Description of Bacterial RNA Transcripts Detected in - Infected Cells from Peripheral Human Granulomas using Single Cell RNA Sequencing.

(Mtb) remains a global human health threat and a significant cause of human morbidity and mortality. We document here the capture of Mtb transcripts in libraries designed to amplify eukaryotic mRNA. These reads are often considered spurious or nuisance and are rarely investigated.

Spatial and phenotypic heterogeneity of resident and monocyte-derived macrophages during inflammatory exacerbations leading to pulmonary fibrosis.

Introduction: Genetic mutations in critical nodes of pulmonary epithelial function are linked to the pathogenesis of pulmonary fibrosis (PF) and other interstitial lung diseases. The slow progression of these pathologies is often intermitted and accelerated by acute exacerbations, complex non-resolving cycles of inflammation and parenchymal damage, resulting in lung function decline and death. Excess monocyte mobilization during the initial phase of an acute exacerbation, and their long-term persistence in the lung, is linked to poor disease outcome.

Single Cell Analysis of Peripheral TB-Associated Granulomatous Lymphadenitis.

We successfully employed a single cell RNA sequencing (scRNA-seq) approach to describe the cells and the communication networks characterizing granulomatous lymph nodes of TB patients. When mapping cells from individual patient samples, clustered based on their transcriptome similarities, we uniformly identify several cell types that known to characterize human and non-human primate granulomas. Whether high or low Mtb burden, we find the T cell cluster to be one of the most abundant.

Inhibition of TRPA1, Endoplasmic Reticulum Stress, Human Airway Epithelial Cell Damage, and Ectopic Expression by Vasaka (; Malabar Nut) Tea.

This study tested whether a medicinal plant, Vasaka, typically consumed as a tea to treat respiratory malaise, could protect airway epithelial cells (AECs) from wood smoke particle-induced damage and prevent pathological mucus production. Wood/biomass smoke is a pneumotoxic air pollutant. Mucus normally protects the airways, but excessive production can obstruct airflow and cause respiratory distress.

MITF Is Regulated by Redox Signals Controlled by the Selenoprotein Thioredoxin Reductase 1.

TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium in a mouse model of UV-induced melanoma prevents oxidative damage to melanocytes and delays melanoma tumor formation. However, TR1 itself is positively associated with progression in human melanomas and facilitates metastasis in melanoma xenografts.

Thioredoxin Reductase 1 Modulates Pigmentation and Photobiology of Murine Melanocytes in vivo.

Pigment-producing melanocytes overcome frequent oxidative stress in their physiological role of protecting the skin against the deleterious effects of solar UV irradiation. This is accomplished by the activity of several endogenous antioxidant systems, including the thioredoxin antioxidant system, in which thioredoxin reductase 1 (TR1) plays an important part. To determine whether TR1 contributes to the redox regulation of melanocyte homeostasis, we have generated a selective melanocytic Txnrd1-knockout mouse model (Txnrd1), which exhibits a depigmentation phenotype consisting of variable amelanotic ventral spotting and reduced pigmentation on the extremities (tail tip, ears, and paws).

Topsentinol L Trisulfate, a Marine Natural Product That Targets Basal-like and Claudin-Low Breast Cancers.

Patients diagnosed with basal-like breast cancer suffer from poor prognosis and limited treatment options. There is an urgent need to identify new targets that can benefit patients with basal-like and claudin-low (BL-CL) breast cancers. We screened fractions from our Marine Invertebrate Compound Library (MICL) to identify compounds that specifically target BL-CL breast cancers.

A `one-two punch' therapy strategy to target chemoresistance in estrogen receptor positive breast cancer.

Cancer cell phenotypes evolve during a tumor's treatment. In some cases, tumor cells acquire cancer stem cell-like (CSL) traits such as resistance to chemotherapy and diminished differentiation; therefore, targeting these cells may be therapeutically beneficial. In this study we show that in progressive estrogen receptor positive (ER+) metastatic breast cancer tumors, resistant subclones that emerge following chemotherapy have increased CSL abundance.

Circulating immune cell phenotype dynamics reflect the strength of tumor-immune cell interactions in patients during immunotherapy.

The extent to which immune cell phenotypes in the peripheral blood reflect within-tumor immune activity prior to and early in cancer therapy is unclear. To address this question, we studied the population dynamics of tumor and immune cells, and immune phenotypic changes, using clinical tumor and immune cell measurements and single-cell genomic analyses. These samples were serially obtained from a cohort of advanced gastrointestinal cancer patients enrolled in a trial with chemotherapy and immunotherapy.

Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model.

Background: CDK4/6 inhibitors such as ribociclib are becoming widely used targeted therapies in hormone-receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, cancers can advance due to drug resistance, a problem in which tumor heterogeneity and evolution are key features.

Methods: Ribociclib-resistant HR+/HER2- CAMA-1 breast cancer cells were generated through long-term ribociclib treatment.

Time- and dose-dependent gene expression analysis of macrophage response as a function of porosity of silica nanoparticles.

There is a limited amount of information available on gene expression regulation of macrophages in response to changing the time of exposure, concentration, and physicochemical properties of nanomaterials. In this study, RAW264.7 macrophages were treated with spherical nonporous and mesoporous silica nanoparticles of similar size at different incubation times and concentrations.

