6-12 sequences. The CD results show that (CG)6-12 repeats were susceptible to the formation of Z-DNA at low concentrations of CeCl3. On the other hand, (GC)6-12 is unable to undergo B-Z DNA transition and instead exhibits condensation with a similar amount of CeCl3. The CD signature was found to be different and unique in both alternate repeats during the interaction with CeCl3. The sequence-specific effects on the B-Z transition are based on the order of nucleotides in DNA. With the addition of EDTA, the Z-form of DNA is reverted to the native B-form. Further, we have reported the positive zeta potential of CeCl3-induced Z-DNA in contrast to the negative zeta potential of B-DNA. The differential zeta-potential value during the B-Z transition is complementary to the conformational changes of DNA. The molecular simulation study also supports the sequence-specific conformational change between the B- and Z-forms of DNA molecules. This newly described reversible topological and sequence-dependent transition is crucial for understanding the structural and biological roles of Z-DNA in response to CeCl3.

Evidence for the Contribution of the miR-206/BDNF Pathway in the Pathophysiology of Depression.

Depression is a complex disorder with substantial impacts on individual health and has major public health implications. Depression results from complex interactions between genetic and environmental factors. Epigenetic mechanisms, including DNA methylation, microRNAs (miRNAs), and histone modifications, can produce heritable phenotypic changes without a change in DNA sequence and recently were proven to mediate lasting increases in the risk of depression following exposure to adverse life events. Of these, miRNAs are gaining attention for their role in the pathogenesis of many stress-associated mental disorders, including depression. One such miRNA is microRNA-206 (miR-206), which is a critical candidate for increasing the susceptibility to stress. Although miR-206 is thought to be a typical muscle-specific miRNA, it is expressed throughout the brain, particularly in the hippocampus and prefrontal cortex. Until now, only a few studies have been conducted on rodents to understand the role of miR-206 in stress-related abnormalities in neurogenesis. However, the precise underlying molecular mechanism of miR-206-mediated depression-like behaviors remains largely unknown. Here, we reviewed recent advances in the field of biomedical and clinical research on the role of miR-206 in the pathogenesis of depression from studies using different tissues and various experimental designs and described how abnormalities in miR-206 expression in these tissues can affect neuronal functions. Moreover, we focused on studies investigating the brain-derived neurotrophic factor (BDNF) as a functional target of miR-206, where miR-206 has been implicated in the pathogenesis of depression by suppressing the expression of the BDNF. In summary, these studies confirm the existence of a tight correlation between the pathogenesis of depression and the miR-206/BDNF pathway.

Review on How Genetic Innovations Revolutionizing Seed Quality Production

The process of genetic engineering modifies the genes regulating various attributes of seed quality by fabricating or redesigning some of the DNA sequences within an organism which affects germination, growth, and storage performance. Providing molecular dissection as a tool for exploiting the genetic blueprint towards the crop improvement strategy as well as improved seed yield or quality is an example showing how important it is to understand these things technically. Techniques like CRISPR and prime editing that have potential to position-specific changes in DNA sequences that helped to improve different traits such as stress resistance, productivity, nutritional value etc. Applications of transgenic approaches for boosting mineral content in certain crops different methods used to deal with micronutrient for malnutrition in developing countries. Development of good quality seeds resistant to environmental conditions are very important for agricultural sustainability under climate change. It ensures crop adaptation, food security and multiplication that must be promoted in future. The regulatory framework rightly requires safety assessments adapted to genetically modified (GM) foodstuffs which not only leads to satisfied public regarding health issues but also ethical standards concerning genetic engineering are upheld. The outcome is that by adhesion to professional ethics and strict safety measures, biotechnology possessing such qualities has been able to make revolutionary contribution into development fostered by stable agriculture system.

Creating Meiotic Recombination-Regulating DNA Sites by SpEDIT in Fission Yeast Reveals Inefficiencies, Target-Site Duplications, and Ectopic Insertions.

