The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy.

Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors-Cortisol, MLN4924, QNZ and TPCA1-on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low µM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.

The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent.

Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48-72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.

Merkel Cell Carcinoma of the Head and Neck: Recommendations for Diagnostics and Treatment.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive tumor that often occurs in the head and neck region. Because of these features, the classifications and diagnostic and treatment regimens are frequently modified. Especially in the anatomically complex head and neck region, it is crucial to be aware of the current recommendations for diagnostics and treatment of MCC to ensure appropriate treatment. This overview aims to summarize the currently available literature. METHODS: The authors reviewed the relevant literature and international guidelines for MCC from 2012 to 2017 with respect to epidemiology and prognosis, diagnostic procedures and imaging, surgery, radiation, systemic treatment, and aftercare. These results were compared with existing guidelines, some of them current, and recommendations were derived. RESULTS: Marked developments in imaging have resulted in an increased use of functional imaging. The surgical concepts have changed regarding safety margins and the use of sentinel node biopsies. In systemic treatment, a move from conventional agents toward immuno-oncology can be observed. CONCLUSIONS: For staging, it is important to be as exact as possible using functional imaging (e.g., positron emission tomography/computed tomography scan), especially in the head and neck area with its complex lymph drainage. This often plays an especially important role in early stages of the tumor, when the resection margin can be reduced to preserve the organ. Aftercare also should include functional imaging. In an advanced, metastatic stage, immuno-oncology (PD-1, PD-L1, CTLA-4) is superior to the previous methods of systemic treatment.

Utilizing BMP-2 muteins for treatment of multiple myeloma.

Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor ß (TGFß) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.

Diagnostic features of prematurely fused cranial sutures on plain skull X-rays.

PURPOSE: The characteristic features of prematurely fused craniosynostosis in plain radiographs have already been described in literature, but there is no clinical trial investigating the individual features of every single form of craniosynostosis. We described suture-specific characteristics as well as its frequency of appearance in plain radiographs in every different form of craniosynostosis. Intraoperative findings served as control to confirm the diagnosis. METHODS: One hundred twenty-seven children with prematurely fused cranial sutures who underwent a skull X-ray from 2008 to 2012 were investigated in the present study. In detail, 34 children with frontal, 60 with sagittal, 13 with unilateral and 14 with bilateral coronal synostosis and 3 with unilateral lambdoid craniosynostosis as well as 3 children with a bilateral lambdoid synostosis were included. RESULTS: Typical radiological characteristics in craniosynostosis exist. These features as well as its frequency in craniosynostosis in plain skull radiographs are presented. In all cases, these typical features enabled a correct diagnosis, which was confirmed by intraoperative findings. CONCLUSION: The frequency of the appearance of typical features is listed and may serve as a "mental internal check list" in the radiological approach to craniosynostosis. The study points out the value of plain skull X-rays as it enabled proper diagnosis in all investigated 127 cases.

Historical development of alloplastic temporomandibular joint replacement before 1945.

Resections of the temporomandibular joint (TMJ) have been carried out for about 150 years. This article reviews the beginning of TMJ surgery technique before 1945 by carrying out extensive inquiries in public and private libraries and collections. Before 1945 the technique of alloplastic reconstruction of the TMJ was mainly influenced by German and French surgeons. Reconstruction was limited to replacement of the condyle. The role of the TMJ within the orofacial system was not considered. Interposition of alloplastic implants, resection dressings and prostheses were the dominant technique. The main concerns were sterilisation, biocompatibility and implant fixation. No evidence-based data on outcomes are available from that time. By 1945 reconstruction of the TMJ involved the close cooperation of surgeons and dentists.