Whole blood transcriptomics reveals granulocyte colony-stimulating factor as a mediator of cardiopulmonary bypass-induced systemic inflammatory response syndrome.

Objectives: Systemic inflammatory response syndrome (SIRS) is a frequent complication of cardiopulmonary bypass (CPB). SIRS is associated with significant morbidity and mortality, but its pathogenesis remains incompletely understood, and as a result, biomarkers are lacking and treatment remains expectant and supportive. This study aimed to understand the pathophysiological mechanisms driving SIRS induced by CPB and identify novel therapeutic targets that might reduce systemic inflammation and improve patient outcomes.

CSL324, a granulocyte colony-stimulating factor receptor antagonist, blocks neutrophil migration markers that are upregulated in hidradenitis suppurativa.

Background: Neutrophils have been shown to contribute to the pathophysiology of hidradenitis suppurativa (HS), a chronic, painful and debilitating inflammatory skin disease, yet their exact role remains to be fully defined. Granulocyte colony-stimulating factor (G-CSF), a major regulator of neutrophil development and survival, can be blocked by the novel, fully human anti-G-CSF receptor (G-CSFR) monoclonal antibody CSL324.

Objectives: We investigated the activation and migration of neutrophils in HS and the impact of blocking G-CSFR with CSL324.

E6AP Promotes a Metastatic Phenotype in Prostate Cancer.

Although primary prostate cancer is largely curable, progression to metastatic disease is associated with very poor prognosis. E6AP is an E3 ubiquitin ligase and a transcriptional co-factor involved in normal prostate development. E6AP drives prostate cancer when overexpressed.

E6AP goes viral: the role of E6AP in viral- and non-viral-related cancers.

Since its discovery, the E3 ubiquitin ligase E6-associated protein (E6AP) has been studied extensively in two pathological contexts: infection by the human papillomavirus (HPV), and the neurodevelopmental disorder, Angelman syndrome. Vital biological links between E6AP and other viruses, namely hepatitis C virus and encephalomyocarditis virus, have been recently uncovered. Critically, oncogenic E6AP activities have been demonstrated to contribute to cancers of both viral and non-viral origins.

Biodosimetric transcriptional and proteomic changes are conserved in irradiated human tissue.

Transcriptional dosimetry is an emergent field of radiobiology aimed at developing robust methods for detecting and quantifying absorbed doses using radiation-induced fluctuations in gene expression. A combination of RNA sequencing, array-based and quantitative PCR transcriptomics in cellular, murine and various ex vivo human models has led to a comprehensive description of a fundamental set of genes with demonstrable dosimetric qualities. However, these are yet to be validated in human tissue due to the scarcity of in situ-irradiated source material.

Copper accumulation in senescent cells: Interplay between copper transporters and impaired autophagy.

Cellular senescence is characterized by irreversible growth arrest incurred through either replicative exhaustion or by pro-oncogenic cellular stressors (radioactivity, oxidative stress, oncogenic activation). The enrichment of senescent cells in tissues with age has been associated with tissue dyshomeostasis and age-related pathologies including cancers, neurodegenerative disorders (e.g.

Exploring the oncoproteomic response of human prostate cancer to therapeutic radiation using data-independent acquisition (DIA) mass spectrometry.

Introduction: The development of radioresistance in prostate cancer (PCa) is an important clinical issue and is still largely uninformed by personalized molecular characteristics. The aim of this study was to establish a platform that describes the early oncoproteomic response of human prostate tissue to radiation therapy (RT) using a prospective human tissue cohort.

Methods: Fresh and fixed transperineal biopsies from eight men with clinically localized tumors were taken prior to and 14 days following a single fraction of high-dose-rate brachytherapy.

Proteotranscriptomic Measurements of E6-Associated Protein (E6AP) Targets in DU145 Prostate Cancer Cells.

Prostate cancer is a common cause of cancer-related death in men. E6AP (E6-Associated Protein), an E3 ubiquitin ligase and a transcription cofactor, is elevated in a subset of prostate cancer patients. Genetic manipulations of E6AP in prostate cancer cells expose a role of E6AP in promoting growth and survival of prostate cancer cells and However, the effect of E6AP on prostate cancer cells is broad and it cannot be explained fully by previously identified tumor suppressor targets of E6AP, promyelocytic leukemia protein and p27.

The Transcriptional Landscape of Radiation-Treated Human Prostate Cancer: Analysis of a Prospective Tissue Cohort.

Purpose: The resistance of prostate cancer to radiation therapy (RT) is a significant clinical issue and still largely unable to be guided by patient-specific molecular characteristics. The present study describes the gene expression changes induced in response to RT in human prostate tissue obtained from a prospective tissue acquisition study designed for radiobiology research.

Methods And Materials: A prospective cohort of 5 men with intermediate-risk and clinically localized tumors were treated with high-dose-rate brachytherapy with 2 × 10-Gy fractions.

Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis.

Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins.

E6AP promotes prostate cancer by reducing p27 expression.

Prostate cancer (PC) is the most common cancer in men. Elevated levels of E3 ligase, E6-Associated Protein (E6AP) were previously linked to PC, consistent with increased protein expression in a subset of PC patients. In cancers, irregular E3 ligase activity drives proteasomal degradation of tumor suppressor proteins.

MDM4 is a rational target for treating breast cancers with mutant p53.