Recombination hotspot-activating DNA sites (e.g., M26, CCAAT, Oligo-C) and their binding proteins (e.g., Atf1-Pcr1 heterodimer; Php2-Php3-Php5 complex, Rst2, Prdm9) regulate the distribution of Spo11 (Rec12)-initiated meiotic recombination. We sought to create 14 different candidate regulatory DNA sites via bp substitutions in the ade6 gene of Schizosaccharomyces pombe. We used a fission yeast-optimized CRISPR-Cas9 system (SpEDIT) and 196 bp-long dsDNA templates with centrally located bp substitutions designed to ablate the genomic PAM site, create specific 15 bp-long DNA sequences, and introduce a stop codon. After co-transformation with a plasmid that encoded both the guide RNA and Cas9 enzyme, about one-third of colonies had a phenotype diagnostic for DNA sequence changes at ade6. PCR diagnostics and DNA sequencing revealed a diverse collection of alterations at the target locus, including: (A) complete or (B) partial template-directed substitutions; (C) non-homologous end joinings; (D) duplications; (E) bp mutations, and (F) insertions of ectopic DNA. We concluded that SpEDIT can be used successfully to generate a diverse collection of DNA sequence elements within a reporter gene of interest. However, its utility is complicated by low efficiency, incomplete template-directed repair events, and undesired alterations to the target locus.

The evolutionary consequences of interactions between the epigenome, the genome and the environment.

The epigenome is the suite of interacting chemical marks and molecules that helps to shape patterns of development, phenotypic plasticity and gene regulation, in part due to its responsiveness to environmental stimuli. There is increasing interest in understanding the functional and evolutionary importance of this sensitivity under ecologically realistic conditions. Observations that epigenetic variation abounds in natural populations have prompted speculation that it may facilitate evolutionary responses to rapid environmental perturbations, such as those occurring under climate change. A frequent point of contention is whether epigenetic variants reflect genetic variation or are independent of it. The genome and epigenome often appear tightly linked and interdependent. While many epigenetic changes are genetically determined, the converse is also true, with DNA sequence changes influenced by the presence of epigenetic marks. Understanding how the epigenome, genome and environment interact with one another is therefore an essential step in explaining the broader evolutionary consequences of epigenomic variation. Drawing on results from experimental and comparative studies carried out in diverse plant and animal species, we synthesize our current understanding of how these factors interact to shape phenotypic variation in natural populations, with a focus on identifying similarities and differences between taxonomic groups. We describe the main components of the epigenome and how they vary within and between taxa. We review how variation in the epigenome interacts with genetic features and environmental determinants, with a focus on the role of transposable elements (TEs) in integrating the epigenome, genome and environment. And we look at recent studies investigating the functional and evolutionary consequences of these interactions. Although epigenetic differentiation in nature is likely often a result of drift or selection on stochastic epimutations, there is growing evidence that a significant fraction of it can be stably inherited and could therefore contribute to evolution independently of genetic change.

Methods and applications of genome-wide profiling of DNA damage and rare mutations.

DNA damage is a threat to genome integrity and can be a cause of many human diseases, owing to either changes in the chemical structure of DNA or conversion of the damage into a mutation, that is, a permanent change in DNA sequence. Determining the exact positions of DNA damage and ensuing mutations in the genome are important for identifying mechanisms of disease aetiology when characteristic mutations are prevalent and probably causative in a particular disease. However, this approach is challenging particularly when levels of DNA damage are low, for example, as a result of chronic exposure to environmental agents or certain endogenous processes, such as the generation of reactive oxygen species. Over the past few years, a comprehensive toolbox of genome-wide methods has been developed for the detection of DNA damage and rare mutations at single-nucleotide resolution in mammalian cells. Here, we review and compare these methods, describe their current applications and discuss future research questions that can now be addressed.

YQTL Pipeline: A structured computational workflow for large scale quantitative trait loci discovery and downstream visualization.

Quantitative trait loci (QTL) denote regions of DNA whose variation is associated with variations in quantitative traits. QTL discovery is a powerful approach to understand how changes in molecular and clinical phenotypes may be related to DNA sequence changes. However, QTL discovery analysis encompasses multiple analytical steps and the processing of multiple input files, which can be laborious, error prone, and hard to reproduce if performed manually. To facilitate and automate large-scale QTL analysis, we developed the yQTL Pipeline, where the 'y' indicates the dependent quantitative variable being modeled. Prior to the association test, the pipeline supports the calculation or the direct input of pre-defined genome-wide principal components and genetic relationship matrix when applicable. User-specified covariates can also be provided. Depending on whether familial relatedness exists among the subjects, genome-wide association tests will be performed using either a linear mixed-effect model or a linear model. The options to run an ANOVA model or testing the interaction with a covariate are also available. Using the workflow management tool Nextflow, the pipeline parallelizes the analysis steps to optimize run-time and ensure results reproducibility. In addition, a user-friendly R Shiny App is developed to facilitate result visualization. It can generate Manhattan and Miami plots of phenotype traits, genotype-phenotype boxplots, and trait-QTL connection networks. We applied the yQTL Pipeline to analyze metabolomics profiles of blood serum from the New England Centenarians Study (NECS) participants. A total of 9.1M SNPs and 1,052 metabolites across 194 participants were analyzed. Using a p-value cutoff 5e-8, we found 14,983 mQTLs associated with 312 metabolites. The built-in parallelization of our pipeline reduced the run time from ~90 min to ~26 min. Visualization using the R Shiny App revealed multiple mQTLs shared across multiple metabolites. The yQTL Pipeline is available with documentation on GitHub at https://github.com/montilab/yQTLpipeline.

