CD4FOXP3Exon2 regulatory T cell frequency predicts breast cancer prognosis and survival.

CD4FOXP3 regulatory T cells (T) suppress immune responses to tumors, and their accumulation in the tumor microenvironment (TME) correlates with poor clinical outcome in several cancers, including breast cancer (BC). However, the properties of intratumoral T remain largely unknown. Here, we found that a functionally distinct subpopulation of T, expressing the FOXP3 Exon2 splicing variants, is prominent in patients with hormone receptor-positive BC with poor prognosis.

L-Arginine supplementation as mitochondrial therapy in diabetic cardiomyopathy.

In patients with type II diabetes, the development of diabetic cardiomyopathy (DC) is associated with a high risk of mortality. Left ventricular hypertrophy, diastolic dysfunction, and exercise intolerance are the first signs of DC. The underlying mechanisms are not fully elucidated, and there is an urgent need for specific biomarkers and molecular targets for early diagnosis and treatment.

Targeting shared pathways in tauopathies and age-related macular degeneration: implications for novel therapies.

The intricate parallels in structure and function between the human retina and the central nervous system designate the retina as a prospective avenue for understanding brain-related processes. This review extensively explores the shared physiopathological mechanisms connecting age-related macular degeneration (AMD) and proteinopathies, with a specific focus on tauopathies. The pivotal involvement of oxidative stress and cellular senescence emerges as key drivers of pathogenesis in both conditions.

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Adeno-Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis.

Objective: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in patients with SSc. Because PDGFRα is targeted by the adeno-associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFRα exposing epitopes that may induce the immune responses to the virus-PDGFRα complex.

Glaucoma as a Tauopathy-Is It the Missing Piece in the Glaucoma Puzzle?

Glaucoma is a chronic neurodegenerative disorder affecting the visual system which can result in vision loss and blindness. The pathogenetic mechanisms underlying glaucomatous optic neuropathy are ultimately enigmatic, prompting ongoing investigations into its potential shared pathogenesis with other neurodegenerative neurological disorders. Tauopathies represent a subclass of neurodegenerative diseases characterized by the abnormal deposition of tau protein within the brain and consequent microtubule destabilization.

ATM inhibition blocks glucose metabolism and amplifies the sensitivity of resistant lung cancer cell lines to oncogene driver inhibitors.

Background: ATM is a multifunctional serine/threonine kinase that in addition to its well-established role in DNA repair mechanisms is involved in a number of signaling pathways including regulation of oxidative stress response and metabolic diversion of glucose through the pentose phosphate pathway. Oncogene-driven tumorigenesis often implies the metabolic switch from oxidative phosphorylation to glycolysis which provides metabolic intermediates to sustain cell proliferation. The aim of our study is to elucidate the role of ATM in the regulation of glucose metabolism in oncogene-driven cancer cells and to test whether ATM may be a suitable target for anticancer therapy.

Specific Methyl-CpG Configurations Define Cell Identity through Gene Expression Regulation.

Cell identity is determined by the chromatin structure and profiles of gene expression, which are dependent on chromatin accessibility and DNA methylation of the regions critical for gene expression, such as enhancers and promoters. These epigenetic modifications are required for mammalian development and are essential for the establishment and maintenance of the cellular identity. DNA methylation was once thought to be a permanent repressive epigenetic mark, but systematic analyses in various genomic contexts have revealed a more dynamic regulation than previously thought.

Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage.

The Thyroid Hormone (TH) activating enzyme, type 2 Deiodinase (D2), is functionally required to elevate the TH concentration during cancer progression to advanced stages. However, the mechanisms regulating D2 expression in cancer still remain poorly understood. Here, we show that the cell stress sensor and tumor suppressor p53 silences D2 expression, thereby lowering the intracellular THs availability.

Inflammation and DNA damage: cause, effect or both.

Inflammation is a biological response involving immune cells, blood vessels and mediators induced by endogenous and exogenous stimuli, such as pathogens, damaged cells or chemicals. Unresolved (chronic) inflammation is characterized by the secretion of cytokines that maintain inflammation and redox stress. Mitochondrial or nuclear redox imbalance induces DNA damage, which triggers the DNA damage response (DDR) that is orchestrated by ATM and ATR kinases, which modify gene expression and metabolism and, eventually, establish the senescent phenotype.

A novel workflow for the qualitative analysis of DNA methylation data.

DNA methylation is an epigenetic modification that plays a pivotal role in major biological mechanisms, such as gene regulation, genomic imprinting, and genome stability. Different combinations of methylated cytosines for a given DNA locus generate different epialleles and alterations of these latter have been associated with several pathological conditions. Existing computational methods and statistical tests relevant to DNA methylation analysis are mostly based on the comparison of average CpG sites methylation levels and they often neglect non-CG methylation.

Epigenetics: An opportunity to shape innate and adaptive immune responses.

Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post-translational modifications and the regulation of chromatin accessibility by non-coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental-driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage-specific transcription factors and maintenance of cell type-specific epigenetic modifications, referred to as 'epigenetic memory', dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells.

A rapid and inexpensive genotyping method using dried blood spots for mutational analysis in a mutant mouse model: an update.

Background: Dried blood spot (DBS) testing is a well-known method of bio-sampling by which blood samples are blotted and dried on filter paper. The dried samples can then be analyzed by several techniques such as DNA amplification and HPLC. We have developed a non-invasive sampling followed by an alternative protocol for genomic DNA extraction from a drop of blood adsorbed on paper support.

Therapeutic opportunities to modulate immune tolerance through the metabolism-chromatin axis.

The ability of the immune system to discriminate external stimuli from self-components - namely immune tolerance - occurs through a coordinated cascade of events involving a dense network of immune cells. Among them, CD4CD25 T regulatory cells are crucial to balance immune homeostasis and function. Growing evidence supports the notion that energy metabolites can dictate T cell fate and function via epigenetic modifications, which affect gene expression without altering the DNA sequence.

Epigenome Chaos: Stochastic and Deterministic DNA Methylation Events Drive Cancer Evolution.

Cancer evolution is associated with genomic instability and epigenetic alterations, which contribute to the inter and intra tumor heterogeneity, making genetic markers not accurate to monitor tumor evolution. Epigenetic changes, aberrant DNA methylation and modifications of chromatin proteins, determine the "epigenome chaos", which means that the changes of epigenetic traits are randomly generated, but strongly selected by deterministic events. Disordered changes of DNA methylation profiles are the hallmarks of all cancer types, but it is not clear if aberrant methylation is the cause or the consequence of cancer evolution.

Tracing and tracking epiallele families in complex DNA populations.

DNA methylation is a stable epigenetic modification, extremely polymorphic and driven by stochastic and deterministic events. Most of the current techniques used to analyse methylated sequences identify methylated cytosines (mCpGs) at a single-nucleotide level and compute the average methylation of CpGs in the population of molecules. Stable epialleles, i.

Methylation of the Suppressor Gene : Mechanism and Consequences.

Tumor suppressor genes in the locus (, , and ) function as biological barriers to transformation and are the most frequently silenced or deleted genes in human cancers. This gene silencing frequently occurs due to DNA methylation of the promoter regions, although the underlying mechanism is currently unknown. We present evidence that methylation of promoter is associated with DNA damage caused by interference between transcription and replication processes.

ROS in cancer therapy: the bright side of the moon.

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells.

RNA Stabilizes Transcription-Dependent Chromatin Loops Induced By Nuclear Hormones.

We show that transcription induced by nuclear receptors for estrogen (E) or retinoic acid (RA) is associated with formation of chromatin loops that juxtapose the 5' end (containing the promoter) with the enhancer and the 3' polyA addition site of the target gene. We find three loop configurations which change as a function of time after induction: 1. RA or E-induced loops which connect the 5' end, the enhancer and the 3' end of the gene, and are stabilized by RNA early after induction; 2.

EGFR activation triggers cellular hypertrophy and lysosomal disease in NAGLU-depleted cardiomyoblasts, mimicking the hallmarks of mucopolysaccharidosis IIIB.

Mucopolysaccharidosis (MPS) IIIB is an inherited lysosomal storage disease caused by the deficiency of the enzyme α-N-acetylglucosaminidase (NAGLU) required for heparan sulfate (HS) degradation. The defective lysosomal clearance of undigested HS results in dysfunction of multiple tissues and organs. We recently demonstrated that the murine model of MPS IIIB develops cardiac disease, valvular abnormalities, and ultimately heart failure.

Non-homologous end joining induced alterations in DNA methylation: A source of permanent epigenetic change.

In addition to genetic mutations, epigenetic revision plays a major role in the development and progression of cancer; specifically, inappropriate DNA methylation or demethylation of CpG residues may alter the expression of genes that promote tumorigenesis. We hypothesize that DNA repair, specifically the repair of DNA double strand breaks (DSB) by Non-Homologous End Joining (NHEJ) may play a role in this process. Using a GFP reporter system inserted into the genome of HeLa cells, we are able to induce targeted DNA damage that enables the cells, after successfully undergoing NHEJ repair, to express WT GFP.

High-coverage methylation data of a gene model before and after DNA damage and homologous repair.

Genome-wide methylation analysis is limited by its low coverage and the inability to detect single variants below 10%. Quantitative analysis provides accurate information on the extent of methylation of single CpG dinucleotide, but it does not measure the actual polymorphism of the methylation profiles of single molecules. To understand the polymorphism of DNA methylation and to decode the methylation signatures before and after DNA damage and repair, we have deep sequenced in bisulfite-treated DNA a reporter gene undergoing site-specific DNA damage and homologous repair.