Targeting the 3D genome by anthracyclines for chemotherapeutic effects.

The chromatins are folded into three-dimensional (3D) structures inside cells, which coordinates the regulation of gene transcription by the non-coding regulatory elements. Aberrant chromatin 3D folding has been shown in many diseases, such as acute myeloid leukemia (AML), and may contribute to tumorigenesis. The anthracycline topoisomerase II inhibitors can induce histone eviction and DNA damage. We performed genome-wide high-resolution mapping of the chemotherapeutic effects of various clinically used anthracycline drugs. ATAC-seq was used to profile the histone eviction effects of different anthracyclines. TOP2A ChIP-seq was used to profile the potential DNA damage regions. Integrated analyses show that different anthracyclines have distinct target selectivity on epigenomic regions, based on their respective ATAC-seq and ChIP-seq profiles. We identified the underlying molecular mechanism that unique anthracycline variants selectively target chromatin looping anchors via disrupting CTCF binding, suggesting an additional potential therapeutic effect on the 3D genome. We further performed Hi-C experiments, and data from K562 cells treated with the selective anthracycline drugs indicate that the 3D chromatin organization is disrupted. Furthermore, AML patients receiving anthracycline drugs showed altered chromatin structures around potential looping anchors, which linked to distinct clinical outcomes. Our data indicate that anthracyclines are potent and selective epigenomic targeting drugs and can target the 3D genome for anticancer therapy, which could be used for personalized medicine to treat tumors with aberrant 3D chromatin structures.

Clinical management of active bleeding: what the emergency radiologist needs to know.

Active bleeding is a clinical emergency that often requires swift action driven by efficient communication. Extravasation of intravenous (IV) contrast on computed tomography (CT) is a hallmark of active hemorrhage. This can be seen on exams performed for a variety of indications and can occur anywhere in the body. As both traumatic and non-traumatic etiologies of significant blood loss are clinical emergencies, exams demonstrating active bleeding are often performed in emergency departments and read by emergency radiologists. Prompt communication of these findings to the appropriate emergency medicine and surgical providers is crucial. Although many types of active hemorrhage can be managed by interventional radiology techniques, endoscopic and surgical management or clinical observation may be appropriate in certain cases. To facilitate optimal care, it is important for emergency radiologists to understand the scope of indications for embolization of bleeding by interventional radiologists (IR) and when an IR consultation is warranted. Similarly, timely comprehensive diagnostic radiology reporting including pertinent positive and negative findings tailored for IR colleagues can expedite the appropriate intervention.

A brain-wide solute transport model of the glymphatic system.

Brain waste is largely cleared via diffusion and advection in cerebrospinal fluid (CSF). CSF flows through a pathway referred to as the glymphatic system, which is also being targeted for delivering drugs to the brain. Despite the importance of solute transport, no brain-wide models for predicting clearance and delivery through perivascular pathways and adjacent parenchyma existed. We devised such a model by upgrading an existing model of CSF flow in the mouse brain to additionally solve advection-diffusion equations, thereby estimating solute transport. We simulated steady-state transport of 3 kDa dextran injected proximal to the perivascular space (PVS) of the middle cerebral artery, mimicking in vivo experiments. We performed a sensitivity analysis of 11 biological properties of PVSs and brain parenchyma by repeatedly simulating solute transport with varying parameter values. Parameter combinations that led to a large total pressure gradient, poor CSF perfusion or a steep solute gradient were deemed unrealistic. Solute concentrations in parenchyma were most sensitive to changes in pial PVS size, as this parameter linearly affects volume flow rates. We also found that realistic transport requires both highly permeable penetrating PVSs and high-resistance parenchyma. This study highlights the potential of brain-wide models to provide insights into solute transport processes.

Reflection function, reflectance, and area function measurements in ears of children and adults.

The main experiment concerned time-domain measurements of the acoustical reflection function (RF) of the human ear in adults and children (aged 5 to 8 years) using a probe inserted into the ear canal. This RF was used to calculate the area function of the ear canal versus distance along its centerline. Acoustical reflectance was calculated in the frequency domain from the RF, as was the difference in sound pressure level near the tympanic membrane relative to the probe tip. Group responses in area function, total ear-canal length, absorbance and group delay, and admittance magnitude and phase were analyzed based on sex, ear, and age. Responses were compared between children/adults and younger/older adults relative to age 50 years. Ear and sex were never significant. Significant differences were observed in children compared to adults in the area function, absorbance and group delay, and admittance magnitude and phase (0.25-4 kHz). Group delay differed between younger and older adults. A second experiment assessed level dependence of responses to better understand limitations in probe performance observed in the main experiment. These results show the utility of time-domain measurements of the area function and derived reflectance to understand sound-transmission differences across age at frequencies important to middle-ear function.