Genotoxicity of amorphous silica nanoparticles: Status and prospects.

Amorphous silica nanoparticles (SNPs) are widely used in biomedical applications and consumer products. Little is known, however, about their genotoxicity and potential to induce gene expression regulation. Despite recent efforts to study the underlying mechanisms of genotoxicity of SNPs, inconsistent results create a challenge.

Differential gene expression patterns in vein regions susceptible versus resistant to neointimal hyperplasia.

Arteriovenous hemodialysis graft (AVG) stenosis results in thrombosis and AVG failure, but prevention of stenosis has been unsuccessful due in large part to our limited understanding of the molecular processes involved in neointimal hyperplasia (NH) formation. AVG stenosis develops chiefly as a consequence of highly localized NH formation in the vein-graft anastomosis region. Surprisingly, the vein region just downstream of the vein-graft anastomosis (herein termed proximal vein region) is relatively resistant to NH.

Publisher Correction: Combating subclonal evolution of resistant cancer phenotypes.

The originally published version of this Article contained an error in Figure 4. In panel a, grey boxes surrounding the subclones associated with patients #2 and #4 obscured adjacent portions of the heatmap. This error has now been corrected in both the PDF and HTML versions of the Article.

Global gene expression analysis of macrophage response induced by nonporous and porous silica nanoparticles.

Little is known about the global gene expression profile of macrophages in response to changes in size and porosity of silica nanoparticles (SNPs). Spherical nonporous SNPs of two different diameters, and mesoporous spherical SNPs with comparable size were characterized. Reactive oxygen species, mitochondrial membrane potential, lysosome degradation capacity, and lysosome pH were measured to evaluate the influence of nonporous and mesoporous SNPs on mitochondrial and lysosomal function.

Combating subclonal evolution of resistant cancer phenotypes.

Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant.

Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.

The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC.

Gene-expression patterns in peripheral blood classify familial breast cancer susceptibility.

Background: Women with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery. Accurate and individualized risk-estimation approaches may help these women make more informed decisions. Although highly penetrant genetic variants have been associated with familial breast cancer (FBC) risk, many individuals do not carry these variants, and many carriers never develop breast cancer.

The role of thioredoxin reductase 1 in melanoma metabolism and metastasis.

Although significant progress has been made in targeted and immunologic therapeutics for melanoma, many tumors fail to respond, and most eventually progress when treated with the most efficacious targeted combination therapies thus far identified. Therefore, alternative approaches that exploit distinct melanoma phenotypes are necessary to develop new approaches for therapeutic intervention. Tissue microarrays containing human nevi and melanomas were used to evaluate levels of the antioxidant protein thioredoxin reductase 1 (TR1), which was found to increase as a function of disease progression.

Genomic classification of the RAS network identifies a personalized treatment strategy for lung cancer.

Better approaches are needed to evaluate a single patient's drug response at the genomic level. Targeted therapy for signaling pathways in cancer has met limited success in part due to the exceedingly interwoven nature of the pathways. In particular, the highly complex RAS network has been challenging to target.

A chimeric p53 evades mutant p53 transdominant inhibition in cancer cells.

Because of the dominant negative effect of mutant p53, there has been limited success with wild-type (wt) p53 cancer gene therapy. Therefore, an alternative oligomerization domain for p53 was investigated to enhance the utility of p53 for gene therapy. The tetramerization domain of p53 was substituted with the coiled-coil (CC) domain from Bcr (breakpoint cluster region).

Transcriptional responses of human aortic endothelial cells to nanoconstructs used in biomedical applications.

Understanding the potential toxicities of manufactured nanoconstructs used for drug delivery and biomedical applications may help improve their safety. We sought to determine if surface-modified silica nanoparticles and poly(amido amine) dendrimers elicit genotoxic responses on vascular endothelial cells. The nanoconstructs utilized in this study had a distinct geometry (spheres vs worms) and surface charge, which were used to evaluate the contributions of these parameters to any potential adverse effects of these materials.

Selenium for the prevention of cutaneous melanoma.

The role of selenium (Se) supplementation in cancer prevention is controversial; effects often depend on the nutritional status of the subject and on the chemical form in which Se is provided. We used a combination of in vitro and in vivo models to study two unique therapeutic windows for intervention in the process of cutaneous melanomagenisis, and to examine the utility of two different chemical forms of Se for prevention and treatment of melanoma. We studied the effects of Se in vitro on UV-induced oxidative stress in melanocytes, and on apoptosis and cell cycle progression in melanoma cells.

Major differences among chemopreventive organoselenocompounds in the sustained elevation of cytoprotective genes.

Cytoprotective enzyme elevation through the nuclear erythroid 2 p45-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1/antioxidant response element pathway has been promulgated for cancer prevention. This study compares the redox insult and sustained cytoprotective enzyme elevation by organoselenocompounds and sulforaphane (SF) in lung cells. SF elicited a rise in reactive oxygen species (ROS) and drop in glutathione (GSH) at 2 h; nuclear accumulation of Nrf2 at 4 h; and a GSH rebound and elevation in NAD(P)H quinone oxidoreductase (NQO1), thioredoxin reductase (TR1), and glutamate-cysteine ligase (GCL) at 24 h.