Mutational landscape of pure ductal carcinoma in situ and associations with disease prognosis and response to radiotherapy.

Background: Managing Ductal Carcinoma in Situ (DCIS) remains challenging due to the lack of reliable biomarkers to predict radiotherapy (RT) response, leading to both overtreatment of indolent disease and undertreatment of aggressive cases.

Results: Through whole-exome sequencing of 147 DCIS cases, we characterized the genomic landscape of pure DCIS and identified genetic alterations associated with the risk of recurrence, either in-situ or invasive. DCIS lesions harbored frequent mutations in established cancer drivers (PIK3CA, TP53) and genes regulating tissue architecture, which likely enhanced pre-invasive cell fitness but lacked prognostic value.

Transcriptomic Features of Recurrence Rates in Idiopathic Subglottic Stenosis.

Objective: Idiopathic subglottic stenosis (iSGS) is a rare disease characterized by narrowing of the upper airway and affects near-exclusively females. Patients often experience recurrent disease and require repeated surgical dilations. The pathophysiology underlying the broad spectrum of disease severity within iSGS remains unknown.

Effect of Serial Intralesional Steroid Injections on Risk of Recurrence in Idiopathic Subglottic Stenosis.

Background: Serial intralesional steroid injections (ILSIs) have been suggested to be an effective adjunct treatment for idiopathic subglottic stenosis (iSGS) by maintaining airway patency and extending inter-surgical intervals. However, evidence for the effectiveness of serial ILSIs remains inconclusive. The current study aimed to assess whether ILSIs reduce the risk of subsequent surgical dilation (i.

Determining the effects of paternal obesity on sperm chromatin at histone H3 lysine 4 tri-methylation in relation to the placental transcriptome and cellular composition.

Paternal obesity has been implicated in adult-onset metabolic disease in offspring. However, the molecular mechanisms driving these paternal effects and the developmental processes involved remain poorly understood. One underexplored possibility is the role of paternally induced effects on placenta development and function.

The Association between Long-Term DDT or DDE Exposures and an Altered Sperm Epigenome-a Cross-Sectional Study of Greenlandic Inuit and South African VhaVenda Men.

Background: The organochlorine dichlorodiphenyltrichloroethane (DDT) is banned worldwide owing to its negative health effects. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the Arctic, where its endocrine disrupting metabolite, dichlorodiphenyldichloroethylene (DDE) accumulates in marine mammals and fish.

Systemic and intrinsic functions of ATRX in glial cell fate and CNS myelination in male mice.

Myelin, an extension of the oligodendrocyte plasma membrane, wraps around axons to facilitate nerve conduction. Myelination is compromised in ATR-X intellectual disability syndrome patients, but the causes are unknown. We show that loss of ATRX leads to myelination deficits in male mice that are partially rectified upon systemic thyroxine administration.

exhibits heterogeneous and adaptive cytoprotective responses to antifungal compounds.

an opportunistic human pathogen, poses a significant threat to human health and is associated with significant socio-economic burden. Current antifungal treatments fail, at least in part, because can initiate a strong drug tolerance response that allows some cells to grow at drug concentrations above their minimal inhibitory concentration. To better characterize this cytoprotective tolerance program at the molecular single-cell level, we used a nanoliter droplet-based transcriptomics platform to profile thousands of individual fungal cells and establish their subpopulation characteristics in the absence and presence of antifungal drugs.

The multifaceted role of GCM1 during trophoblast differentiation in the human placenta.

Remodeling of the uterine vasculature by invasive extravillous trophoblasts (EVTs) is a critical aspect of human placentation. Insufficient EVT invasion can lead to severe obstetrical complications like preeclampsia, intrauterine growth restriction, and preterm birth. Glial cells missing-1 (GCM1) is a transcription factor that is crucial for proper placentation in mice, and is highly expressed in human syncytiotrophoblast (ST) and EVTs.

A Deep Learning Approach to Capture the Essence of Candida albicans Morphologies.

We present deep learning-based approaches for exploring the complex array of morphologies exhibited by the opportunistic human pathogen Candida albicans. Our system, entitled Candescence, automatically detects C. albicans cells from differential image contrast microscopy and labels each detected cell with one of nine morphologies.

Sperm histone H3 lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction.

Objective: Parental environmental exposures can strongly influence descendant risks for adult disease. How paternal obesity changes the sperm chromatin leading to the acquisition of metabolic disease in offspring remains controversial and ill-defined. The objective of this study was to assess (1) whether obesity induced by a high-fat diet alters sperm histone methylation; (2) whether paternal obesity can induce metabolic disturbances across generations; (3) whether there could be cumulative damage to the sperm epigenome leading to enhanced metabolic dysfunction in descendants; and (4) whether obesity-sensitive regions associate with embryonic epigenetic and transcriptomic profiles.

The zinc cluster transcription factor Rha1 is a positive filamentation regulator in Candida albicans.

Zinc cluster transcription factors (TFs) are essential fungal regulators of gene expression. In the pathogen Candida albicans, the gene orf19.1604 encodes a zinc cluster TF regulating filament development.

Whole-genome sequencing of H3K4me3 and DNA methylation in human sperm reveals regions of overlap linked to fertility and development.

The paternal environment has been linked to infertility and negative outcomes. Such effects may be transmitted via sperm through histone modifications. To date, in-depth profiling of the sperm chromatin in men has been limited.

ChIP-seq protocol for sperm cells and embryos to assess environmental impacts and epigenetic inheritance.

