A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma

Glioblastoma is one of the most common and lethal types of primary brain tumor. Despite aggressive treatment with chemotherapy and radiotherapy, tumor recurrence within 6–9 months is common. To overcome this, more effective therapies targeting cancer cell stemness, invasion, metabolism, cell death resistance and the interactions of tumor cells with their surrounding microenvironment are required. In this study, we performed a systematic review of the molecular mechanisms that drive glioblastoma progression, which led to the identification of 65 drugs/inhibitors that we screened for their efficacy to kill patient-derived glioma stem cells in two dimensional (2D) cultures and patient-derived three dimensional (3D) glioblastoma explant organoids (GBOs). From the screening, we found a group of drugs that presented different selectivity on different patient-derived in vitro models. Moreover, we found that Costunolide, a TERT inhibitor, was effective in reducing the cell viability in vitro of both primary tumor models as well as tumor models pre-treated with chemotherapy and radiotherapy. These results present a novel workflow for screening a relatively large groups of drugs, whose results could lead to the identification of more personalized and effective treatment for recurrent glioblastoma.     

Interface strength effects on the compressive-flexural/shear failure mode transition of composites subjected to four-point bending

Wang's microbuckling model [1] has been extended to oriented fibre composites loaded in four-point bending. The modified model shows that when any internal parameter (e.g. the interface strength) is changed, the resultant change of the interlaminar shear strength and that of the compressive strength are always of the same sense. Additionally, the degree of change of the shear strength is always larger than that of the compressive strength. As a consequence of this conclusion, a four-point bend test piece which normally fails in the flexural compressive mode may fail in the shear mode upon interface degradation. This was rationalized with the aid of the failure-mode transition diagram [2]. This diagram has been used to explain the change in bend failure mode resulting from a change of the external parameters, such as the span-to-thickness ratio, and the fibre fraction. Experiments were conducted to verify such a failure-mode transition behaviour for fibreglass composites of different interface conditions, when the flexural compressive failure mechanism was of the microbuckling type.     

Assessment of curriculum by medical students: comparison of participants and non-participants in voluntary anamnesis groups. An empirical study

A representative sample of medical students (n = 121) was given a questionnaire to assess parts of their medical education (lectures, seminars, clerkships) and to design a subjectively ideal timetable, which was compared with the real faculty program. Overall traditional lectures received a low rating (n = 0.17) and individual studies with the textbooks a high rating (n = 0.53). The information given in programs in psychiatry and psychosomatics in significantly less motivating than information to be learned in other medical subjects. This is surprising because the ground work for training in the doctor-patient relationship should be in these fields. Students with former group experience (participation in peer groups on history taking (wish to have more practically oriented education compared with the students without group experience. It is not clear whether the important factor is participation in group experience before starting medical school. (64% of the participants had group experience in the first group as opposed to only 45% of the other group). This information should be taken into consideration when reforming medical school programs.     

Investigation of a wet dust scrubber with a pneumatic nozzle: Dust collection based on turbulent diffusion

The “nozzle scrubber” is a wet scrubber in which the scrubbing water is dispersed in dust laden gas stream by means of one or more pneumatic nozzle. This scrubber is distinguished by an excellent collection efficiency for submicron dust at an unusually low energy and water consumption. So far, the physical effects affecting the separation cannot be explained by a well-defined theory. Therefore, it is sensible to investigate the collection efficiency with regard to the mechanisms of inertial impaction, turbulent diffusion and coalescence induced by turbulence. The experimental equipment is of a very simple design. A light scattering device was used to measure the particle distributions. In addition, electron micrographs were analyzed to obtain information about the submicron particles. The influence of operating parameters on grade efficiency has been demonstrated by their systematic variation. The contribution of turbulent diffusion to the collection efficiency has been confirmed; nevertheless, grade efficiencies were also measured when inertial impaction prevailed.     

Developmental and tissue-specific expression of human CD4 in transgenic rabbits

A major obstacle to understanding AIDS is the lack of a suitable small animal model for studying HIV-1 infection and the subsequent development of AIDS, and for testing diagnostic, therapeutic, and preventive modalities. Our goal is to produce a rabbit model for the study of AIDS. Here we report on the generation of transgenic rabbits that express the human CD4 (hCD4) gene. The transgene, which contains the coding region for hCD4 and approximately 23 kb of sequence upstream of the translation start site, was used previously to direct hcD4 expression on the surface of CD4+ T cells of transgenic mice (Gillespie et al., 1993: Mol Cell Biol 13:2952-2958). The hCD4 transgene was detected in five males and two females derived from the microinjection in five males and two females derived from the microinjection of 271 rabbit embryos. Both hCD4 RNA and protein were expressed in peripheral blood lymphocytes (PBLs) from all five males but neither of the females. Human CD4 was expressed on PBLs from F1 offspring of all founder males. T-cell subset analysis revealed that hCD4 expression was restricted to rabbit CD4 (rCD4) expressing lymphocytes; mature rCD4- rCD8+ lymphocytes did not express hCD4. In preliminary studies, PBLs from hCD4 transgenic rabbits produced greater amounts of HIV-1 p24 core protein following HIV-1 infection in vitro than HIV-1 p24 antigen in nontransgenic rabbit infected cultures. These results extend to rabbits our previous observation that this transgene contains the sequence elements required for high-level expression in the appropriate cells of transgenic mice. Furthermore, these and previous studies demonstrating that expression of hCD4 protein enhances HIV-1 infection of rabbit T cells in vitro, coupled with reports that normal, nontransgenic rabbits are susceptible to HIV-1 infection, suggests that the hCD4 transgenic rabbits described herein will have an increased susceptibility to HIV-1 infection. In vivo HIV-1 infection studies with these rabbits are under way.     

Dislocation creep controlled superplasticity in the high carbon steel 140NiCr16-6

Superplasticity in the alloyed high carbon-steel 140NiCr16-6 with phosphorus additions and a fine grained microdupiex structure – containing cementite in volume fractions of 22 % (Fe,Cr,Ni)₃C, particle size of about 1 μm and with a medium ferrite grain size of about 2 μm – has been investigated in the temperature regime of 550 to 675°C and in the strain rate range of 10^?5 to 5 · 10^?2 s^?1. Maximum strain rate exponents of m = 0,45 at 675°C with strain rates of the order of 10^?4 s^?1 have been determined. Maximum superplastic elongations of about 700 % were detected. At higher strain rates of 10^?3 s^?1 superplastic elongations of about 570 % were achieved. At relatively low test temperatures of 550°C elongations up to 230 % were recorded. The activation analysis in the temperature regime of 550 to 650°C show an activation energy for superplastic flow of 250 ± 20 kJ/mol. This is in agreement with the activation energy for lattice self diffusion of iron in α-iron. Above 650°C the activation energy decreases to 70 kJ/mol. This is due to a stress induced decrease in the eutectoid α-γ-transformation temperature from 685°C to somewhat lower temperatures during superplastic deformation. The superplastic deformability (m > 0.3) of this steel in a wide strain rate range at relatively low temperatures above 550°C allows near net shape forming of complex parts applying low flow stresses.