Heterogeneity and transcriptional drivers of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.

Breast cancer prevention by short-term inhibition of TGFß signaling.

Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFß signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFß in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.

Anti-inflammaging effects of human alpha-1 antitrypsin.

Inflammaging plays an important role in most age-related diseases. However, the mechanism of inflammaging is largely unknown, and therapeutic control of inflammaging is challenging. Human alpha-1 antitrypsin (hAAT) has immune-regulatory, anti-inflammatory, and cytoprotective properties as demonstrated in several disease models including type 1 diabetes, arthritis, lupus, osteoporosis, and stroke. To test the potential anti-inflammaging effect of hAAT, we generated transgenic Drosophila lines expressing hAAT. Surprisingly, the lifespan of hAAT-expressing lines was significantly longer than that of genetically matched controls. To understand the mechanism underlying the anti-aging effect of hAAT, we monitored the expression of aging-associated genes and found that aging-induced expressions of Relish (NF-ĸB orthologue) and Diptericin were significantly lower in hAAT lines than in control lines. RNA-seq analysis revealed that innate immunity genes regulated by NF-kB were significantly and specifically inhibited in hAAT transgenic Drosophila lines. To confirm this anti-inflammaging effect in human cells, we treated X-ray-induced senescence cells with hAAT and showed that hAAT treatment significantly decreased the expression and maturation of IL-6 and IL-8, two major factors of senescence-associated secretory phenotype. Consistent with results from Drosophila,RNA-seq analysis also showed that hAAT treatment significantly inhibited inflammation related genes and pathways. Together, our results demonstrated that hAAT significantly inhibited inflammaging in both Drosophila and human cell models. As hAAT is a FDA-approved drug with a confirmed safety profile, this novel therapeutic potential may make hAAT a promising candidate to combat aging and aging-related diseases.

Polyvinylpyrrolidone-induced anisotropic growth of gold nanoprisms in plasmon-driven synthesis.

After more than a decade, it is still unknown whether the plasmon-mediated growth of silver nanostructures can be extended to the synthesis of other noble metals, as the molecular mechanisms governing the growth process remain elusive. Herein, we demonstrate the plasmon-driven synthesis of gold nanoprisms and elucidate the details of the photochemical growth mechanism at the single-nanoparticle level. Our investigation reveals that the surfactant polyvinylpyrrolidone preferentially adsorbs along the nanoprism perimeter and serves as a photochemical relay to direct the anisotropic growth of gold nanoprisms. This discovery confers a unique function to polyvinylpyrrolidone that is fundamentally different from its widely accepted role as a crystal-face-blocking ligand. Additionally, we find that nanocrystal twinning exerts a profound influence on the kinetics of this photochemical process by controlling the transport of plasmon-generated hot electrons to polyvinylpyrrolidone. These insights establish a molecular-level description of the underlying mechanisms regulating the plasmon-driven synthesis of gold nanoprisms.

Cortical processing during smartphone text messaging.

OBJECTIVE: The objective of this study was to report the EEG features of text messaging using smartphones. METHODS: One hundred twenty-nine patients were prospectively evaluated during video-EEG monitoring (VEM) over 16months. A reproducible texting rhythm (TR) present during active text messaging with a smartphone was compared with passive and forced audio telephone use, thumb/finger movements, cognitive testing/calculation, scanning eye movements, and speech/language tasks in patients with and without epilepsy. Statistical significance was set at p<0.05. RESULTS: Twenty-seven patients with a TR were identified from a cohort of 129 (93 female, mean age: 36; range: 18-71) unselected VEM patients. Fifty-three out of 129 patients had epileptic seizures (ES), 74/129 had nonepileptic seizures (NES), and 2/129 were dual-diagnosed. A reproducible TR was present in 27/129 (20.9%) specific to text messaging (p<0.0001) and present in 28% of patients with ES and 16% of patients with NES (p=NS). The TR was absent during independent tasks and audio cellular telephone use (p<0.0001). Age, gender, epilepsy type, MRI results, and EEG lateralization in patients with focal seizures were unrelated (p=NS). CONCLUSIONS: Our results suggest that the TR on scalp EEG represents a novel technology-specific neurophysiological alteration of brain networks. We propose that cortical processing in the contemporary brain is uniquely activated by the use of PEDs. SIGNIFICANCE: These findings have practical implications that could impact industry and research in nonverbal communication.

The Texting Rhythm: A Novel EEG Waveform Using Smartphones.

INTRODUCTION: We report a unique EEG phenomenon in patients with paroxysmal neurological events undergoing video EEG monitoring. METHODS: Two epilepsy centers analyzed the interictal scalp EEG in patients using personal electronic devices during epilepsy monitoring. The texting rhythm (TR) was defined as a reproducible, stimulus-evoked, generalized frontocentral monomorphic burst of 5-6 Hz theta consistently induced by active text messaging. An independent prospective and retrospective cohort was analyzed and compared from two sites in Florida and Illinois. We assessed age, gender, diagnosis, epilepsy classification, MRI, and EEG to compare patients with a TR. Analysis was performed with statistical significance set at P < 0.05. RESULTS: We identified 24 of 98 evaluable patients with a TR in a prospective arm at one center and 7 of 31 patients in a retrospective arm at another totaling 31/129 (24.0%). The waveform prevalence was similar at both centers independent of location. TR was highly specific to active texting. A similar waveform during independent cognitive, speech or language, motor activation and audio cellular telephone use was absent (P < 0.0001). It appeared to be increased in patients with epilepsy in one cohort (P = 0.03) and generalized seizures in the other (P = 0.025). Age, gender, epilepsy type, MRI results, and EEG lateralization in patients with focal epileptic seizures did not bear a relationship to the presence of a TR in either arm of the study (P = NS). CONCLUSIONS: The TR is a novel waveform time-locked to text messaging and associated with active use of smartphones. Electroencephalographers should be aware of the TR to separate it from an abnormality in patients undergoing video EEG monitoring. Larger sample sizes and additional research may help define the significance of this unique cognitive-visual-cognitive-motor network that is technology-related and task-specific with implications in communication research and transportation safety.