Hypoxia Abrogates Tumor-Suppressive Activities of C/EBPδ in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a low 5-year survival rate of only 13%. Despite intense research efforts, PDAC remains insufficiently understood. In part, this is attributed to opposing effects of key players being unraveled, including the stroma but also molecules that act in a context-dependent manner.

Pulmonary herpes simplex virus and cytomegalovirus in patients with acute respiratory distress syndrome related to COVID-19.

Purpose: Human herpesviruses, particularly cytomegalovirus (CMV) and herpes simplex virus (HSV), frequently reactivate in critically ill patients, including those with acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19). The clinical interpretation of pulmonary herpesvirus reactivation is challenging and there is ongoing debate about its association with mortality and benefit of antiviral medication. We aimed to quantify the incidence and pathogenicity of pulmonary CMV and HSV reactivations in critically ill COVID-19 patients.

The alveolar fibroproliferative response in moderate to severe COVID-19-related acute respiratory distress syndrome and 1-yr follow-up.

COVID-19-related acute respiratory distress syndrome (ARDS) can lead to long-term pulmonary fibrotic lesions. Alveolar fibroproliferative response (FPR) is a key factor in the development of pulmonary fibrosis. N-terminal peptide of procollagen III (NT-PCP-III) is a validated biomarker for activated FPR in ARDS.

Persistent alveolar inflammatory response in critically ill patients with COVID-19 is associated with mortality.

Introduction: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) show limited systemic hyperinflammation, but immunomodulatory treatments are effective. Little is known about the inflammatory response in the lungs and if this could be targeted using high-dose steroids (HDS). We aimed to characterise the alveolar immune response in patients with COVID-19-related ARDS, to determine its association with mortality, and to explore the association between HDS treatment and the alveolar immune response.

The dual role of C/EBPδ in cancer.

CCAAT/Enhancer-Binding Protein delta (C/EBPδ) is a transcription factor involved in differentiation and inflammation. While sparsely expressed in adult tissues, aberrant expression of C/EBPδ has been associated with different cancers. Initially, re-expression of C/EBPδ in cell cultures limited tumor cell proliferation, assigning it a tumor suppressor role.

C/EBP-Family Redundancy Determines Patient Survival and Lymph Node Involvement in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor clinical prognosis and unsatisfactory treatment options. We previously found that the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) is lowly expressed in PDAC compared to healthy pancreas duct cells, and that patient survival and lymph node involvement in PDAC is correlated with the expression of C/EBPδ in primary tumor cells. C/EBPδ shares a homologous DNA-binding sequence with other C/EBP-proteins, leading to the presumption that other C/EBP-family members might act redundantly and compensate for the loss of C/EBPδ.

C/EBPδ Suppresses Motility-Associated Gene Signatures and Reduces PDAC Cell Migration.

Pancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive human cancers and occurs globally at an increasing incidence. Metastases are the primary cause of cancer-related death and, in the majority of cases, PDAC is accompanied by metastatic disease at the time of diagnosis, making it a particularly lethal cancer. Regrettably, to date, no curative treatment has been developed for patients with metastatic disease, resulting in a 5-year survival rate of only 11%.

Novel tracers for molecular imaging of interstitial lung disease: A state of the art review.

Interstitial lung disease is an overarching term for a wide range of disorders characterized by inflammation and/or fibrosis in the lungs. Most prevalent forms, among others, include idiopathic pulmonary fibrosis (IPF) and connective tissue disease associated interstitial lung disease (CTD-ILD). Currently, only disease modifying treatment options are available for IPF and progressive fibrotic CTD-ILD, leading to reduction or stabilization in the rate of lung function decline at best.

Myeloid DNA methyltransferase3b deficiency aggravates pulmonary fibrosis by enhancing profibrotic macrophage activation.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and severe disease characterized by excessive matrix deposition in the lungs. Macrophages play crucial roles in maintaining lung homeostasis but are also central in the pathogenesis of lung diseases like pulmonary fibrosis. Especially, macrophage polarization/activation seems to play a crucial role in pathology and epigenetic reprograming is well-known to regulate macrophage polarization.

Lung Microbiota of Critically Ill Patients with COVID-19 Are Associated with Nonresolving Acute Respiratory Distress Syndrome.

Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19.

Macrophage C/EBPδ Drives Gemcitabine, but Not 5-FU or Paclitaxel, Resistance of Pancreatic Cancer Cells in a Deoxycytidine-Dependent Manner.

Treatment of pancreatic ductal adenocarcinoma (PDAC), a dismal disease with poor survival rates, is hampered by the high prevalence of chemotherapy resistance. Resistance is accompanied by macrophage infiltration into the tumor microenvironment, and infiltrated macrophages are key players in chemotherapy resistance. In the current manuscript, we identify CCAAT/enhancer-binding protein delta (C/EBPδ) as an important transcription factor driving macrophage-dependent gemcitabine resistance.