Prevention and Co-Management of Breast Cancer-Related Osteoporosis Using Resveratrol.

Breast cancer (BC) is currently one of the most common cancers in women worldwide with a rising tendency. Epigenetics, generally inherited variations in gene expression that occur independently of changes in DNA sequence, and their disruption could be one of the main causes of BC due to inflammatory processes often associated with different lifestyle habits. In particular, hormone therapies are often indicated for hormone-positive BC, which accounts for more than 50-80% of all BC subtypes. Although the cure rate in the early stage is more than 70%, serious negative side effects such as secondary osteoporosis (OP) due to induced estrogen deficiency and chemotherapy are increasingly reported. Approaches to the management of secondary OP in BC patients comprise adjunctive therapy with bisphosphonates, non-steroidal anti-inflammatory drugs (NSAIDs), and cortisone, which partially reduce bone resorption and musculoskeletal pain but which are not capable of stimulating the necessary intrinsic bone regeneration. Therefore, there is a great therapeutic need for novel multitarget treatment strategies for BC which hold back the risk of secondary OP. In this review, resveratrol, a multitargeting polyphenol that has been discussed as a phytoestrogen with anti-inflammatory and anti-tumor effects at the epigenetic level, is presented as a potential adjunct to both support BC therapy and prevent osteoporotic risks by positively promoting intrinsic regeneration. In this context, resveratrol is also known for its unique role as an epigenetic modifier in the regulation of essential signaling processes-both due to its catabolic effect on BC and its anabolic effect on bone tissue.

Hardware acceleration of DNA pattern matching using analog resistive CAMs

DNA pattern matching is essential for many widely used bioinformatics applications. Disease diagnosis is one of these applications since analyzing changes in DNA sequences can increase our understanding of possible genetic diseases. The remarkable growth in the size of DNA datasets has resulted in challenges in discovering DNA patterns efficiently in terms of run time and power consumption. In this paper, we propose an efficient pipelined hardware accelerator that determines the chance of the occurrence of repeat-expansion diseases using DNA pattern matching. The proposed design parallelizes the DNA pattern matching task using associative memory realized with analog content-addressable memory and implements an algorithm that returns the maximum number of consecutive occurrences of a specific pattern within a DNA sequence. We fully implement all the required hardware circuits with PTM 45-nm technology, and we evaluate the proposed architecture on a practical human DNA dataset. The results show that our design is energy-efficient and accelerates the DNA pattern matching task by more than 100× compared to the approaches described in the literature.

Epigenetic regulation in cancer therapy: From mechanisms to clinical advances

AbstractEpigenetic regulation refers to the alteration of gene expression independent of changes in DNA sequence. It involves chemical modifications such as DNA methylation, histone methylation, and histone acetylation, which are regulated by a coordinated interplay of various regulators to ensure precise spatial and temporal regulation of gene expression. Epigenetic aberrations are commonly observed in cancer and are considered as hallmarks of cancer. In recent years, small molecules targeting specific epigenetic regulators have been developed and are demonstrating promising therapeutic potential in preclinical and clinical trials for cancer treatment. In this review, we summarize the essential regulatory mechanisms and dysfunctions of epigenetic regulators involved in DNA methylation, histone methylation, and histone acetylation during tumor development and progression. Moreover, we discuss the current advances and challenges in cancer epigenetic therapy that target these mechanisms in both hematologic malignancies and solid tumors. Finally, we discuss the potential of combining epigenetic drugs with other therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, as a promising approach for cancer treatment. Overall, we aim to enhance the understanding of epigenetic regulation in cancer therapy and explore targeted therapeutic strategies based on these mechanisms, to ultimately advance cancer therapy and improve patient prognosis.

