The role of 6-phosphogluconate dehydrogenase in vascular smooth muscle cell phenotypic switching and angioplasty-induced intimal hyperplasia.

Background: Restenosis poses a significant challenge for individuals afflicted with peripheral artery diseases, often leading to considerable morbidity and necessitating repeated interventions. The primary culprit behind the pathogenesis of restenosis is intimal hyperplasia (IH), in which the hyperproliferative and migratory vascular smooth muscle cell (VSMC) accumulate excessively in the tunica intima. 6-Phosphogluconate dehydrogenase (6PGD), sometimes referred to as PGD, is one of the critical enzymes in pentose phosphate pathway (PPP).

RNA splicing variants of the novel long non-coding RNA, CyKILR, possess divergent biological functions in non-small cell lung cancer.

The CDKN2A gene, responsible for encoding the tumor suppressors p16(INK4A) and p14(ARF), is frequently inactivated in non-small cell lung cancer (NSCLC). Herein, an uncharacterized long non-coding RNA (lncRNA) (ENSG00000267053) on chromosome 19p13.12 was found to be overexpressed in NSCLC cells with an active, wild-type CDKN2A gene.

Ceramide-1-phosphate is a regulator of Golgi structure and is co-opted by the obligate intracellular bacterial pathogen .

Many intracellular pathogens structurally disrupt the Golgi apparatus as an evolutionarily conserved promicrobial strategy. Yet, the host factors and signaling processes involved are often poorly understood, particularly for , the agent of human granulocytic anaplasmosis. We found that elevated cellular levels of the bioactive sphingolipid, ceramide-1-phosphate (C1P), to promote Golgi fragmentation that enables bacterial proliferation, conversion from its non-infectious to infectious form, and productive infection.

Neointima abating and endothelium preserving - An adventitia-localized nanoformulation to inhibit the epigenetic writer DOT1L.

Open vascular reconstructions such as bypass are common treatments for cardiovascular disease. Unfortunately, neointimal hyperplasia (IH) follows, leading to treatment failure for which there is no approved therapy. Here we combined the strengths of tailoring nanoplatforms for open vascular reconstructions and targeting new epigenetic mechanisms.

Skewing cPLAα activity toward oxoeicosanoid production promotes neutrophil N2 polarization, wound healing, and the response to sepsis.

Uncontrolled inflammation is linked to poor outcomes in sepsis and wound healing, both of which proceed through distinct inflammatory and resolution phases. Eicosanoids are a class of bioactive lipids that recruit neutrophils and other innate immune cells. The interaction of ceramide 1-phosphate (C1P) with the eicosanoid biosynthetic enzyme cytosolic phospholipase A (cPLA) reduces the production of a subtype of eicosanoids called oxoeicosanoids.

miR579-3p is an inhibitory modulator of neointimal hyperplasia and transcription factors c-MYB and KLF4.

Neointimal hyperplasia (IH) is a common vascular pathology that typically manifests in in-stent restenosis and bypass vein graft failure. Smooth muscle cell (SMC) phenotypic switching is central to IH, both regulated by some microRNAs, yet the role of miR579-3p, a scarcely studied microRNA, is not known. Unbiased bioinformatic analysis suggested that miR579-3p was repressed in human primary SMCs treated with different pro-IH cytokines.

Smad2 inhibition of transcription potentiates human vascular smooth muscle cell apoptosis.

Background: Vascular smooth muscle cell (SMC) apoptosis is involved in major cardiovascular diseases. Smad2 is a transcription factor implicated in aortic aneurysm. The molecular mediators of Smad2-driven SMC apoptosis are not well defined.

Angioplasty induces epigenomic remodeling in injured arteries.

Neointimal hyperplasia/proliferation (IH) is the primary etiology of vascular stenosis. Epigenomic studies concerning IH have been largely confined to in vitro models, and IH-underlying epigenetic mechanisms remain poorly understood. This study integrates information from in vivo epigenomic mapping, conditional knockout, gene transfer and pharmacology in rodent models of IH.

Repositioning Fenofibrate to Reactivate p53 and Reprogram the Tumor-Immune Microenvironment in HPV+ Head and Neck Squamous Cell Carcinoma.

Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV- HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo.

miR548ai antagonism attenuates exosome-induced endothelial cell dysfunction.

Endothelial cell (EC) and smooth muscle cell (SMC) are major cell types adjacent in the vascular wall. Recent progress indicates that their communication is crucial for vascular homeostasis and pathogenesis. In particular, dysfunctional (proliferative) SMCs through exosomes can induce EC dysfunction (impaired growth).

An adventitial painting modality of local drug delivery to abate intimal hyperplasia.

A major medical problem is the persistent lack of approved therapeutic methods to prevent postoperative intimal hyperplasia (IH) which leads to high-rate failure of open vascular reconstructions such as bypass grafting. Hydrogel has been widely used in preclinical trials for perivascular drug administration to mitigate postoperative IH. However, bulky hydrogel is potentially pro-inflammatory, posing a significant hurdle to clinical translation.

BRD2 regulation of sigma-2 receptor upon cholesterol deprivation.

The sigma-2 receptor (S2R) has long been pharmacologically targeted for antipsychotic treatment and tumor imaging. Only recently was it known for its coding gene and for its role implicated in cholesterol homeostasis. Here, we have investigated the transcriptional control of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, and 4) upon cholesterol perturbation.

Smad3 Regulates Neuropilin 2 Transcription by Binding to its 5' Untranslated Region.