CEBPD Potentiates the Macrophage Inflammatory Response but CEBPD Knock-Out Macrophages Fail to Identify CEBPD-Dependent Pro-Inflammatory Transcriptional Programs.

CCAAT/enhancer-binding protein delta (C/EBPδ) is a member of the C/EBP family of transcription factors. According to the current paradigm, C/EBPδ potentiates cytokine production and modulates macrophage function thereby enhancing the inflammatory response. Remarkably, however, C/EBPδ deficiency does not consistently lead to a reduction in Lipopolysaccharide (LPS)-induced cytokine production by macrophages.

Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation.

CCAAT/enhancer-binding protein delta (C/EBPδ) is a transcription factor involved in apoptosis and proliferation, which is downregulated in pancreatic ductal adenocarcinoma (PDAC) cells. Loss of nuclear C/EBPδ in PDAC cells is associated with decreased patient survival and pro-tumorigenic properties in vitro. Interestingly however, next to C/EBPδ expression in tumor cells, C/EBPδ is also expressed by cells constituting the tumor microenvironment and by cells comprising the organs and parenchyma.

Pulmonary Procoagulant and Innate Immune Responses in Critically Ill COVID-19 Patients.

Rationale: Systemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited.

Objectives: To evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome.

Alveolar epithelial TET2 is not involved in the development of bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology with minimal treatment options. Repetitive alveolar epithelial injury has been suggested as one of the causative mechanisms of this disease. Type 2 alveolar epithelial cells (AEC2) play a crucial role during fibrosis by functioning as stem cells able to repair epithelial damage.

Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19.

Background: Knowledge of the pathophysiology of COVID-19 is almost exclusively derived from studies that examined the immune response in blood. We here aimed to analyse the pulmonary immune response during severe COVID-19 and to compare this with blood responses.

Methods: This was an observational study in patients with COVID-19 admitted to the intensive care unit (ICU).

Enrichment of CCR6 CD8 T cells and CCL20 in the lungs of mechanically ventilated patients with COVID-19.

Despite high levels of CXCR3 ligands in mechanically ventilated COVID-19 patients, BALF CD8 T cells were not enriched in CXCR3 cells but rather CCR6 , likely due to high CCL20 levels in BALF, and had very high PD-1 expression. In mechanically ventilated, but not ward, patients Th-1 immunity is impaired. ​.

CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells.

CCAAT/enhancer-binding protein δ (C/EBPδ) is a transcription factor involved in growth arrest and differentiation, which has consequently been suggested to harbor tumor suppressive activities. However, C/EBPδ over-expression correlates with poor prognosis in glioblastoma and promotes genomic instability in cervical cancer, hinting at an oncogenic role of C/EBPδ in these contexts. Here, we explore the role of C/EBPδ in pancreatic cancer.

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

Pancreatic cancer is a dismal disorder that is histologically characterized by a dense fibrotic stroma around the tumor cells. As the extracellular matrix comprises the bulk of the stroma, matrix degrading proteases may play an important role in pancreatic cancer. It has been suggested that matrix metalloproteases are key drivers of both tumor growth and metastasis during pancreatic cancer progression.

Immune Checkpoints as Promising Targets for the Treatment of Idiopathic Pulmonary Fibrosis?

Idiopathic pulmonary fibrosis is a rare, progressive and fatal lung disease which affects approximately 5 million persons worldwide. Although pirfenidone and/or nintedanib treatment improves patients' wellbeing, the prognosis of IPF remains poor with 5-year mortality rates still ranging from 70 to 80%. The promise of the anti-cancer agent nintedanib in IPF, in combination with the recent notion that IPF shares several pathogenic pathways with cancer, raised hope that immune checkpoint inhibitors, the novel revolutionary anticancer agents, could also be the eagerly awaited ground-breaking and unconventional novel treatment modality limiting IPF-related morbidity/mortality.

Pharmacological PAR-1 inhibition reduces blood glucose levels but does not improve kidney function in experimental type 2 diabetic nephropathy.

Vorapaxar-dependent protease-activated receptor (PAR)-1 inhibition diminishes diabetic nephropathy in experimental type 1 diabetes. As most patients with diabetic nephropathy suffer from type 2 diabetes, the aim of this study was to investigate whether PAR-1 inhibition also limits diabetic nephropathy in experimental type 2 diabetes. Consequently, leptin-deficient black and tan brachyuric (BTBR) mice were randomly assigned to vorapaxar (1.

CCAAT/enhancer binding protein delta (C/EBPδ) deficiency does not affect bleomycin-induced pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis is a devastating fibrotic diffuse parenchymal lung disorder that remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. CCAAT/enhancer binding protein delta (C/EBPδ) is a transcription factor that mediates critical cellular functions in pathophysiology and which was recently suggested to be a key regulatory component in IPF.