Mitochondrial DNA patterns describe the evolutionary history of the bonnethead shark Sphyrna tiburo (Linneus 1758) complex in the western Atlantic Ocean.

The apparent lack of physical barriers in the marine realm has created the conception that many groups have a constant gene flow. However, changes in ocean circulation patterns, glacial cycles, temperature, and salinity gradients are responsible for vicariant events in many fish species, including sharks. The bonnethead shark, Sphyrna tiburo, is an endangered small coastal shark species. Although considerable efforts have recently been undertaken, little remains known about the possible biogeographic scenario that can explain its actual distribution within the western Atlantic (WA). Here, we used 599 mitochondrial sequences to assess the phylogeographic structure and implement Bayesian phylogenetic analyses to obtain divergence times and reconstruct the ancestral geographic range. This allowed us to infer processes responsible for the diversification of S. tiburo into major divergent lineages. Our results indicated that S. tiburo in the WA represents three independent lineages, with Brazilian samples differentiated into a distinct genetic cluster. The posterior probability of ancestral range analysis indicated that the species likely originated in the northern region (Carolina Province and the southern Gulf of Mexico), where it colonized southward through the uplifting of the Central American Isthmus (CAI). The Northern and Caribbean genetic clusters appear to have arisen from the intensification of the Loop Current, which currently flows northward passing the Yucatan Peninsula, Gulf of Mexico, and east Florida. Following initial colonization, the Northeastern Brazil group differentiated from the Caribbean region due to the sediment and freshwater discharge of the Amazon-Orinoco Plume. Thus, the evolutionary history of the S. tiburo complex can be explained by a combination of dispersal and vicariance events that occurred over the last ~5 million years (MY). We established and confirmed the species and population limits, demonstrating that the Amazon-Orinoco Plume constitutes a significant dispersal barrier for coastal sharks. Finally, we discuss some recommendations for the conservation of the bonnethead shark.

The Significance of Intracellular versus Extracellular Calcium Pyrophosphate Crystals in Diagnosing Calcium Pyrophosphate Crystal Arthritis.

OBJECTIVE: Acute and chronic calcium pyrophosphate (CPP) crystal arthritis is characterised by the presence of synovial CPP crystals within a clinically inflamed joint. CPP crystals may be situated intracellularly or extracellularly, however the clinical significance of their location remains under studied. The objective of this retrospective cohort study was to assess the relevance of the CPP crystal location in diagnosing acute/chronic CPP crystal arthritis. METHODS: Data was collected from Waikato District Health Board to identify a study population with synovial fluid samples positive for CPP crystals. The cohort was stratified into two groups based on crystal location: intracellular and extracellular. The proportion of acute/chronic CPP crystal arthritis cases were compared between these groups. Acute/chronic CPP crystal arthritis was diagnosed when synovial CPP crystals were present, with objective evidence of joint inflammation and no other alternative diagnosis. Further analysis was made with respect to demographics, other laboratory results and cartilage calcification. RESULTS: This study included 134 patients, 108 with intracellular CPP crystals and 26 with extracellular CPP crystals. Acute/chronic CPP crystal arthritis was diagnosed in 85% of the intracellular and 50% of the extracellular group (p<0.001). Following exclusion of the septic arthritis cases, acute/chronic CPP crystal arthritis was diagnosed in 97% of the intracellular and 62% of the extracellular group (p<0.001). CONCLUSION: The presence of intracellular CPP crystals is more strongly associated with acute/chronic CPP crystal arthritis, whereas an extracellular CPP crystal location appears less specific.

Landscape Homogeneity May Drive the Distribution of Koala Vehicle Collisions on a Major Highway in the Clarke-Connors Range in Central Queensland, Australia.

