Cell Fragmentation and Permeabilization by a 1 ns Pulse Driven Triple-Point Electrode

Ultrashort electric pulses (ns-ps) are useful in gaining understanding as to how pulsed electric fields act upon biological cells, but the electric field intensity to induce biological responses is typically higher than longer pulses and therefore a high voltage ultrashort pulse generator is required. To deliver 1 ns pulses with sufficient electric field but at a relatively low voltage, we used a glass-encapsulated tungsten wire triple-point electrode (TPE) at the interface among glass, tungsten wire, and water when it is immersed in water. A high electric field (2 MV/cm) can be created when pulses are applied. However, such a high electric field was found to cause bubble emission and temperature rise in the water near the electrode. They can be attributed to Joule heating near the electrode. Adherent cells on a cover slip treated by the combination of these stimuli showed two major effects: (1) cells in a crater (

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Identification of Gastric Cancer-Related Circular RNA through Microarray Analysis and Bioinformatics Analysis

Gastric cancer is one of the common malignant tumors worldwide. Increasing studies have indicated that circular RNAs (circRNAs) play critical roles in the cancer progression and have shown great potential as useful markers and therapeutic targets. However, the precise mechanism and functions of most circRNAs are still unknown in gastric cancer. In the present study, we performed a microarray analysis to detect circRNA expression changes between tumor samples and adjacent nontumor samples. The miRNA expression profiles were obtained from the National Center of Biotechnology Information Gene Expression Omnibus (GEO). The differentially expressed circRNAs and miRNAs were identified through fold change filtering. The interactions between circRNAs and miRNAs were predicted by Arraystar's home-made miRNA target prediction software. After circRNA-related miRNAs and dysregulated miRNAs were intersected, 23 miRNAs were selected. The target mRNAs of miRNAs were predicted by TarBase v7.0. Gene ontology (GO) enrichment analysis and pathway analysis were performed using standard enrichment computational methods for the target mRNAs. The results of pathway analysis showed that p53 signaling pathway and hippo signal pathway were significantly enriched and CCND2 was a cross-talk gene associated with them. Finally, a circRNA-miRNA-mRNA regulation network was constructed based on the gene expression profiles and bioinformatics analysis results to identify hub genes and hsa_circRNA_101504 played a central role in the network.

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Antioxidant, Hepatoprotective, and Antidepression Effects of Rumex tingitanus Extracts and Identification of a Novel Bioactive Compound

Over the last few decades, Rumex species have been recognized as a promising source of new compounds with numerous pharmacological activities. Therefore, the antioxidant activity of Rumex tingitanus (R. tingitanus) leaves extracts was evaluated in vitro and then confirmed in vivo as well as the antidepressant-like and toxicological effects of the extracts. The ethyl acetate fraction (Rt EtOAcF) followed by hydroalcoholic extract (Rt EtOH-H2O) showed a remarkable in vitro antioxidant activity. The hydroalcoholic extract (Rt EtOH-H2O) showed significant hepatoprotective activity against carbon tetrachloride- (CCl4-) induced liver toxicity which is seen from inhibition of the malondialdehyde (MDA) accumulation and enhancement of the liver antioxidant enzymes activities. The Rt EtOH-H2O and Rt EtOAcF extracts were able to reduce the immobility time in mice and then elicited a significant antidepressant-like effect. The ethyl acetate fraction (Rt EtOAcF) was purified and resulted in the identification of a new antioxidant component called 4′-p-acetylcoumaroyl luteolin. The Rt EtOAcF and the 4′-p-acetylcoumaroyl luteolin revealed a strong antioxidant activity using DPPH test with IC50 of 11.7 ± 0.2 and 20.74 ± 0.6 μg/ml, respectively, and AAI of 3.39 and 1.92 better than that of BHT, used as control.

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The Role of Cardiokines in Heart Diseases: Beneficial or Detrimental?

Cardiovascular disease remains the leading cause of morbidity and mortality, imposing a major disease burden worldwide. Therefore, there is an urgent need to identify new therapeutic targets. Recently, the concept that the heart acts as a secretory organ has attracted increasing attention. Proteins secreted by the heart are called cardiokines, and they play a critical physiological role in maintaining heart homeostasis or responding to myocardial damage and thereby influence the development of heart diseases. Given the critical role of cardiokines in heart disease, they might represent a promising therapeutic target. This review will focus on several cardiokines and discuss their roles in the pathogenesis of heart diseases and as potential therapeutics.

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Cancers, Vol. 10, Pages 78: New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response

Cancers, Vol. 10, Pages 78: New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response

Cancers doi: 10.3390/cancers10030078

Authors: Klaudia Szymonowicz Sebastian Oeck Nathalie Malewicz Verena Jendrossek

Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or for one of the three Akt isoforms as well as loss of the tumor suppressor Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) lead to constitutive activation of Akt. By activating Akt, these genetic alterations not only promote growth, proliferation and malignant behavior of cancer cells by phosphorylation of various downstream signaling molecules and signaling nodes but can also contribute to chemo- and radioresistance in many types of tumors. Here we review current knowledge on the mechanisms dictating Akt's activation and target selection including the involvement of miRNAs and with focus on compartmentalization of the signaling network. Moreover, we discuss recent advances in the cross-talk with DNA damage response highlighting nuclear Akt target proteins with potential involvement in the regulation of DNA double strand break repair.

