A number of prostate cancer (PCa)‐specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration‐resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first‐line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion‐positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first‐line endocrine therapy for PCa patients with diagnosed BRCAness.
The CovILD study is a prospective, multicenter, observational cohort study to systematically follow up patients after coronavirus disease-2019 (COVID-19). We extensively evaluated 145 COVID-19 patients at 3 follow-up visits scheduled for 60, 100, and 180 days after initial confirmed diagnosis based on typical symptoms and a positive reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We employed comprehensive pulmonary function and laboratory tests, including serum concentrations of IgG against the viral spike (S) glycoprotein, and compared the results to clinical data and chest computed tomography (CT). We found that at the 60 day follow-up, 131 of 145 (90.3%) participants displayed S-specific serum IgG levels above the cut-off threshold. Notably, the highly elevated IgG levels against S glycoprotein positively correlated with biomarkers of immune activation and negatively correlated with pulmonary function and the extent of pulmonary CT abnormalities. Based on the association between serum S glycoprotein-specific IgG and clinical outcome, we generated an S-specific IgG-based recovery score that, when applied in the early convalescent phase, accurately predicted delayed pulmonary recovery after COVID-19. Therefore, we propose that S-specific IgG levels serve as a useful immunological surrogate marker for identifying at-risk individuals with persistent pulmonary injury who may require intensive follow-up care after COVID-19.
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