After the loss and fragmentation of habitat, vehicle collisions are one of the main threats to the long-term survival of wild koalas. Koala road strike data were analysed for a section of the Peak Downs Highway between Nebo and Spencer's Gap, west of Mackay, Queensland, Australia. The analysis was carried out on 345 records (October 2014 to November 2023), and results suggested the spatial distribution of koala road strike followed a random pattern along this section of the highway, assuming a Poisson point pattern on a linear network. An analysis of the candidate predictors of koala vehicle collisions, including habitat and road variables, found that the amount of high-quality koala habitat (as defined by the local koalas' tree species preference) present and the driver visibility were the only significant predictors. The relative homogeneity of landuse and vegetation across this landscape may mean that koalas do not concentrate at specific crossing points. More research, including detailed habitat mapping, is needed into this population, which currently lacks government and conservation attention, to inform mitigation efforts and reduce mortality rates for this potentially nationally significant population.

Facial growth parameters in Down syndrome: Review of the literature and forensic application for missing persons age progression.

PURPOSE: Individuals with Down syndrome (DS) show growth trajectories which deviate from standard ones due to variations in the growth of facial structures. Studying the effect of aging on the faces of DS individuals is necessary to obtain an accurate result through age progression, a technique based on the study of physiognomic features and used in cases of missing persons. Here we present scientific publications that delve into the rhythms of aging and morphological characteristics of facial features in DS individuals to enable appropriate age progression in cases of missing DS individuals. RESULTS: The scientific literature considered in this review studies the growth of soft tissue and bone substrate by comparing standard growth values with those measured through anthropometric measurements of individuals with DS. Growth trajectories are described by considering morphological trends both by comparing standard values with those found in individuals with DS and by observing individual physiognomic traits. CONCLUSIONS: When a young individual with DS goes missing, the realization of an age progression requires knowledge of the aging dynamics peculiar to the DS face. Therefore, physical, cognitive, and clinical factors must be considered. Delayed physical development and early aging, such as the onset of puberty and weight gain, have an important impact on the realization of age progression. In fact, depending on the life period to be considered, the effects of aging must be calibrated based on the knowledge gathered from scientific research.

Deciphering the functional impact of Alzheimer's Disease-associated variants in resting and proinflammatory immune cells.

Genome-wide association studies have identified loci associated with Alzheimer's Disease (AD), but identifying the exact causal variants and genes at each locus is challenging due to linkage disequilibrium and their largely non-coding nature. To address this, we performed a massively parallel reporter assay of 3,576 AD-associated variants in THP-1 macrophages in both resting and proinflammatory states and identified 47 expression-modulating variants (emVars). To understand the endogenous chromatin context of emVars, we built an activity-by-contact model using epigenomic maps of macrophage inflammation and inferred condition-specific enhancer-promoter pairs. Intersection of emVars with enhancer-promoter pairs and microglia expression quantitative trait loci allowed us to connect 39 emVars to 76 putative AD risk genes enriched for AD-associated molecular signatures. Overall, systematic characterization of AD-associated variants enhances our understanding of the regulatory mechanisms underlying AD pathogenesis.

B Cells Influence Encephalitogenic T Cell Frequency to Myelin Oligodendrocyte Glycoprotein (MOG)38-49 during Full-length MOG Protein-Induced Demyelinating Disease.

Although T cells are encephalitogenic during demyelinating disease, B cell-depleting therapies are a successful treatment for patients with multiple sclerosis. Murine models of demyelinating disease utilizing myelin epitopes, such as myelin oligodendrocyte glycoprotein (MOG)35-55, induce a robust CD4 T cell response but mitigate the contribution of pathological B cells. This limits their efficacy for investigating how B cell depletion affects T cells. Furthermore, induction of experimental autoimmune encephalomyelitis with a single CD4 T cell epitope does not reflect the breadth of epitopes observed in the clinic. To better model the adaptive immune response, mice were immunized with the full-length MOG protein or the MOG1-125 extracellular domain (ECD) and compared with MOG35-55. Mature MOG-reactive B cells were generated only by full-length MOG or ECD. The CNS-localized T cell response induced by full-length MOG is characterized by a reduction in frequency and the percentage of low-affinity T cells with reactivity toward the core epitope of MOG35-55. B cell depletion with anti-CD20 before full-length MOG-induced, but not ECD-induced, demyelinating disease restored T cell reactivity toward the immunodominant epitope of MOG35-55, suggesting the B cell-mediated control of encephalitogenic epitopes. Ultimately, this study reveals that anti-CD20 treatment can influence T cell epitopes found in the CNS during demyelinating disease.

What R Mandarin Chinese /ɹ/s? - acoustic and articulatory features of Mandarin Chinese rhotics.

