Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), has been shown to be an effective tool in cancer treatment. Although its ability to induce apoptosis has been described in many cancer types, the data come from experiments performed in normoxic (21% O2) conditions only. Therefore, we questioned whether VPA would be equally effective under hypoxic conditions (1% O2), which is known to induce resistance to apoptosis. Four neuroblastoma cell lines were used: UKF-NB-3, SK-N-AS, plus one cisplatin-resistant subline derived from each of the two original sensitive lines. All were treated with VPA and incubated under hypoxic conditions. Measurement of apoptosis and viability using TUNEL assay and Annexin V/propidium iodide labeling revealed that VPA was even more effective under hypoxic conditions. We show here that hypoxia-induced resistance to chemotherapeutic agents such as cisplatin could be overcome using VPA. We also demonstrated that apoptosis pathways induced by VPA do not differ between normoxic and hypoxic conditions. VPA-induced apoptosis proceeds through the mitochondrial pathway, not the extrinsic pathway (under both normoxia and hypoxia), since inhibition of caspase-8 failed to decrease apoptosis or influence bid cleavage. Our data demonstrated that VPA is more efficient in triggering apoptosis under hypoxic conditions and overcomes hypoxia-induced resistance to cisplatin. The results provide additional evidence for the use of VPA in neuroblastoma (NBL) treatment.
Cancer stem cells (CSCs) form a small proportion of tumor cells that have stem cell properties: self-renewal capacity, the ability to develop into different lineages and proliferative potential. The interest in CSCs emerged from their expected role in initiation, progression and recurrence of many tumors. They are generally resistant to conventional chemotherapy and radiotherapy. There are two hypotheses about their origin: The first assumes that CSCs may arise from normal stem cells, and the second supposes that differentiated cells acquire the properties of CSCs. Both hypotheses are not mutually exclusive, as it is possible that CSCs have a diverse origin in different tumors. CD133+ cells (CD133 is marker of CSC in some tumors) isolated from NBL, osteosarcoma and Ewing sarcoma cell lines are resistant to cisplatin, carboplatin, etoposide and doxorubicin than the CD133-ones. Being resistant to chemotherapy, there were many attempts to target CSCs epigenetically including the use of histone deacetylase inhibitors. The diverse influence of valproic acid (histone deacetylase inhibitor) on normal and cancer stem cells was proved in different experiments. We have found an increase percentage of CD133+ NBL cells after their incubation with VPA in a dose that does not induce apoptosis. Further researches on CSCs and clinical application for their detection are necessary: (i) to define the CSC function in carcinogenesis, cancer development and their role in metastasis; (ii) to find a specific marker for CSCs in different tumors; (iii) to explain the role of different pathways that determine their behavior and (iv) to explain mechanisms of chemoresistance of CSCs.
Intracranial ependymoma represents one of the most common pediatric central nervous system malignancies, and exhibits a wide range of clinical behavior from relatively indolent lesions to highly malignant anaplastic ependymomas. Due to the heterogeneous nature of this disease there is lack of prognostic markers, which would reliably predict the outcome of patients. MicroRNAs (miRNAs) have emerged as important molecules in cancer biology during past decade; however, very little is known about their role in ependymomas. The aim of the present study was to evaluate expression of miRNAs in archived formalin-fixed paraffin-embedded (FFPE) samples of pediatric intracranial ependymomas. The expression of miRNAs were examined in 29 samples of ependymoma and we observed that miR-135a-3p, miR-137, miR-17-5p, miR-181d and let-7d-5p were upregulated. In addition, a significantly higher expression of miR-203a was detected in Grade III tumors suggesting its possible use as a prognostic or diagnostic marker. The present study also demonstrated that storage of (FFPE) ependymoma samples for >20 years did not result in a deterioration of miRNAs. The present findings broaden the presently available knowledge regarding miRNA expression in ependymomas and provide further evidence for the employment of miRNA analysis as a supplementary method for the morphological assessment of ependymoma samples. Materials and methods Patients and samples. A total of 29 formalin-fixed paraffin-embedded (FFPE) specimens of ependymomas were collected retrospectively from the archives of
