Einleitung: Effektive konservative Therapien zur Behandlung des Pankreaskarzinoms fehlen weiterhin und dies trägt zur schlechten Prognose der Erkrankung bei. Vor kurzem haben wir die Überexpression der Histon Deacetylase 2 (HDAC2) im Pankreaskarzinom demonstrieren können. Zusätzlich konnten wir zeigen, dass HDAC2 Resistenz gegen Topoisomerase II Inhibitoren vermittelt.
Although histone deacetylase inhibitors (HDACi) are promising cancer therapeutics regulating proliferation, differentiation and apoptosis, molecular pathways engaged by specific HDAC isoenzymes in cancer are ill defined.
Results:
In this study we demonstrate that HDAC2 is highly expressed in pancreatic ductal adenocarcinoma (PDAC), especially in undifferentiated tumours. We show that HDAC2, but not HDAC1, confers resistance towards the topoisomerase II inhibitor etoposide in PDAC cells. Correspondingly, the class I selective HDACi valproic acid (VPA) synergises with etoposide to induce apoptosis of PDAC cells. Transcriptome profiling of HDAC2-depleted PDAC cells revealed upregulation of the BH3-only protein NOXA. We show that the epigenetically silenced NOXA gene locus is opened after HDAC2 depletion and that NOXA upregulation is sufficient to sensitise PDAC cells towards etoposide-induced apoptosis.
Conclusions:
In summary, our data characterise a novel molecular mechanism that links the epigenetic regulator HDAC2 to the regulation of the pro-apoptotic BH3-only protein NOXA in PDAC. Targeting HDAC2 will therefore be a promising strategy to overcome therapeutic resistance of PDAC against chemotherapeutics that induce DNA damage.
Introduction: Boerhaave syndrome, a spontaneous esophageal perforation in the setting of increased intraesophageal pressure, is associated with significant morbidity and mortality. It is a rare condition with an estimated annual incidence of 3.1/1,000,000. This is an unusual case of Boerhaave syndrome with associated EKG and cardiac enzymes abnormalities prompting a diagnosis of acute coronary syndrome. Case Description/Methods: A 63-year-old man with HIV, maintained on highly active antiretroviral therapy (CD4 counts in 400s), prior pulmonary embolism (not on anticoagulation) presented to the ER with 3 days of persistent, diffuse chest pain radiating to his abdomen, dyspnea and fatigue. Exam revealed a pale-appearing man who was hypotensive and had chest wall and abdominal tenderness with involuntary guarding. An EKG showed inferolateral ST elevations. Labs demonstrated a bandemia of 19%, lactate of 4.9 and troponin of 0.013. During a coronary angiography, a drug-eluting stent was placed in a 70% occlusion of the left anterior descending artery (LAD). Following angiography, he had continued chest and abdominal discomfort with ST elevations on EKG. CT chest angiography showed an esophageal perforation at the level of the carina, diffuse pneumomediastinum and possible mediastinitis. Contrast extravasation on esophagram confirmed perforation. An EGD showed nodular, necrotic and friable esophageal mucosa with 4 large perforations occurring 25-40 cm from the incisors. Fluoroscopy-guided placement of fully covered flexible stents were performed. He remained intubated for 2 weeks until end of life. Medical records noted that 5 months prior, a neck CT scan performed for dysphagia, revealed upper esophageal distension with air and fluid layering in the mid-esophagus at the level of the carina associated with a lobulated wall thickening consistent with possible neoplasm. He left against medical advice. Discussion: Boerhaave syndrome typically presents with severe chest, neck or upper abdominal pain and subcutaneous emphysema often associated with vomiting or retching, although atypical presentations may occur. Esophageal perforation may result in pericardial irritation due to mediastinal proximity which can mimic acute coronary syndrome. This case was notable for persistent symptoms and EKG changes despite LAD stenting of a 70% occlusion. It is critical that there is a high index of suspicion for Boerhaave syndrome in appropriate clinical circumstances to potentially improve clinical outcomes (see Figure 1).Figure 1.: A. EKG showing anterolateral and inferior ST elevations. B. CT Angiogram with findings of an esophageal perforation at the level of the carina, diffuse pneumomediastinum and possible mediastinitis.