Rhotic sounds are well known for their considerable phonetic variation within and across languages and their complexity in speech production. Although rhotics in many languages have been examined and documented, the phonetic features of Mandarin rhotics remain unclear, and debates about the prevocalic rhotic (the syllable-onset rhotic) persist. This paper extends the investigation of rhotic sounds by examining the articulatory and acoustic features of Mandarin Chinese rhotics in prevocalic, syllabic (the rhotacized vowel [ɚ]), and postvocalic (r-suffix) positions. Eighteen speakers from Northern China were recorded using ultrasound imaging. Results showed that Mandarin syllabic and postvocalic rhotics can be articulated with various tongue shapes, including tongue-tip-up retroflex and tongue-tip-down bunched shapes. Different tongue shapes have no significant acoustic differences in the first three formants, demonstrating a many-to-one articulation-acoustics relationship. The prevocalic rhotics in our data were found to be articulated only with bunched tongue shapes, and were sometimes produced with frication noise at the start. In general, rhotics in all syllable positions are characterized by a close F2 and F3, though the prevocalic rhotic has a higher F2 and F3 than the syllabic and postvocalic rhotics. The effects of syllable position and vowel context are also discussed.

Departure Decisions: Exit Survey of Family Medicine Residency Directors.

Background and Objectives: Program director (PD) tenure, continuity, and stability may enhance residency program quality, yet many PDs do not stay long in their positions. No prior study has taken a comprehensive census of departing PDs to determine reasons for leaving the role. This study aimed to survey all exiting family medicine (FM) PDs to identify decision factors contributing to their departure. Methods: From October 2021 to October 2022, we sent a web-based exit survey to all departing FM PDs. The survey asked departing PDs to rate the strength of 36 factors in the decision to exit the PD role in terms of job satisfaction, accomplishments, career choices, workload, preparation, expectations, and support. We used the Fisher exact test to assess all 36 decision factors and PD characteristics for significant associations with shorter or longer PD tenures. Results: PDs submitted 73 surveys out of 109 invitations (67.0% response). We analyzed 68 with complete data. The median PD tenure was 5.6 years (mean 6.9 years). Most respondents (66/68, 97.1%) identified three or more strong factors in their decision to leave. The strongest factors reflected stable residency programs, an established succession plan, a desire for more personal/family time, and a sense that the time was right. PDs with tenures longer than 3 years were more likely to have completed the National Institute for Program Director Development (P=.001). Conclusions: PDs leave the position for multiple reasons, often positive, and not necessarily due to lack of support and preparation. Further exploration of decision factors may inform strategies to support PDs in their positions.

Asymptomatic carriage of Plasmodium falciparum in children living in a hyperendemic area occurs independently of IgG responses but is associated with a balanced inflammatory cytokine ratio.

BACKGROUND: Asymptomatic carriage of infected red blood cells (iRBCs) can be prevalent in communities regardless of transmission patterns and can occur with infection of different Plasmodium species. Clinical immunity dampens the inflammatory responses leading to disease symptoms in malaria. The aim of this study was to define the immunological correlates of asymptomatic carriage of Plasmodium falciparum in a highly exposed population. METHODS: 142 asymptomatic Plasmodium-infected individuals greater than 2 years of age without fever (body temperature <37.5 ℃) were followed weekly for 10 weeks before being treated with artemisinin-based combination therapy (ACT). Plasma levels of 38 cytokines were measured at baseline by Luminex and the quantity and growth inhibitory activities of circulating parasite-reactive antibodies measured. The Plasmodium antigen tested included P. falciparum merozoite extract (ME) and schizont extract (SE), and the recombinant proteins erythrocyte binding antigen 175 (EBA-175) and merozoite surface protein 1 (MSP-119). RESULTS: Median levels of IgG against P. falciparum EBA-175 and MSP-119 at baseline were significantly higher in those older than 20 years of age compared with the younger age group and appeared to correlate with better parasite control. Amongst all participants there were no discernible changes in IgG levels over time. Parasite density was higher in the younger age group and associated with IL-10, TNF and MCP-1 levels. A balanced IL-10:TNF ratio was associated with asymptomatic malaria regardless of age, and balanced ratios of IL-10/TNF and IL-10/IFN-γ were the only significant correlate of maintenance of asymptomatic malaria over the course of the study in individuals 20 years of age and younger. CONCLUSION: The above findings indicate that asymptomatic carriage of P. falciparum in children living in a hyperendemic area occurs independently of IgG but is associated with a balanced inflammatory cytokine ratio.