Background Vascular smooth muscle cell phenotypic change and consequential intimal hyperplasia (IH) cause arterial stenosis and posttreatment restenosis. Smad3 is a master transcription factor, yet its underlying functional mechanisms in this disease context are not well defined. Methods and Results In cultured smooth muscle cells, Smad3 silencing and overexpression respectively reduced and increased the mRNA and protein of NRP2 (neuropilin 2), a recently reported pro-IH signaling factor.

p53 functional states are associated with distinct aldehyde dehydrogenase transcriptomic signatures.

p53 and aldehyde dehydrogenase (ALDH) have been implicated in key tumorigenesis processes including cancer initiating cell (CIC) maintenance; however, the relationship between these two mediators remains poorly defined. In this study, ALDH isoform expression diversity was revealed in CICs with disparate p53 functional states: gain of function, high risk p53 mutation (p53HRmut) and wildtype p53 (p53WT) inactivated by the human papillomavirus 16 (HPV16) E6 oncogene. Interrogation of head and neck squamous cell carcinoma (HNSCC) cell lines and patient tumors showed that HPV16+/p53WT cases have higher ALDH variance score (AVS), a measure of tumor ALDH isoform expression diversity, compared to HPV-/p53HRmut cases (p = 0.

ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation.

Vascular smooth muscle cell (VSMC) proliferation promotes intimal hyperplasia (IH) in occluding vascular diseases. Here we identified a positive role of ALDH1A3 (an aldehyde dehydrogenase) in this pro-IH process. The expression of ALDH1A3, but not that of 18 other isoforms of the ALDH family, was substantially increased in cytokine-stimulated VSMCs.

Immunotherapy for head and neck cancer: the future of treatment?

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with >500,000 cases diagnosed each year. HNSCC patients often present to the clinic with advanced disease and are managed with a multi-disciplinary approach consisting of surgery, chemotherapy, and/or radiation. Morbidity and quality of life issues are major challenges in this patient population due to the debilitating effects of standard of care treatment paradigms.

TriCurin, a novel formulation of curcumin, epicatechin gallate, and resveratrol, inhibits the tumorigenicity of human papillomavirus-positive head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with about 600,000 new cases diagnosed in the last year. The incidence of human papillomavirus-positive head and neck squamous cell carcinoma (HPV-positive HNSCC) has rapidly increased over the past 30 years prompting the suggestion that an epidemic may be on the horizon. Therefore, there is a clinical need to develop alternate therapeutic strategies to manage the growing number of HPV-positive HNSCC patients.

miR-124 Regulates the Epithelial-Restricted with Serine Box/Epidermal Growth Factor Receptor Signaling Axis in Head and Neck Squamous Cell Carcinoma.

Epithelial-restricted with serine box (ESX), a member of the ETS transcription factor family, is elevated and regulates EGFR in head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanisms that contribute to ESX dysregulation remain to be elucidated. In this study, in silico analysis of the 3'-untranslated region (UTR) of ESX predicted two miR-124-binding sites.

Are all cancer stem cells created equal?

Numerous solid malignancies have been reported to contain cancer stem cells (CSCs). Distinct functional characteristics have been attributed to CSCs, and thus it is widely believed that these unique cells may have genetic and phenotypic homogeneity. Recent exciting but limited evidence, however, contradicts this tenet and supports the intriguing concept of genetic and phenotypic diversity in the CSC population.

Elevated intrinsic cancer stem cell population in human papillomavirus-associated head and neck squamous cell carcinoma.

Background: Human papillomavirus 16 (HPV16) is a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC), particularly the development of oropharyngeal squamous cell carcinoma (OPSCC). Cancer stem cells (CSCs) are resistant to conventional therapies, and it is postulated that they are responsible for disease recurrence and/or progression. Because the prognoses of patients with HPV16-positive and HPV-negative HNSCC are distinct, the authors sought to determine whether differences in the number of CSCs could account for this clinical observation.

Emerging role of nanog in tumorigenesis and cancer stem cells.

Nanog is a transcription factor that is well-established as a key regulator of embryonic stem cell (ESC) maintenance. Recent evidence demonstrates that Nanog is dysregulated and intimately involved in promoting tumorigenesis in part through regulation of the cancer stem cell (CSC) population. Elevated Nanog is associated with poorer outcome in numerous epithelial malignancies.

PKC ε Phosphorylates and Mediates the Cell Membrane Localization of RhoA.

Protein kinase C ε (PKC ε ) signals through RhoA to modulate cell invasion and motility. In this study, the multifaceted interaction between PKC ε and RhoA was defined. Phosphopeptide mapping revealed that PKC ε phosphorylates RhoA at T127 and S188.

Source, distribution, and health risk assessment of polycyclic aromatic hydrocarbons in urban street dust from Tianjin, China.

To better assess and understand potential health risk of urban residents exposed to urban street dust, the total concentration, sources, and distribution of 16 polycyclic aromatic hydrocarbons (PAHs) in 87 urban street dust samples from Tianjin as a Chinese megacity that has undergone rapid urbanization were investigated. In the meantime, potential sources of PAHs were identified using the principal component analysis (PCA), and the risk of residents' exposure to PAHs via urban street dust was calculated using the Incremental Lifetime Cancer Risk (ILCR) model. The results showed that the total PAHs (∑PAHs) in urban street dust from Tianjin ranged from 538 μg kg(-1) to 34.

Genetic and chemical targeting of epithelial-restricted with serine box reduces EGF receptor and potentiates the efficacy of afatinib.

EGF receptor (EGFR) is elevated in more than 90% of head and neck squamous cell carcinoma (HNSCC). However, a majority of patients with HNSCC do not respond to anti-EGFR therapeutics. Insensitivity to EGFR inhibitors may be due to kinase-independent actions of EGFR and/or activation of Her2.