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Cancers, Vol. 10, Pages 77: Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy

Cancers, Vol. 10, Pages 77: Should We Keep Walking along the Trail for Pancreatic Cancer Treatment? Revisiting TNF-Related Apoptosis-Inducing Ligand for Anticancer Therapy

Cancers doi: 10.3390/cancers10030077

Authors: Anna-Laura Kretz Silvia von Karstedt Andreas Hillenbrand Doris Henne-Bruns Uwe Knippschild Anna Trauzold Johannes Lemke

Despite recent advances in oncology, diagnosis, and therapy, treatment of pancreatic ductal adenocarcinoma (PDAC) is still exceedingly challenging. PDAC remains the fourth leading cause of cancer-related deaths worldwide. Poor prognosis is due to the aggressive growth behavior with early invasion and distant metastasis, chemoresistance, and a current lack of adequate screening methods for early detection. Consequently, novel therapeutic approaches are urgently needed. Many hopes for cancer treatment have been placed in the death ligand tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) since it was reported to induce apoptosis selectively in tumor cells in vitro and in vivo. TRAIL triggers apoptosis through binding of the trans-membrane death receptors TRAIL receptor 1 (TRAIL-R1) also death receptor 4 (DR4) and TRAIL receptor 2 (TRAIL-R2) also death receptor 5 (DR5) thereby inducing the formation of the death-inducing signaling complex (DISC) and activation of the apoptotic cascade. Unlike chemotherapeutics, TRAIL was shown to be able to induce apoptosis in a p53-independent manner, making TRAIL a promising anticancer approach for p53-mutated tumors. These cancer-selective traits of TRAIL led to the development of TRAIL-R agonists, categorized into either recombinant variants of TRAIL or agonistic antibodies against TRAIL-R1 or TRAIL-R2. However, clinical trials making use of these agonists in various tumor entities including pancreatic cancer were disappointing so far. This is thought to be caused by TRAIL resistance of numerous primary tumor cells, an insufficient agonistic activity of the drug candidates tested, and a lack of suitable biomarkers for patient stratification. Nevertheless, recently gained knowledge on the biology of the TRAIL-TRAIL-R system might now provide the chance to overcome intrinsic or acquired resistance against TRAIL and TRAIL-R agonists. In this review, we summarize the status quo of clinical studies involving TRAIL-R agonists for the treatment of pancreatic cancer and critically discuss the suitability of utilizing the TRAIL-TRAIL-R system for successful treatment.

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Outcomes of Computed Tomography-Guided Image-Based Interstitial Brachytherapy for Cancer of the Cervix Using GEC-ESTRO Guidelines

Abstract

Locally advanced cancer of the cervix is treated by concurrent chemoradiation followed by brachytherapy. Interstitial brachytherapy is used to treat large tumors with involvement of parametrium, post-hysterectomy, and narrow, conical vagina. The GYN GEC-ESTRO working group described target volume delineation and also 3D image-based planning using MRI and 3D dose-volume parameters for brachytherapy of carcinoma cervix. CT-based as compared to MR-based image-guided brachytherapy (IGBT) is much more feasible and practical because MR access is still difficult for most departments. This is a retrospective study done to assess the local control in cancer of the cervix, treated based on these guidelines and dose received by 2 cm³ of the rectum as defined by the GEC-ESTRO guidelines and its correlation with long-term toxicity. Sixty-three patients of cancer of the cervix received 45 Gy/25 fractions of external beam radiotherapy with concurrent weekly cisplatin followed by interstitial brachytherapy. A central tandem was inserted into the uterine cavity. The needles were inserted based on the concept of gross tumor volume (GTV), high-risk clinical target volume (HRCTV), and intermediate-risk CTV (IR CTV) as defined by the GYN GEC-ESTRO guidelines. All patients underwent CT-based planning. A dose of 6.5 Gy × 4 fractions was delivered in two sessions such that the HRCTV received a total dose of 26 Gy. Dose optimization was done to prevent 2 cm³ of rectum from receiving > 400 cGy (60% of prescribed dose) per fraction and 2 cm³ of bladder from receiving 500 cGy per fraction. At a median follow-up of 41.5 months (range 6–106 months), 74.6% (47/63) of the patients were alive, with no local, loco-regional, or distant metastasis. Loco-regional control rate was 88% (56/63). Eight percent (5/63) of the patients developed grade I proctitis which was managed conservatively. There was no grades II, III, or IV proctitis. There was no bladder or sigmoid toxicity. GEC-ESTRO guidelines can be modified for CT-based planning also with very minimal late toxicity without compromising local control.

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