Mutation of the key tumour suppressor p53 defines a transition in the progression towards aggressive and metastatic breast cancer (BC) with the poorest outcome. Specifically, the p53 mutation frequency exceeds 50% in triple-negative BC. Key regulators of mutant p53 that facilitate its oncogenic functions are potential therapeutic targets.

Reduced abundance of the E3 ubiquitin ligase E6AP contributes to decreased expression of the INK4/ARF locus in non-small cell lung cancer.

The tumor suppressor p16, one protein encoded by the INK4/ARF locus, is frequently absent in multiple cancers, including non-small cell lung cancer (NSCLC). Whereas increased methylation of the encoding gene (CDKN2A) accounts for its loss in a third of patients, no molecular explanation exists for the remainder. We unraveled an alternative mechanism for the silencing of the INK4/ARF locus involving the E3 ubiquitin ligase and transcriptional cofactor E6AP (also known as UBE3A).

Ubiquitin ligase E6AP mediates nonproteolytic polyubiquitylation of β-catenin independent of the E6 oncoprotein.

Recently, we showed that the ubiquitin ligase E6AP stabilizes β-catenin and activates its transcriptional activity. These activities were enhanced by the human papillomavirus (HPV) E6 protein. In the present study, we explored the function of E6AP, which increases β-catenin stabilization and transcriptional activation.

PML tumour suppression and beyond: therapeutic implications.

Recognition of the tumour suppressive capacity of the Promyelocytic Leukemia protein (PML) has emerged beyond its identification through APL, to a broad spectrum of tumors. This ability has chiefly been linked to its role as a core component of dynamic structures termed PML Nuclear Bodies (PML-NBs). In response to a variety of stresses, key factors and their molecular modifiers are recruited to PML-NBs, where activating modifications are facilitated, leading to a cellular stress response.

LIMK2 mediates resistance to chemotherapeutic drugs in neuroblastoma cells through regulation of drug-induced cell cycle arrest.

Drug resistance is a major obstacle for the successful treatment of many malignancies, including neuroblastoma, the most common extracranial solid tumor in childhood. Therefore, current attempts to improve the survival of neuroblastoma patients, as well as those with other cancers, largely depend on strategies to counter cancer cell drug resistance; hence, it is critical to understand the molecular mechanisms that mediate resistance to chemotherapeutics. The levels of LIM-kinase 2 (LIMK2) are increased in neuroblastoma cells selected for their resistance to microtubule-targeted drugs, suggesting that LIMK2 might be a possible target to overcome drug resistance.

Tubulin polymerization promoting protein 1 (TPPP1) increases β-catenin expression through inhibition of HDAC6 activity in U2OS osteosarcoma cells.

The Rho-associated coiled-coil kinase (ROCK) family of proteins, including ROCK1 and ROCK2, are key regulators of actin and intermediate filament morphology. The newly discovered ROCK substrate Tubulin polymerization promoting protein 1 (TPPP1) promotes microtubule polymerization and inhibits the activity of Histone deacetylase 6 (HDAC6). The effect of TPPP1 on HDAC6 activity is inhibited by ROCK signaling.

Tubulin polymerization promoting protein 1 (Tppp1) phosphorylation by Rho-associated coiled-coil kinase (rock) and cyclin-dependent kinase 1 (Cdk1) inhibits microtubule dynamics to increase cell proliferation.

Tubulin polymerization promoting protein 1 (Tppp1) regulates microtubule (MT) dynamics via promoting MT polymerization and inhibiting histone deacetylase 6 (Hdac6) activity to increase MT acetylation. Our results reveal that as a consequence, Tppp1 inhibits cell proliferation by delaying the G1/S-phase and the mitosis to G1-phase transitions. We show that phosphorylation of Tppp1 by Rho-associated coiled-coil kinase (Rock) prevents its Hdac6 inhibitory activity to enable cells to enter S-phase.

Noncanonical BMP signaling regulates cyclooxygenase-2 transcription.

Activation of p38 MAPK has been shown to be relevant for a number of bone morphogenetic protein (BMP) physiological effects. We report here the involvement of noncanonical phosphorylated mothers against decapentaplegic (Smad) signaling in the transcriptional induction of Cox2 (Ptgs2) by BMP-2 in mesenchymal cells and organotypic calvarial cultures. We demonstrate that different regulatory elements are required for regulation of Cox2 expression by BMP-2: Runt-related transcription factor-2 and cAMP response element sites are essential, whereas a GC-rich Smad binding element is important for full responsiveness.

The p38/MK2/Hsp25 pathway is required for BMP-2-induced cell migration.

Background: Bone morphogenetic proteins (BMPs) have been shown to participate in the patterning and specification of several tissues and organs during development and to regulate cell growth, differentiation and migration in different cell types. BMP-mediated cell migration requires activation of the small GTPase Cdc42 and LIMK1 activities. In our earlier report we showed that activation of LIMK1 also requires the activation of PAKs through Cdc42 and PI3K.

BMP2 induction of actin cytoskeleton reorganization and cell migration requires PI3-kinase and Cdc42 activity.

Bone morphogenetic proteins (BMPs) are potent regulators of several cellular events. We report that exposure of C2C12 cells to BMP2 leads to an increase in cell migration and a rapid rearrangement of the actin filaments into cortical protrusions. These effects required independent and parallel activation of the Cdc42 small GTPase and the alpha-isoform of the phosphoinositide 3-kinase (PI3Kalpha), because ectopic expression of a dominant-negative form of Cdc42 or distinct pharmacological PI3K inhibitors abrogated these responses.