On the binding of auranofin to Prdx6 and its potential role in cancer cell sensitivity to treatment.

In this study, we demonstrate that ferroptosis is a component of the cell death mechanism induced by auranofin in HT-1080 cells, in contrast to the gold(III) compounds [Au(phen)Cl2]PF6 and [Au(bnpy)Cl2]. Additionally, we identify a potential role of Prdx6 in modulating the sensitivity of A-375 cells to auranofin treatment, whereas the gold(III) compounds evaluated here exhibit Prdx6-independent cytotoxicity. Finally, using mass spectrometry, we show that auranofin binds selectively to the catalytic Cys47 residue of Prdx6 in vitro under acidic conditions. No binding was observed with the C47S mutant or at neutral pH.

Nandrolone Abuse Prior to Head Trauma Mitigates Endoplasmic Reticulum Stress, Mitochondrial Bioenergetic Deficits, and Markers of Neurodegeneration.

The abuse of synthetic steroids, such as nandrolone decanoate (ND), is often associated with violent behavior, increasing the risk of traumatic brain injury (TBI). After a TBI, proteins like APP, ß-amyloid peptide-42 (Aß42), and phosphorylated tau (pTau) accumulate and trigger endoplasmic reticulum (ER) stress associated with an unfolded protein response (UPR). The involvement of mitochondrial bioenergetics in this context remains unexplored. We interrogate whether the abuse of ND before TBI alters the responses of ER stress and mitochondrial bioenergetics in connection with neurodegeneration and memory processing in mice. Male CF1 adult mice were administered ND (15 mg/kg) or vehicle (VEH) s.c. for 19 days, coinciding with the peak day of aggressive behavior, and then underwent cortical controlled impact (CCI) or sham surgery. Spatial memory was assessed through the Morris water maze task (MWM) post-TBI. In synaptosome preparations, i) we challenged mitochondrial complexes (I, II, and V) in a respirometry assay, employing metabolic substrates, an uncoupler, and inhibitors; and ii) assessed molecular biomarkers through Western blot. TBI significantly increased APP, Aß42, and pTauSer396 levels, along with ER-stress proteins, GRP78, ATF6, and CHOP, implying it primed apoptotic signaling. Concurrently, TBI reduced mitochondrial Ca2+ efflux in exchange with Na+, disturbed the formation/dissipation of membrane potential, increased H2O2 production, decreased biogenesis (PGC-1⍺ and TOM20), and ATP biosynthesis coupled with oxygen consumption. Unexpectedly, ND abuse before TBI attenuated the elevations in APP, Aß42, and pTauSer396, accompanied by a decrease in GRP78, ATF6, and CHOP levels, and partial normalization of mitochondrial-related endpoints. A principal component analysis revealed a key hierarchical signature featuring mitochondrial Ca2+ efflux, CHOP, GRP78, TOM20, H2O2, and bioenergetic efficiency as a unique variable (PC1) able to explain the memory deficits caused by TBI, as well as the preservation of memory fitness induced by prior ND abuse.

Forensic International Dental Database (FIDBv2) for adult age-at-death estimation in multiple forensic contexts: Strengthening the operationalization of the Lamendin criteria in a global scope model.

The aim of this study is to validate the FIDBv2 online procedure for adult age-at-death estimation using root dentine translucency (RDT) and periodontal retraction (PR) of single-rooted teeth in a worldwide sample. The sample includes 4810 teeth of 2559 individuals from 16 countries of America, Europe and Asia. Bias and inaccuracy between documented (DA) and estimated ages (EA) were calculated. Pearson and Intraclass Correlation Coefficients were computed to assess the strength of agreement between pairs of data, while Kolmogorov-Smirnov Z was used to evaluate the statistical significance of the differences. The percentages of correctly estimated cases within different age ranges were obtained to find trends in the reliability of the results. Most of the biases (-4.61-1.31 years) and inaccuracies (4.81-9.72 years) are low. The dispersion of EA increases with age and almost all the DA-EA correlations are above 0.75. DA-RDT and DA-PR correlations are positive, most of the former being high (0.74-0.91), and the latter being low (0.11-0.54). The highest percentages of correct estimations are identified for the ±7.5 and ±10 years ranges, and most comparisons of bias and inaccuracy between countries are non-significant. The high correlations between DA and EA suggest that the method is robust and reliable for a global application. Mean errors are low, with the best results found in the 30-69-year-old cohort. This research supports that the method is effective and accurate for age estimation in forensic contexts worldwide, thus reaffirming it is a generalizable procedure locally and internationally.

