The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer

The p53/MDM2 interaction has been a well-studied target for new drug design leading to the development of the small molecule inhibitor Nutlin-3. Our objectives were to combine Nutlin-3 with cisplatin (CDDP), a well-known activator of the p53 pathway, in a series of non-small cell lung cancer cell lines in order to increase the cytotoxic response to CDDP. We report that sequential treatment (CDDP followed by Nutlin-3), but not simultaneous treatment, resulted in strong synergism. Combination treatment induced p53's transcriptional activity, resulting in increased mRNA and protein levels of MDM2, p21, PUMA and BAX. In addition we report the induction of a strong p53 dependent apoptotic response and induction of G2/M cell cycle arrest. The strongest synergistic effect was observed at low doses of both CDDP and Nutlin-3, which could result in fewer (off-target) side effects while maintaining a strong cytotoxic effect. Our results indicate a promising preclinical potential, emphasizing the importance of the applied treatment scheme and the presence of wild type p53 for the combination of CDDP and Nutlin-3

Sensitive detection methods are key to identify secondary EGFR c.2369C>T p.(Thr790Met) in non-small cell lung cancer tissue samples

Background: Correct identification of the EGFR c.2369C>T p.(Thr790Met) variant is key to decide on a targeted therapeutic strategy for patients with acquired EGFR TKI resistance in non-small cell lung cancer. The aim of this study was to evaluate the correct detection of this variant in 12 tumor tissue specimens tested by 324 laboratories participating in External Quality Assessment (EQA) schemes. Methods: Data from EQA schemes were evaluated between 2013 and 2018 from cell lines (6) and resections (6) containing the EGFR c.2369C>T p.(Thr790Met) mutation. Adequate performance was defined as the percentage of tests for w

Embryo transfer as a method to eliminate pathogenic agents in a rabbit colony

peer reviewedTo regain the SPF status of a contaminated but genetically valuable rabbit breeding unit, embryos from the contaminated does were transferred into SPF recipient females. Embryos were collected on day 3 of gestation by flushing uterine horns. All usable embryos were frozen, part of them were not transferred and kept in liquid nitrogen forming a stock of highly valuable genotypes. Thirty-two stimulated does produced 893 embryos, among which 821 (92%) had an intact zona pellucida and were cryopreserved. From this stock, 478 embryos were thawed, 466 were recovered (97.5%) and 417 were of good quality (87.2%). In 30 does, 10 to 18 embryos were surgically transferred per recipient doe and 24.9% (104/417) of them developed to term after transfer. This corresponds to an average number of 3.47 (104/30) live newborns per recipient. Health screenings performed on sanitized rabbits confirmed the disappearance of pathogenic agents

Are anaplastic lymphoma kinase (ALK) and O6-methylguanine- DNA methyltransferase (MGMT) promoter methylation driver biomarkers of pulmonary neuroendocrine tumors (NETs) and carcinomas (NECs)?

Background: Novel targets in neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are needed to improve outcome. The presence of O6- Methylguanine-DNA methyltransferase (MGMT) promoter methylation in NETs and NECs may act as a predictive marker for response on treatment with temozolomide. As anaplastic lymphoma kinase (ALK) plays an important role in the nervous system we hypothesized that ALK rearrangement can act as a biomarker in patients with NETs and NECs. Materials and Methods: We performed a retrospective analysis to establish the frequency of MGMT promoter methylation and ALK expression in tissue samples of patients with NETs and NECs. Results: 21% (14/67) of patients tested positive for MGMT promoter methylation. MGMT promoter methylation was present in 33% (3/9) patients with typical carcinoid, in 22% (2/9) patients with atypical carcinoid, in 22% (8/37) patients with small cell lung cancer and in 8% (1/12) patient with large cell neuroendocrine carcinoma. ALK- expression was present in 14% (10 of 70 patients). In all of these patients, no ALK-rearrangement nor ALK-mutation was revealed. Conclusions: Routine testing of NET and NEC samples for an ALK rearrangement is not recommended as ALK-expression is not associated with an ALK-rearrangement. Routine testing of NET and NEC samples for MGMT will detect a promoter hypermethylation in a sizable minority of patients who are eligible for a targeted treatment with temozolomide

Immune checkpoint inhibitory therapy in sarcomas : is there light at the end of the tunnel?

Soft tissue and bone sarcomas are a very heterogeneous group of tumors with many subtypes for which diagnosis and treatment remains a very challenging task. On top of that, the treatment choices are limited, and the prognosis of aggressive sarcomas remains poor. Immune checkpoint inhibitors (ICIs) have drawn a lot of attention last years because of their promising response rates and their durable effects. ICIs are currently widely used in the daily routine practice for the treatment of a different malignancies, such as melanoma, Hodgkin lymphoma, and non-small cell lung carcinoma. Still, ICIs are not included in the standard treatment protocols of the different sarcoma types. However, a plethora of clinical trials investigates the clinical benefit of ICIs in sarcomas. There is clear need to develop predictive biomarkers to determine which sarcoma patients are most likely to benefit from immune checkpoint blockade. This review will focus on (i) the clinical trial results on the use of ICIs in different sarcoma types; and on (ii) possible biomarkers predictive for the effectiveness of these drugs in sarcomas

accepted on the recommendation of

iv Workstations in networks of workstations (NOWs) are sometimes little used, espe-cially in multi-user environments. Employing their compute power for parallel pro-cessing when not used otherwise is an attractive venture, if a practical means to do so can be found. In non-dedicated NOW environments, individual machines become available or unavailable as the workstation “owner ” goes away or returns, so the de-sired parallel processing system must be able to adapt to a continually changing pool of available nodes. Such adaptations should be transparent, allowing the user to program in a relatively standard way, without requiring special-purpose code in the application. In dedicated NOW environments, adaptation permits the job mix to be changed easily. This dissertation claims to demonstrate that attractive solutions for such adaptive parallel processing are feasible, fulfilling the above requirements. To this end, the dissertation presents the design, implementation and evaluation of a system runnin