Objectives Although there are many reports about risk factors for

SUMMARYRecent years have led to a better understanding of the mechanisms underlying cisplatin response and resistance in germ cell tumours (GCT), and several promising targets have been identified. Two main mechanisms of the responsiveness to DNA damaging agents have been postulated. Firstly, GCT readily activate a DNA damage response, but show deficits in several damage repair pathways. In particular, they have been found to have defects in interstrand crosslink repair and in homologous recombination (HR). Secondly, GCT, especially embryonal carcinoma (EC) cells, show a hypersensitive apoptotic response to DNA damage, which activates p53, and leads to up-regulation of the pro-apoptotic factors Noxa, Puma and Fas in non-resistant EC. These cells fail to activate p21 which induces a G1/S arrest, but accumulate in G2/M phase. In the absence of functional p53, family members like p73 and GTAp63 might be important in initiating this response. Mechanisms involved in cisplatin resistance are as follows: down-regulation of Oct4 (e.g. as a result of hypoxia, treatment with retinoic acid or exposure to cisplatin) and failure to induce Puma and Noxa; changes in the expression levels of micro-RNAs such as miR-17/-106b, miR-302a, or miR-371 to -373; elevated levels of MDM2 and cytoplasmic translocation of p21 by phosphorylation; and activation of the PDGFRb/PI3K/pAKT pathway. Several approaches to overcome resistance have been successfully examined in vitro and in vivo, including PARP inhibitors, especially in cells showing deficient HRrepair; stabilization of p53 using nutlin-3; inhibition of several components of the PI3K/pAKT pathway using small molecules; and DNA demethylation by 5-azacytidine or 5-aza-deoxy-cytidine, among others. Many of these substances deserve further exploration, alone or in combination with DNA damaging agents, and the most promising approaches should be taken forward to clinical testing. Targeted therapy based on mechanistic insights holds the promise to turn cisplatin-resistant GCT into a curable disease.

Needle breakage in the oral cavity after local anesthesia is a common complication with possible serious complications of injuring vital structures. There are different possible reasons for needle breakage, with a main focus on preventable mistakes in treatment. In this study, an analysis of literature of the last 50 years as well as own cases has been performed to renew knowledge and prevention and therapy strategies for this serious complication. A systematic, multilingual review of medical literature from 1900 until today was conducted and information was evaluated systematically. In the majority of cases needle fracture happened during inferior alveolar nerve block. It is mainly a problem due to inadequate technique or the use of too thin needles for the performance of inferior alveolar nerve block. Different arguments about possible therapy strategies and methods exist. Basically, if a hypodermic needle fractures, it should be removed surgically under general anesthesia. To localize the fragment, use of either multi-plane X-rays or fluoroscopy with at least two reference needles in place or, if possible, of three-dimensional CT scans is recommended. This article shows, that despite progression in material, needle fracture is still an existing, preventable problem, if some basic rules are followed.

Aaptamine is a marine compound isolated from the sponge Aaptos aaptos showing antiproliferative properties via an undefined mode of action. We analyzed the effects of aaptamine treatment on the proliferation and protein expression of the pluripotent human embryonal carcinoma cell line NT2. Effects on proliferation, cell cycle distribution, and induction of apoptosis were analyzed. At lower concentrations, including the IC 50 of 50 μM, aaptamine treatment resulted in a G2/M phase cell cycle arrest, whereas at higher concentrations, induction of apoptosis was seen. Differentially expressed proteins were assessed by 2D-PAGE and mass spectrometry, followed by verification and analysis of protein modifications of the most significantly up-and down-regulated proteins. Aaptamine treatment at the IC 50 for 48 h resulted in alteration of 10 proteins, of which five each showed upand down-regulation. Changes in the 2D map were frequently noticed as a result of post-transcriptional modifications, e.g., of the hypusine modification of the eukaryotic initiation factor 5A (eIF5A). Observed alterations such as increased expression of CRABP2 and hypusination of eIF5A have previously been identified during differentiation of pluripotent cells. For the first time, we describe changes in protein expression caused by aaptamine, providing valuable information regarding the mode of action of this compound.