Faculty Bibliography

BACKGROUND:The rs1344706 single nucleotide polymorphism in the ZNF804A gene has been associated with risk for psychosis in multiple genome-wide association studies, yet mechanisms underlying this association are not known. Given preclinical work suggesting an impact of ZNF804A on dopamine receptor gene transcription and clinical studies establishing dopaminergic dysfunction in patients with schizophrenia, we hypothesized that the ZNF804A risk single nucleotide polymorphism would be associated with variation in dopamine receptor availability in the human brain. METHODS:receptor availability, respectively. Genetic effects on estimates of binding potential for each ligand were tested first with canonical subject-specific striatal regions of interest analyses, followed by exploratory whole-brain voxelwise analyses to test for more localized striatal signals and for extrastriatal effects. RESULTS:receptor availability. CONCLUSIONS:These data suggest that ZNF804A genotype may be meaningfully linked to dopaminergic function in the human brain. The results also may provide information to guide future studies of ZNF804A-related mechanisms of schizophrenia risk.

Host cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here we describe a histone acetylome-wide association study (HAWAS) of an infectious disease, on the basis of genome-wide H3K27 acetylation profiling of peripheral blood granulocytes and monocytes from persons with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Singapore Chinese discovery cohort (n = 46), which were validated in a subsequent multi-ethnic Singapore cohort (n = 29), as well as a longitudinal cohort from South Africa (n = 26), thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulates apoptosis and promotes Mtb clearance in vitro. We performed histone acetylation quantitative trait locus (haQTL) analysis on the dataset and identified 69 candidate causal variants for immune phenotypes among granulocyte haQTLs and 83 among monocyte haQTLs. Our study provides proof-of-principle for HAWAS to infer mechanisms of host response to pathogens.

BACKGROUND:Retrograde intrarenal surgery (RIRS) has become the preferred treatment modality for nephrolithiasis. However, because of ongoing uncertainties regarding the optimal perioperative management, operative technique, and postoperative follow-up, as well as a lack of standardization for outcome reporting, consensus is needed to achieve more uniform clinical practice worldwide. OBJECTIVE:To develop recommendations for RIRS on the basis of existing data and expert consensus. DESIGN, SETTING, AND PARTICIPANTS:A protocol-driven, three-phase study was conducted by the European Association of Urology Section of Urolithiasis (EULIS) and the International Alliance of Urolithiasis (IAU). The process included: (1) a nonsystematic review of the literature to define domains for discussion; (2) a two-round modified Delphi survey involving experts in this field; and (3) an additional group meeting and third-round survey involving 64 senior representative members to formulate the final conclusions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The results from each previous round were returned to the participants for re-evaluation of their decisions during the next round. The agreement threshold was set at 70%. RESULTS AND LIMITATIONS:The panel included 209 participants who developed 29 consensus statements on the following topics of interest: (1) perioperative infection management; (2) perioperative antithrombotic therapy; (3) fundamentals of the operative technique; and (4) standardized outcome reporting. Although this consensus can be considered as a useful reference for more clinically oriented daily practice, we also acknowledge that a higher level of evidence from further clinical trials is needed. CONCLUSIONS:The consensus statements aim to guide and standardize clinical practice and research on RIRS and to recommend standardized outcome reporting. PATIENT SUMMARY:An international consensus on the best practice for minimally invasive surgery for kidney stones was organized and developed by two international societies. It is anticipated that this consensus will provide further guidance to urologists and may help to improve clinical outcomes for patients.

A leading theory for ovarian carcinogenesis proposes that inflammation associated with incessant ovulation is a driver of oncogenesis. Consistent with this theory, nonsteroidal anti-inflammatory drugs (NSAIDs) exert promising chemopreventive activity for ovarian cancer. Unfortunately, toxicity is associated with long-term use of NSAIDs due to their cyclooxygenase (COX) inhibitory activity. Previous studies suggest the antineoplastic activity of NSAIDs is COX independent, and rather may be exerted through phosphodiesterase (PDE) inhibition. PDEs represent a unique chemopreventive target for ovarian cancer given that ovulation is regulated by cyclic nucleotide signaling. Here we evaluate PDE10A as a novel therapeutic target for ovarian cancer. Analysis of The Cancer Genome Atlas (TCGA) ovarian tumors revealed PDE10A overexpression was associated with significantly worse overall survival for patients. PDE10A expression also positively correlated with the upregulation of oncogenic and inflammatory signaling pathways. Using small molecule inhibitors, Pf-2545920 and a novel NSAID-derived PDE10A inhibitor, MCI-030, we show that PDE10A inhibition leads to decreased ovarian cancer cell growth and induces cell cycle arrest and apoptosis. We demonstrate these pro-apoptotic properties occur through PKA and PKG signaling by using specific inhibitors to block their activity. PDE10A genetic knockout in ovarian cancer cells through CRISP/Cas9 editing lead to decreased cell proliferation, colony formation, migration and invasion, and in vivo tumor growth. We also demonstrate that PDE10A inhibition leads to decreased Wnt-induced β-catenin nuclear translocation, as well as decreased EGF-mediated activation of RAS/MAPK and AKT pathways in ovarian cancer cells. These findings implicate PDE10A as novel target for ovarian cancer chemoprevention and treatment.