Restoration of cervical lymphatic vessel function in aging rescues cerebrospinal fluid drainage.

Cervical lymphatic vessels (cLVs) have been shown to drain solutes and cerebrospinal fluid (CSF) from the brain. However, their hydrodynamical properties have never been evaluated in vivo. Here, we developed two-photon optical imaging with particle tracking in vivo of CSF tracers (2P-OPTIC) in superficial and deep cLVs of mice, characterizing their flow and showing that the major driver is intrinsic pumping by contraction of the lymphatic vessel wall. Moreover, contraction frequency and flow velocity were reduced in aged mice, which coincided with a reduction in smooth muscle actin expression. Slowed flow in aged mice was rescued using topical application of prostaglandin F2α, a prostanoid that increases smooth muscle contractility, which restored lymphatic function in aged mice and enhanced central nervous system clearance. We show that cLVs are important regulators of CSF drainage and that restoring their function is an effective therapy for improving clearance in aging.

Second language learning in older adults modulates Stroop task performance and brain activation.

Introduction: Numerous studies have highlighted cognitive benefits in lifelong bilinguals during aging, manifesting as superior performance on cognitive tasks compared to monolingual counterparts. Yet, the cognitive impacts of acquiring a new language in older adulthood remain unexplored. In this study, we assessed both behavioral and fMRI responses during a Stroop task in older adults, pre- and post language-learning intervention. Methods: A group of 41 participants (age:60-80) from a predominantly monolingual environment underwent a four-month online language course, selecting a new language of their preference. This intervention mandated engagement for 90 minutes a day, five days a week. Daily tracking was employed to monitor progress and retention. All participants completed a color-word Stroop task inside the scanner before and after the language instruction period. Results: We found that performance on the Stroop task, as evidenced by accuracy and reaction time, improved following the language learning intervention. With the neuroimaging data, we observed significant differences in activity between congruent and incongruent trials in key regions in the prefrontal and parietal cortex. These results are consistent with previous reports using the Stroop paradigm. We also found that the amount of time participants spent with the language learning program was related to differential activity in these brain areas. Specifically, we found that people who spent more time with the language learning program showed a greater increase in differential activity between congruent and incongruent trials after the intervention relative to before. Discussion: Future research is needed to determine the optimal parameters for language learning as an effective cognitive intervention for aging populations. We propose that with sufficient engagement, language learning can enhance specific domains of cognition such as the executive functions. These results extend the understanding of cognitive reserve and its augmentation through targeted interventions, setting a foundation for future investigations.

CRISPR Screening of Transcribed Super-Enhancers Identifies Drivers of Triple-Negative Breast Cancer Progression.

Triple-negative breast cancer (TNBC) is the most therapeutically recalcitrant form of breast cancer, which is due in part to the paucity of targeted therapies. A systematic analysis of regulatory elements that extend beyond protein coding genes could uncover avenues for therapeutic intervention. To this end, we analyzed the regulatory mechanisms of TNBC-specific transcriptional enhancers together with their non-coding enhancer RNA (eRNA) transcripts. The functions of the top 30 eRNA-producing super-enhancers were systematically probed using high-throughput CRISPR-interference assays coupled to RNA-seq that enabled unbiased detection of target genes genome-wide. Generation of high resolution Hi-C chromatin interaction maps enabled annotation of the direct target genes for each super-enhancer, which highlighted their proclivity for genes that portend worse clinical outcomes in TNBC patients. Illustrating the utility of this dataset, deletion of an identified super-enhancer controlling the nearby PODXL gene or specific degradation of its enhancer RNAs led to profound inhibitory effects on target gene expression, cell proliferation, and migration. Furthermore, loss of this super-enhancer suppressed tumor growth and metastasis in TNBC mouse xenograft models. Single-cell RNA-seq and ATAC-seq analyses demonstrated the enhanced activity of this super-enhancer within the malignant cells of TNBC tumor specimens compared to non-malignant cell types. Collectively, this work examines several fundamental questions about how regulatory information encoded into eRNA-producing super-enhancers drives gene expression networks that underlie the biology of triple-negative breast cancer.