Inhibition of the Cyclin K-CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate cancer.

Androgen deprivation therapy (ADT) is the mainstay of the current first-line treatment concepts for patients with advanced prostate carcinoma (PCa). However, due to treatment failure and recurrence investigation of new targeted therapeutics is urgently needed. In this study, we investigated the suitability of the Cyclin K-CDK12 complex as a novel therapeutic approach in PCa using the new covalent CDK12/13 inhibitor THZ531. Here we show that THZ531 impairs cellular proliferation, induces apoptosis, and decreases the expression of selected DNA repair genes in PCa cell lines, which is associated with an increasing extent of DNA damage. Furthermore, combination of THZ531 and ADT leads to an increase in these anti-tumoral effects in androgen-sensitive PCa cells. The anti-proliferative and pro-apoptotic activity of THZ531 in combination with ADT was validated in an ex vivo PCa tissue culture model. In a retrospective immunohistochemical analysis of 300 clinical tissue samples we show that Cyclin K (CycK) but not CDK12 expression correlates with a more aggressive type of PCa. In conclusion, this study demonstrates the clinical relevance of the CycK-CDK12 complex as a promising target for combinational therapy with ADT in PCa and its importance as a prognostic biomarker for patients with PCa.

First detection of Erysipelothrix sp. infection in western mosquitofish Gambusia affinis inhabiting catfish aquaculture ponds in Mississippi, USA.

Native and introduced fish can serve as reservoirs for pathogens of cultured fish species. In the current study, 351 archived western mosquitofish Gambusia affinis collected from experimental catfish production ponds in Mississippi, USA, were surveyed histologically to evaluate their potential as vectors for fish pathogens. In addition to epitheliocystis and multiple metazoan parasites, 8 fish had widespread basophilic colonies of small Gram-positive rods associated primarily with stroma supporting the skeletal muscle and bone, as well as connective tissue components of other tissues and organ systems, such as perivascular adventitia and basement membranes. These findings were consistent with spaC-type Erysipelothrix sp. infections in ornamental fish cultured in the USA. The 16S rRNA, gyrase B (gyrB), and surface protective antigen (spa) genes were amplified and sequenced from bacterial colonies excised from paraffin-embedded tissue sections using laser capture microdissection. Molecular data confirmed the identity of a spaC-type Erysipelothrix sp., which grouped phylogenetically with spaC-type Erysipelothrix sp. from diseased ornamental fish. Given the significance of commercial catfish aquaculture in the southeastern USA and the widespread distribution of mosquitofish in catfish ponds throughout the region, infectivity trials with channel catfish Ictalurus punctatus were conducted. Catfish fingerlings were exposed to a spaC-type Erysipelothrix sp. isolate by intracoelomic injection and gavage. No mortality was observed in catfish exposed by either route, and surviving fish demonstrated no significant histopathologic lesions, suggesting channel catfish have low susceptibility to the bacteria. Further research is warranted to investigate the susceptibility of other cultured fish species to this emergent fish pathogen.