Research hotspots and trends of epigenetic therapy in oncology: a bibliometric analysis from 2004 to 2023.

Epigenetics denotes heritable alterations in gene expression patterns independent of changes in DNA sequence. Epigenetic therapy seeks to reprogram malignant cells to a normal phenotype and has been extensively investigated in oncology. This study conducts a bibliometric analysis of epigenetic therapy in cancer, providing a comprehensive overview of current research, identifying trends, and highlighting key areas of investigation. Publications concerning epigenetic inhibitors in cancer spanning 2004 to 2023 were retrieved from the Web of Science Core Collection (WoSCC). Co-occurrence analysis using VOSviewer assessed current status and focal points. Evolutionary trends and bursts in the knowledge domain were analyzed using CiteSpace. Bibliometrix facilitated topic evolution and revealed trends in keywords. National, institutional, and author affiliations and collaborations were also examined. A total of 2,153 articles and reviews on epigenetic therapy in oncology were identified, demonstrating a consistent upward trend over time. The United States (745 papers), University of Texas MD Anderson Cancer Center (57 papers), and Stephen B. Baylin (27 papers) emerged as the most productive country, institution, and author, respectively. Keyword co-occurrence analysis identified five primary clusters: tumor, DNA methylation, epigenetic therapy, expression, and immunotherapy. In the past 5years, newly emerging themes with increased centrality and density include "drug resistance," "immunotherapy," and "combination therapy." The most cited publication reviewed current understanding of potential causes of epigenetic diseases and proposed future therapeutic strategies. In the past twodecades, the importance of epigenetic therapy in cancer research has become increasingly prominent. The United States occupies a key position in this field, while China, despite having published a large number of related papers, still has relatively limited influence. Current research focuses on the "combination therapy" of epigenetic drugs. Future studies should further explore the sequencing and scheduling of combination therapies, optimize trial designs and dosing regimens to improve clinical efficacy.

Novel methylation specific bisulfite primer pairs for epigenetic studies of Capsicum spp.

Over the past ten years, interest in epigenetic has rapidly increased. Heritable and stable changes in gene expression without any change in DNA sequence is in the field of epigenetics. Plants have a well-preserved epigenetic signature called DNA methylation. It is an essential epigenetic mark that protects genomic stability, silences harmful transposon insertions, and controls global gene expression in all developmental stages and environmental circumstances. All three sequence contexts, the asymmetric CpHpH context and the symmetric CpG and CpHpG contexts (where H is C, A, or T), are among DNA methylation sites in plants. Particularly, DNA cytosine methylation affects a wide range of biological processes, such as gene expression, chromatin structure, DNA packing, recombination, genomic imprinting, and DNA replication. The choice of primer pairs that flank cytosine methylation contexts is critical when designing for the detection of DNA cytosine methylation using bisulfite sequencing. We have developed and synthesized 26 bisulfite specific primer pairs suitable for DNA cytosine methylation investigations in peppers. These primers are specific to certain promoters, intergenic regions, and gene bodies (exons, introns, and UTRs). DNA samples taken from various tissues and developmental stages of Capsicum annuum L. Demre Sivrisi were analyzed by these primer pairs to confirm their utilization.

Cisplatin exposure alters tRNA-derived small RNAs but does not affect epimutations in C. elegans

BackgroundThe individual lifestyle and environment of an organism can influence its phenotype and potentially the phenotype of its offspring. The different genetic and non-genetic components of the inheritance system and their mutual interactions are key mechanisms to generate inherited phenotypic changes. Epigenetic changes can be transmitted between generations independently from changes in DNA sequence. In Caenorhabditis elegans, epigenetic differences, i.e. epimutations, mediated by small non-coding RNAs, particularly 22G-RNAs, as well as chromatin have been identified, and their average persistence is three to five generations. In addition, previous research showed that some epimutations had a longer duration and concerned genes that were enriched for multiple components of xenobiotic response pathways. These results raise the possibility that environmental stresses might change the rate at which epimutations occur, with potential significance for adaptation.ResultsIn this work, we explore this question by propagating C. elegans lines either in control conditions or in moderate or high doses of cisplatin, which introduces genotoxic stress by damaging DNA. Our results show that cisplatin has a limited effect on global small non-coding RNA epimutations and epimutations in gene expression levels. However, cisplatin exposure leads to increased fluctuations in the levels of small non-coding RNAs derived from tRNA cleavage. We show that changes in tRNA-derived small RNAs may be associated with gene expression changes.ConclusionsOur work shows that epimutations are not substantially altered by cisplatin exposure but identifies transient changes in tRNA-derived small RNAs as a potential source of variation induced by genotoxic stress.

