Our findings reveal that clonogenic cellular survival is not solely determined by the DNA-DSB response. This finding may suggest the involvement of extra-nuclear radiosensitive targets in cell inactivation. For example, the mitochondria or the cell membrane could be affected by Tc-HMPAO.

The aim of the study was to increase the uptake of the SSTR2-targeted radioligand Lu-177-DOTATATE using the DNA methyltransferase inhibitor (DNMTi) 5-aza-2′-deoxycytidine (5-aza-dC) and the histone deacetylase inhibitor (HDACi) valproic acid (VPA). The HEKsst2 and PC3 cells were incubated with variable concentrations of 5-aza-dC and VPA to investigate the uptake of Lu-177-DOTATATE. Cell survival, subsequent to external X-rays (0.6 or 1.2 Gy) and a 24 h incubation with 57.5 or 136 kBq/mL Lu-177-DOTATATE, was investigated via colony formation assay to examine the effect of the epidrugs. In the case of stimulated HEKsst2 cells, the uptake of Lu-177-DOTATATE increased by a factor of 28 in comparison to the unstimulated cells. Further, stimulated HEKsst2 cells demonstrated lower survival fractions (factor 4). The survival fractions of the PC3 cells remained almost unchanged. VPA and 5-aza-dC did not induce changes to the intrinsic radiosensitivity of the cells after X-ray irradiation. Clear stimulatory effects on HEKsst2 cells were demonstrated by increased cell uptake of the radioligand and enhanced SST2 receptor quantity. In conclusion, the investigated approach is suitable to stimulate the somatostatin receptor expression and thus the uptake of Lu-177-DOTATATE, enabling a more efficient treatment for patients with poor response to peptide radionuclide therapy (PRRT).

Aim The combination of conventional chemotherapeutic drugs with radionuclides or external radiation is discussed for a long period of time. The major advantage of a successful combination therapy is the reduction of severe side effects by decreasing the needed dose and simultaneously increasing therapeutic efficiency. Methods In this study, pUC19 plasmid DNA was incubated with the cytostatic drug cisplatin and additionally irradiated with 99mTc, 188Re and 223Ra. To verify the contribution of possibly excited platinum atoms to the emission of Auger electrons we determined DNA damages, such as single- and double strand breaks. Results The threshold concentration value of cisplatin, which was tolerated by pUC19 plasmid DNA was determined to be 18–24 nM. Nevertheless, even at higher dose values (>100 Gy) and simultaneous incubation of cisplatin to 200 ng plasmid DNA, no significant increase in the number of induced single- and double-strand breaks was obtained, compared to the damage solely caused by the radionuclides. Conclusion We thereby conclude that there is no direct dependence of the mechanism of strand break induction to the absence or presence of platinum atoms attached to the DNA. Reported increasing DNA damages in therapy approaches on a cellular level strongly depend on the study design and are mainly influenced by repair mechanisms in living cells. Nevertheless, the use of radioactive cisplatin, containing the Auger electron emitter 191Pt, 193mPt or 195mPt, is a bright prospect for future therapy by killing tumor cells combining two operating principles: a cytostatic drug and a radiopharmaceutical at the same time.

The precise development of the neocortex is a prerequisite for higher cognitive and associative functions. Despite numerous advances that have been made in understanding neuronal differentiation and cortex development, our knowledge regarding the impact of specific genes associated with neurodevelopmental disorders on these processes is still limited. Here, we show that Taok2, which is encoded in humans within the autism spectrum disorder (ASD) susceptibility locus 16p11.2, is essential for neuronal migration. Overexpression of de novo mutations or rare variants from ASD patients disrupts neuronal migration in an isoform-specific manner. The mutated TAOK2α variants but not the TAOK2β variants impaired neuronal migration. Moreover, the TAOK2α isoform colocalizes with microtubules. Consequently, neurons lacking Taok2 have unstable microtubules with reduced levels of acetylated tubulin and phosphorylated JNK1. Mice lacking Taok2 develop gross cortical and cortex layering abnormalities. Moreover, acute Taok2 downregulation or Taok2 knockout delayed the migration of upper-layer cortical neurons in mice, and the expression of a constitutively active form of JNK1 rescued these neuronal migration defects. Finally, we report that the brains of the Taok2 KO and 16p11.2 del Het mouse models show striking anatomical similarities and that the heterozygous 16p11.2 microdeletion mouse model displayed reduced levels of phosphorylated JNK1 and neuronal migration deficits, which were ameliorated upon the introduction of TAOK2α in cortical neurons and in the developing cortex of those mice. These results delineate the critical role of TAOK2 in cortical development and its contribution to neurodevelopmental disorders, including ASD.