In the field of epigenetic inheritance, delineating molecular mechanisms implicated in the transfer of paternal environmental conditions to descendants has been elusive. This protocol details how to track sperm chromatin intergenerationally. We describe mouse model design to probe chromatin states in single mouse sperm and techniques to assess pre-implantation embryo chromatin and gene expression.

Signal-mediated localization of Candida albicans pheromone response pathway components.

Unlabelled: A MAPK cascade consists of three kinases, (MEKK, MEK and MAPK), that are sequentially activated in response to a stimulus and serve to transmit signals. In C. albicans and in yeast, an MAPK cascade is linked to the pheromone pathway through a scaffold protein (Cst5 and Ste5, respectively).

Modulation of the complex regulatory network for methionine biosynthesis in fungi.

The assimilation of inorganic sulfate and the synthesis of the sulfur-containing amino acids methionine and cysteine is mediated by a multibranched biosynthetic pathway. We have investigated this circuitry in the fungal pathogen Candida albicans, which is phylogenetically intermediate between the filamentous fungi and Saccharomyces cerevisiae. In S.

Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring.

A father's lifestyle impacts offspring health; yet, the underlying molecular mechanisms remain elusive. We hypothesized that a diet that changes methyl donor availability will alter the sperm and embryo epigenomes to impact embryonic gene expression and development. Here, we demonstrate that a folate-deficient (FD) diet alters histone H3 lysine 4 trimethylation (H3K4me3) in sperm at developmental genes and putative enhancers.

Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance.

Advancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer.

Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits.

ATRX gene mutations have been identified in syndromic and non-syndromic intellectual disabilities in humans. ATRX is known to maintain genomic stability in neuroprogenitor cells, but its function in differentiated neurons and memory processes remains largely unresolved. Here, we show that the deletion of neuronal Atrx in mice leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions.

Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts.

Cell fusion occurs when several cells combine to form a multinuclear aggregate (syncytium). In human placenta, a syncytialized trophoblast (syncytiotrophoblast) layer forms the primary interface between maternal and fetal tissue, facilitates nutrient and gas exchange, and produces hormones vital for pregnancy. Syncytiotrophoblast development occurs by differentiation of underlying progenitor cells called cytotrophoblasts, which then fuse into the syncytiotrophoblast layer.

The time-varying effect of radiotherapy after breast-conserving surgery for DCIS.

Background: A better understanding underlying radiation (RT) response after breast-conserving surgery (BCS) is needed to mitigate over-treatment of DCIS. The hazard ratio (HR) measures the effect of RT but assumes the effect is constant over time. We examined the hazard function adjusted for adherence to surveillance mammography to examine variations in LR risk and the effect of RT over time.

Screening of Candida albicans GRACE library revealed a unique pattern of biofilm formation under repression of the essential gene ILS1.

Candida albicans biofilm formation is governed by a regulatory circuit comprising nine transcription factors which control a network of target genes. However, there are still unknown genes contributing to biofilm features. Thus, the GRACE library was screened to identify genes involved in mature biofilm development.

Mms21: A Putative SUMO E3 Ligase in That Negatively Regulates Invasiveness and Filamentation, and Is Required for the Genotoxic and Cellular Stress Response.

In the life cycle of the fungal pathogen , the formation of filamentous cells is a differentiation process that is critically involved in host tissue invasion, and in adaptation to host cell and environmental stresses. Here, we have used the Gene Replacement And Conditional Expression library to identify genes controlling invasiveness and filamentation; conditional repression of the library revealed 69 mutants that triggered these processes. Intriguingly, the genes encoding the small ubiquitin-like modifier (SUMO) E3 ligase Mms21, and all other tested members of the sumoylation pathway, were both nonessential and capable of triggering filamentation upon repression, suggesting an important role for sumoylation in controlling filamentation in We have investigated Mms21 in detail.

Role of SUMOylation in differential ERα transcriptional repression by tamoxifen and fulvestrant in breast cancer cells.

Antiestrogens (AEs) are widely used for treatment of estrogen receptor alpha (ERα)-positive breast cancer, but display variable degrees of partial agonism in estrogen target tissues and breast cancer (BC) cells. The fact that BC cells resistant to selective ER modulators (SERMs) like tamoxifen (Tam) can still be sensitive to pure AEs, also called selective ER downregulators, suggests different mechanisms of action, some of which may contribute to the more complete suppression of estrogen target genes by pure AEs. We report herein that pure AEs such as fulvestrant induce transient binding of ERα to DNA, followed by rapid release after 30-40 min without loss of nuclear localization.

Interactions between the tumor and the blood systemic response of breast cancer patients.

Although systemic immunity is critical to the process of tumor rejection, cancer research has largely focused on immune cells in the tumor microenvironment. To understand molecular changes in the patient systemic response (SR) to the presence of BC, we profiled RNA in blood and matched tumor from 173 patients. We designed a system (MIxT, Matched Interactions Across Tissues) to systematically explore and link molecular processes expressed in each tissue.

The prognostic ease and difficulty of invasive breast carcinoma.

Breast carcinoma (BC) has been extensively profiled by high-throughput technologies for over a decade, and broadly speaking, these studies can be grouped into those that seek to identify patient subtypes (studies of heterogeneity) or those that seek to identify gene signatures with prognostic or predictive capacity. The sheer number of reported signatures has led to speculation that everything is prognostic in BC. Here, we show that this ubiquity is an apparition caused by a poor understanding of the interrelatedness between subtype and the molecular determinants of prognosis.