Plain language summary of erdafitinib in locally advanced or metastatic urothelial carcinoma: a phase 2 study with long-term follow-up.

This is a plain language summary of two articles describing the results from a study called BLC2001. The study examined the effect of a medication called erdafitinib on participants with a type of cancer known as urothelial carcinoma that had either spread beyond the bladder or urinary tract into surrounding organs and/or nearby muscles (locally advanced) and was not removable by surgery (unresectable) or had spread to other parts of the body (metastatic). In this study, researchers wanted to learn if erdafitinib was safe and effective at stopping or reducing tumor growth in participants with locally advanced and unresectable or metastatic urothelial carcinoma with certain genetic alterations (changes in DNA sequence) in two related genes called fibroblast growth factor receptor 2 (FGFR2) and 3 (FGFR3). Treatment options for people with this disease are very limited; some may not have responded to other therapies, or their tumors continued to grow after they received other treatments. 212 participants took part in the study. 111 participants were treated with oral (by mouth) erdafitinib at different doses to find a recommended dose regimen. 101 additional participants then received the recommended starting dose of erdafitinib at 8mg daily with possible increase to 9mg daily, these participants make up the 8mg regimen group. Researchers found that tumors decreased in size or completely disappeared in 40% of participants. With approximately 1year of follow-up, an estimated 55% of participants were still alive, and after 2years, an estimated 31% of participants were still alive. Common side effects of erdafitinib included high phosphate levels in the blood (hyperphosphatemia), an inflamed and sore mouth, diarrhea, and dry mouth. Participants had locally advanced and unresectable or metastatic urothelial carcinoma with certain FGFR gene alterations that had been treated with erdafitinib after previous chemotherapy and/or a type of medicine that uses the immune system to help the body fight cancer (immunotherapy). The BLC2001 study found that some participants treated with 8mg erdafitinib had the benefit of a longer period without their cancer growing or spreading to other parts of the body. About 80% of participants achieved some level of disease control where their tumor shrank or remained stable.

РОЛЬ ЭПИГЕНЕТИЧЕСКИХ ФАКТОРОВ В РАЗВИТИИ И ДИАГНОСТИКЕ ИШЕМИЧЕСКОЙ БОЛЕЗНИ СЕРДЦА

Abstract. Introduction. Understanding the role of epigenetic regulation and studying how it affects the pathogenesis of many polygenic diseases have become a breakthrough in modern medicine over the past decade. Today, it is obvious that epigenetic mechanisms, despite their inheritable nature, can become modified under the influence of lifestyle and environment. Epigenetics is the science of inherited body properties that are not related to any changes in the actual nucleotide DNA sequence and can be encoded in the genome rather indirectly than directly. Gaining the knowledge on these mechanisms opened up new opportunities for understanding the origin of some cardiovascular diseases. Promoting this trend has serious consequences for the development and progression of diseases, as well as creates possible new strategies for preventing cardiovascular diseases. Due to this, some fundamental epigenetic regulation mechanisms in the development of coronary heart disease were identified in recent years, which disease is one of the leading causes of mortality in today’s context. Aim. To study the role of the epigenetic mechanisms of early vascular inflammation in the development of coronary heart disease and the prognostic value of epigenetic biomarkers in diagnosing this disease. Material and Methods. We analyzed the findings of studies conducted in 2001-2022 regarding epigenetic mechanisms and their role in the pathogenesis and diagnosis of coronary heart disease, using new epigenetic markers. Sources. PubMed, ResearchGate, eLibrary, Cyberleninka. Results and Discussion. Among all epigenetic mechanisms, DNA methylation, histone modification, and transcription of non-coding RNA sequences, particularly micro-RNA, are currently considered to be most extensively studied and most significant. Conclusion Understanding the basic regulation mechanisms of epigenetic modifications in the development of coronary heart disease will increase knowledge about the etiopathogenesis of this disease and facilitate the transition to personalized medicine.

Mechanisms of Intrinsic Postzygotic Isolation: From Traditional Genic and Chromosomal Views to Genomic and Epigenetic Perspectives.