OBJECTIVE:Identifying the transcripts which mediate genetic association signals for type 2 diabetes (T2D) is critical to understand disease mechanisms. Studies in pancreatic islets support the transcription factor ZMIZ1 as a transcript underlying a T2D GWAS signal, but how it influences T2D risk is unknown. METHODS:mice and their control littermates on chow diet (CD) and high fat diet (HFD). Islet morphology and function were examined by immunohistochemistry and in vitro islet function was assessed by dynamic insulin secretion assay. Transcript and protein expression were assessed by RNA sequencing and Western blotting. In islets isolated from genotyped human donors, we assessed glucose-dependent insulin secretion and islet insulin content by static incubation assay. RESULTS:mice fail to expand β-cell mass and become severely diabetic. Human islets from carriers of the ZMIZ1-linked T2D-risk alleles have reduced islet insulin content and glucose-stimulated insulin secretion. CONCLUSIONS:β-Cell Zmiz1 is required for normal glucose homeostasis. Genetic variation at the ZMIZ1 locus may influence T2D-risk by reducing islet mass expansion upon metabolic stress and the ability to maintain a mature β-cell state.

BACKGROUND/UNASSIGNED:Rapid eye movement (REM) sleep behavior disorder (RBD), a parasomnia, after being diagnosed, can predict the emergence of an alpha-synuclein-associated neurodegenerative disease (NDD) in 20-45% and 92% of patients within 5 and 14 years, respectively. RBD is less common in tauopathies, and the studies to evaluate its association with polyglutamine diseases have been very few. OBJECTIVE/UNASSIGNED:To revisit our knowledge on the significance of RBD in the emergence of NDDs and to review the recent updates in the potential biomarkers, which can help predict the risk of phenconversion into NDDs in idiopathic RBD (iRBD) patients. We also aimed to look at the potential neuroprotective therapies that can potentially be used earlier in iRBD patients. METHODS/UNASSIGNED:We conducted a review of the papers, after selecting them from the PubMed database. After a thorough screening, 51 articles were chosen to be included in this review. RESULTS AND CONCLUSION/UNASSIGNED:The prospective studies showed that the risk of phenoconversion of iRBD into overt NDDs increased over the longer duration of follow up. Magnetic resonance imaging (MRI) findings, Electroencephalographic findings along with subtle motor signs, autonomic dysfunction, impaired olfaction, and color vision, among others, can be used to predict the onset of an NDD in iRBD. Phytocannabinoids showed a possible neuroprotective effect in animal studies. Considering how RBD is the antecedent of NDDs, there is a need for additional studies to better understand the utility of the aforementioned biomarkers and institute potential neuroprotective therapies early in the process.

Meningiomas are the most common non-metastatic brain tumors, and although the majority are relatively slow-growing and histologically benign, a subset of meningiomas are aggressive and remain challenging to treat. Despite a standard of care that includes surgical resection and radiotherapy, and recent advances in meningioma molecular grouping, there are no systemic medical options for patients with meningiomas that are resistant to standard interventions. Misactivation of the cell cycle at the level of CDK4/6 is common in high-grade or molecularly aggressive meningiomas, and CDK4/6 has emerged as a potential target for systemic meningioma treatments. In this review, we describe the preclinical evidence for CDK4/6 inhibitors as a treatment for high-grade meningiomas and summarize evolving clinical experience with these agents. Further, we highlight upcoming clinical trials for patients meningiomas, and discuss future directions aimed at optimizing the efficacy of these therapies and selecting patients most likely to benefit from their use.