Background: Recent genomic profiling has identified a subtype of prostate cancer (PCa) characterized by two key genetic alterations: missense mutation of speckletype POZ protein (SPOP) and homozygous deletion of chromodomain helicase DNAbinding protein 1 (CHD1). Mutually exclusive with E26 transformation-specific (ETS) rearrangements, this subtype displays high genomic instability. Previous studies indicate that deficient SPOP or CHD1 alone leads to feeble prostate abnormalities and each protein is involved in DNA damage response (DDR). It remains to be determined whether CHD1 and SPOP cooperate to suppress prostate tumorigenesis and DDR. Methods: Prostate-specific single or double knockout of Spop and Chd1 was generated with the Cre/loxP system in mice. Wild-type or mutant SPOP (F102C, F133V) overexpression and CHD1 knockdown with short hairpin RNA were created in human benign prostatic hyperplasia cell line BPH1. The levels of DNA damage and homologous recombination repair were measured by immunofluorescence staining of γH2AX and RAD51, respectively. Results: Spop/Chd1 double-knockout mice displayed prostatic intraepithelial neoplasia at both young (3 months) and old (12 months) ages and failed to generate prostate adenocarcinoma. Compared with wild-type or single-knockout mice, the double-knockout prostate harbored moderately higher proliferating cells and dramatically augmented the level of γH2AX staining, although androgen receptorpositive cells and apoptotic cells remained at a similar level. In BPH1 cell line, SPOP mutant overexpression and CHD1 silencing synergistically sensitized the cells to DNA damage by camptothecin, an inducer of double-strand breaks. Conclusions: Our results indicate that SPOP and CHD1 can synergistically promote repair of naturally occurring or chemically induced DNA damages in prostate epithelial cells. Regarding the progression of the SPOP/CHD1 subtype of PCa, other functionally complementary drivers warrant further identification. The clinical implication is that this subtype of PCa may be particularly sensitive to poly(ADPribose) polymerase inhibitors or DNA-damaging agents.

The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell–intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 ( PYGO2 ) as the driver oncogene for the amplicon at 1q21.3 in prostate cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8 + T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate cancer.

Currently, the tracking of seizures is highly subjective, dependent on qualitative information provided by the patient and family instead of quantifiable seizure data. Usage of a seizure detection device to potentially detect seizure events in a population of epilepsy patients has been previously done. Therefore, we chose the Fitbit Charge 2 smart watch to determine if it could detect seizure events in patients when compared to continuous electroencephalographic (EEG) monitoring for those admitted to an epilepsy monitoring unit. A total of 40 patients were enrolled in the study that met the criteria between 2015 and 2016. All seizure types were recorded. Twelve patients had a total of 53 epileptic seizures. The patient-aggregated receiver operating characteristic curve had an area under the curve of 0.58 [0.56, 0.60], indicating that the neural network models were generally able to detect seizure events at an above-chance level. However, the overall low specificity implied a false alarm rate that would likely make the model unsuitable in practice. Overall, the use of the Fitbit Charge 2 activity tracker does not appear well suited in its current form to detect epileptic seizures in patients with seizure activity when compared to data recorded from the continuous EEG.

The International Classification of Diseases (ICD) system includes sub codes to indicate that an individual with epilepsy is treatment resistant. These codes would be a valuable tool to identify individuals for quality improvement and population health, as well as for recruitment into clinical trials. However, the accuracy of these codes is unclear. We performed a single center cross sectional study to understand the accuracy of ICD codes for treatment resistant epilepsy. We identified 344 individuals, roughly half with treatment resistant epilepsy The ICD code had a sensitivity of 90% (147 of 164) and specificity of 86% (155 of 180). The miscoding of children with refractory epilepsy was attributed to the following reasons: 5 patients had epilepsy surgery, 4 had absence epilepsy, 4 patients were seen by different providers, and 1 patient was most recently seen in movement disorders clinic. ICD codes accurately identify children with treatment resistant epilepsy.

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