In childhood cancer, the frequency of cancer-associated germline variants and their inheritance patterns are not thoroughly investigated. Moreover, the identification of children carrying a genetic predisposition by clinical means remains challenging. In this single-center study, we performed trio whole-exome sequencing and comprehensive clinical evaluation of a prospectively enrolled cohort of 160 children with cancer and their parents. We identified in 11/160 patients a pathogenic germline variant predisposing to cancer and a further eleven patients carried a prioritized VUS with a strong association to the cancerogenesis of the patient. Through clinical screening, 51 patients (31.3%) were identified as suspicious for an underlying cancer predisposition syndrome (CPS), but only in ten of those patients a pathogenic variant could be identified. In contrast, one patient with a classical CPS and ten patients with prioritized VUS were classified as unremarkable in the clinical work-up. Taken together, a monogenetic causative variant was detected in 13.8% of our patients using WES. Nevertheless, the still unclarified clinical suspicious cases emphasize the need to consider other genetic mechanisms including new target genes, structural variants, or polygenic interactions not previously associated with cancer predisposition.
BackgroundGlioblastoma multiforme (GBM) is the most common and lethal brain tumor in adults, highlighting the need for novel treatment strategies. Patient derived xenografts (PDX) represent a valuable tool to accomplish this task.MethodsPDX were established by implanting GBM tissue subcutaneously. Engraftment success was compared between NMRI Foxn1nu and NOD/SCID as well as between fresh and cryopreserved tissue. Established PDX were analyzed histologically and molecularly. Five PDX were experimentally treated with different drugs to assess their potential for preclinical drug testing.ResultsEstablishment of PDX was attempted for 36 consecutive GBM cases with an overall success rate of 22.2% in NMRI Foxn1nu mice. No difference was observed between fresh or cryopreserved (20–1057 days) tissue in direct comparison (n = 10 cases). Additionally, engraftment was better in NOD/SCID mice (38.8%) directly compared to NMRI Foxn1nu mice (27.7%) (n = 18 cases). Molecular data and histology of the PDX compare well to the primary GBM. The experimental treatment revealed individual differences in the sensitivity towards several clinically relevant drugs.ConclusionsThe use of vitally frozen GBM tissue allows a more convenient workflow without efficiency loss. NOD/SCID mice appear to be better suited for initial engraftment of tumor tissue compared to NMRI Foxn1nu mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1128-5) contains supplementary material, which is available to authorized users.
SummaryProteinase inhibitor 9 (PI-9) is an intracellular serpin expressed in lymphocytes and monocyte-derived cells. It is the only known endogenous natural antagonist of granzyme B (GrB), and its proposed function is protection of cells from misdirected GrB. We have studied the regulation of PI-9 in primary peripheral blood mononuclear cells (PBMCs) following ex-vivo stimulation, and in PBMCs from patients suffering from viral or bacterial infections. By intracellular flow cytometry, we found identical PI-9 expression in all lymphocyte subsets, lower levels in monocytes and none in granulocytes. PI-9 was stable for 48 h in the presence of cycloheximide, indicating slow protein turnover. Incubation of PBMCs with several stimuli including lipopolysaccharide (LPS) led to up-regulation in the monocyte, but not the lymphocyte fraction, within 48 h, inhibitable by the NF-κ κ κ κ B inhibitor pyrrolidin dithiocarbamate (PTDC). Up-regulation of PI-9 was observed in lymphocytes and monocytes of patients with acute Epstein-Barr virus (EBV), but not bacterial infection. Preterm infants had similar PI-9 expression as adults in monocytes, but lower in lymphocytes, decreasing during bacterial infection. Taken together, our data indicate that PI-9 is rapidly up-regulated upon stimulation of monocytes, but not lymphocytes. By protecting monocytes and macrophages from misdirected GrB in the inflammatory process, PI-9 might be involved in the regulation of antigen presentation.
Cyclin-dependent kinases (CDK) control the cell cycle and play a crucial role in oncogenesis. Pharmacologic inhibition of CDK has contributed to the recent clinical approval of dual CDK4/6 inhibitors for the treatment of breast and small cell lung cancer. While the anticancer cell effects of CDK inhibitors are well-established, preclinical and early clinical studies describe additional mechanisms of action such as chemo- and radiosensitization or immune stimulation. The latter offers great potential to incorporate CDK inhibitors in immune-based treatments. However, dosing schedules and accurate timing of each combination partner need to be respected to prevent immune escape and resistance. In this review, we provide a detailed summary of CDK inhibitors in the two solid cancer types head and neck cancer and glioblastoma multiforme; it describes the molecular mechanisms of response vs. resistance and covers strategies to avoid resistance by the combination of immunotherapy or targeted therapy.
Killing of target cells by cytotoxic T cells is mediated by induc
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