Intrinsic postzygotic isolation typically appears as reduced viability or fertility of interspecific hybrids caused by genetic incompatibilities between diverged parental genomes. Dobzhansky-Muller interactions among individual genes, and chromosomal rearrangements causing problems with chromosome synapsis and recombination in meiosis, have both long been considered as major mechanisms behind intrinsic postzygotic isolation. Recent research has, however, suggested that the genetic basis of intrinsic postzygotic isolation can be more complex and involves, for example, overall divergence of the DNA sequence or epigenetic changes. Here, we review the mechanisms of intrinsic postzygotic isolation from genic, chromosomal, genomic, and epigenetic perspectives across diverse taxa. We provide empirical evidence for these mechanisms, discuss their importance in the speciation process, and highlight questions that remain unanswered.

From Environmental Epigenetics to the Inheritance of Acquired Traits: A Historian and Molecular Perspective on an Unnecessary Lamarckian Explanation.

In the last decade, it has been suggested that epigenetics may enhance the adaptive possibilities of animals and plants to novel environments and/or habitats and that such epigenetic changes may be inherited from parents to offspring, favoring their adaptation. As a consequence, several Authors called for a shift in the Darwinian paradigm, asking for a neo-Lamarckian view of evolution. Regardless of what will be discovered about the mechanisms of rapid adaptation to environmental changes, the description of epigenetic inheritance as a Lamarckian process is incorrect from a historical point of view and useless at a scientific level. At the same time, even if some examples support the presence of adaptation without the involvement of changes in DNA sequences, in the current scenario no revolution is actually occurring, so we are simply working on a stimulating research program that needs to be developed but that is, at present, completely Darwinian.

Detection of rare mutations, copy number alterations, and methylation in the same template DNA molecules

The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here, we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic and genetic alterations present in the DNA molecules can then be obtained from the original and copied strands, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung, and colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics.

Dynamic equilibrium of cellular plasticity: The origin of diseases

Since its inception, cellular plasticity has undergone many iterations. Today we define it as the ability of mature, terminally differentiated cells to change their identity, meaning lineage change of the cells by transdifferentiation, dedifferentiation and reprogramming. This process does not involve a single DNA sequence change or a mutation. We now know that the behavior of a cell is profoundly affected by the surrounding environment. There is a perpetual pressure placed on the genetic expression of the cells. The external environment and specifically the microenvironment of the cells greatly influences the genotype. There is a never-ending dynamic interplay between the genotype and the phenotype. Incremental phenotypic adjustments are continuously occurring to yield improved cell survival. These changes are beneficial to the cells at a given moment. As the environmental condition declines, then more extensive phenotypic transformation (via transdifferentiation and dedifferentiation) can follow. When the cellular environment further deteriorates, cellular plasticity can trigger a pathologic sequence that eventually leads to cancers/diseases. These modifications are all part of an adaptive process that enhances the survival of the cells. They can offer short term advantages, but they can also lead to diseases. Oxygen level plays a pivotal role in the development of chronic diseases. Cellular response to hypoxia is mediated through hypoxia inducible factor (HIF). HIF is an oxygen sensor that is closely involved in the pathophysiologic adaptation to hypoxia. Our hypothesis centers on hypoxia as the major stressor initiating cellular plasticity and restoring normoxia is an essential step in the healing process. This theory could be tested using chronic pathological processes in animal models whereby achieving an adequate cellular oxygen level could improve or halt both plastic change and diseases.

The Epigenesis of Salivary Glands Carcinoma: From Field Cancerization to Carcinogenesis

Salivary gland carcinomas (SGCs) are a diverse collection of malignant tumors with marked differences in biological activity, clinical presentation and microscopic appearance. Although the etiology is varied, secondary radiation, oncogenic viruses as well as chromosomal rearrangements have all been linked to the formation of SGCs. Epigenetic modifications may also contribute to the genesis and progression of SGCs. Epigenetic modifications are any heritable changes in gene expression that are not caused by changes in DNA sequence. It is now widely accepted that epigenetics plays an important role in SGCs development. A basic epigenetic process that has been linked to a variety of pathological as well as physiological conditions including cancer formation, is DNA methylation. Transcriptional repression is caused by CpG islands hypermethylation at gene promoters, whereas hypomethylation causes overexpression of a gene. Epigenetic changes in SGCs have been identified, and they have been linked to the genesis, progression as well as prognosis of these neoplasms. Thus, we conduct a thorough evaluation of the currently known evidence on the involvement of epigenetic processes in SGCs.