Abstract. Neuroblastoma is a tumor accounting for approximately 10% of all childhood malignancies and 50% of all childhood cancer-related deaths. MYCN gene copy number variation represents the most important prognostic factor in neuroblastoma. Prognostic significance of MYCN gene expression is more complicated and may depend on other factors such as MYCN gene copy number status. In the present study, we assessed MYCN gene expression using real-time RT-PCR following cisplatin treatment in three human neuroblastoma cell lines (UKF-NB-3, UKF-NB-4 and SK-N-AS) and their cisplatin-resistant counterparts. We also examined MYCN gene status and copy number (gain and amplification) variations using interphase and metaphase fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA). Only cisplatin-sensitive UKF-NB-4 cells exhibited decreased MYCN expression following treatment with cisplatin. Other sensitive neuroblastoma cells did not exhibit a change in MYCN expression. In contrast, cisplatin-resistant UKF-NB-4 and SK-N-AS cells exhibited increased MYCN expression irrespective of the number of MYCN copies or concentration of cisplatin in the medium. In MYCN-amplified neuroblastoma cells we did not observe any significant change in the number of MYCN copies after cisplatin treatment, whereas MYCN-non-amplified SK-N-AS cells revealed during cisplatin treatment an increased number of MYCN gene copies caused by 2p gain in the majority of cells by FISH. We postulated that cisplatin treatment does not result directly in altered transcription of MYCN. A functional change in MYCN mRNA levels and increased MYCN expression in cisplatin-resistant neuroblastoma cells do not have a clear relationship to MYCN copy numbers. These findings may further contribute to the understanding of cisplatin chemotherapy in connection with MYCN expression, and the possible copy number variations in MYCN neuroblastoma cells may be of importance since targeting of MYCN is being tested as neuroblastoma therapy.
Outcomes of patients resuscitated for out-of-hospital cardiac arrest (OHCA) complicating ST-elevation myocardial infarction (STEMI) who achieve return of spontaneous circulation (ROSC) before urgent coronary angiography have already been investigated in several retrospective and prospective series. Inhospital mortality or poor neurological outcome has been reported in 23% of these patients.1,2 Thirty-day mortality was 33% 3 and complete neurological recovery or moderate neurological disability was found in 58% of patients with STEMI successfully resuscitated for OHCA. 4 This is in contrast with the population of unselected patients treated for OHCA of supposedly cardiac origin where survival rates remain still under 20%. Predictors of deleterious outcome were found to be delayed in basic life support and OHCA before arrival of the emergency medical services. On the contrary, predictors of favorable outcome used an automated external defibrillator and ventricular fibrillation (VF) as first observed rhythm. 1 However, we do not know the extent of damage that prolonged cardiopulmonary resuscitation with mechanical chest compression device causes to the heart and whether it has an impact on outcomes of resuscitated patients. Case ReportA 60-year-old man without a history of coronary artery disease called an ambulance for typical chest pain at rest. Keywords► cardiac arrest ► mechanical chest compressions ► ST-elevation myocardial infarction ► percutaneous coronary intervention ► myocardial contusion AbstractAcute coronary syndrome is a common cause of sudden cardiac death. We present a case report of a 60-year-old man without a history of coronary artery disease who presented with ST-elevation myocardial infarction. During transportation to the hospital, he developed ventricular fibrillation (VF) and later pulseless electrical activity. Chest compressions with LUCAS 2 (Medtronic, Minneapolis, MN) automated mechanical compression-decompression device were initiated. Coronary angiography showed total occlusion of the left main coronary artery and primary percutaneous coronary intervention (PCI) was performed. After the PCI, his heart started to generate effective contractions and LUCAS could be discontinued. Return of spontaneous circulation was achieved after 90 minutes of cardiac arrest. The patient died of cardiogenic shock 11 hours later. An autopsy revealed a transmural anterolateral myocardial infarction but also massive subepicardial hemorrhage and interstitial edema and hemorrhages on histologic samples from regions of the myocardium outside the infarction itself and also from the right ventricle. These lesions were concluded to be a myocardial contusion. The true incidence of myocardial contusion as a consequence of mechanical chest compressions is not known. We speculate that severe myocardial contusion might have influenced outcome of our patient.
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