Citations

Abstract Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479–90. ©2017 AACR.

AbstractObjectiveTo assess the predictive potential of the complete response pattern from the University of Pennsylvania Smell Identification Test for the diagnosis of Parkinson's disease.MethodsWe analyzed a large dataset from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study of health and disease in elderly volunteers. Using the complete pattern of responses to all 40 items in each subject's test, we built predictive models of neurodegenerative disease, and we validated these models out of sample by comparing model predictions against postmortem pathological diagnosis.ResultsConsistent with anatomical considerations, we found that the specific test response pattern had additional predictive power compared with a conventional measure – total test score – in Parkinson's disease, but not Alzheimer's disease. We also identified specific test questions that carry the greatest predictive power for disease diagnosis.InterpretationOlfactory ability has typically been assessed with either self‐report or total score on a multiple choice test. We showed that a more accurate clinical diagnosis can be made using the pattern of responses to all the test questions, and validated this against the “gold standard” of pathological diagnosis. Information in the response pattern also suggests specific modifications to the standard test that may optimize predictive power under the typical clinical constraint of limited time. We recommend that future studies retain the individual item responses for each subject, and not just the total score, both to enable more accurate diagnosis and to enable additional future insights.

Abstract Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.

AbstractMost FDA‐approved drugs are not equally effective in all patients, suggesting that identification of biomarkers to predict responders to a chemoprevention agent will be needed to stratify patients and achieve maximum benefit. The goal of this study was to investigate both patient‐specific and cell context‐specific heterogeneity of metformin response, using fibroblast cell lines and induced pluripotent stem cells differentiated into lung epithelial lineages. We performed cell survival analysis, transcriptome and whole exome sequencing analysis on both patient‐derived cell lines and cancer cell lines to assess differential metformin response and identify response genes. We found differences in response to metformin treatment across a variety of cell lines and cellular contexts, suggesting that heterogeneity may be patient‐ and cell type‐specific. Gene expression profiling and analysis of metformin‐sensitive and metformin‐resistant cells identified differentially expressed genes that may be able to stratify patients into metformin responders and non‐responders. Sequencing analysis found genomic alterations that correlated with metformin response. These results suggest that the identification of genomic biomarkers for patients who may respond to metformin treatment can provide an opportunity for individualizing metformin chemoprevention in the clinical setting.

Background and purpose Mutations in the glucocerebrosidase ( GBA ) gene are known to be a risk factor for Parkinson's disease ( PD ). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene. Methods Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation. Clinical and neuropathological data were compared. Results Twelve PD cases had a GBA mutation and 102 did not. The GBA mutation cases died younger (76 vs. 81 years of age) but there was no difference in disease duration or clinical examination findings. No neuropathological differences were found in total or regional semi‐quantitative scores for Lewy‐type synucleinopathy, senile plaques, neurofibrillary tangles, white matter rarefaction or cerebral amyloid angiopathy scores. Conclusions In longitudinally assessed, autopsied PD cases, those with GBA mutations had a younger age at death but there was no evidence for clinical or neuropathological differences compared to cases without GBA mutations. Due to the small GBA group size, small differences cannot be excluded.

Abstract Background Adverse childhood experiences ( ACE s) are associated with adult high‐risk behaviors and diseases. There is value in screening parents for ACE s given the repercussions parental ACE s may have on parenting behaviors and child development. The primary aim of this study was to assess the feasibility of parental ACE screening in the home setting. A secondary aim was to evaluate whether or not maternal ACE s correlated with maternal mental health measures. Methods Two home visiting programs that support early childhood development and conduct parental mental health screening implemented ACE screening for parents of infants <1 year of age. Descriptive statistics were produced for population surveillance of ACE s as well as standard practice screens for depression, anxiety, substance use, and intimate partner violence. Logistic models were used to examine associations between ACE score and mental health measures. Results A total of 110 parents completed the ACE screen. All possible ACE score outcomes were represented (0–10). A trend toward association of positive prenatal maternal depression screen with ACE score was identified ( p = .05). Conclusion This novel prospective home‐based screening program for parental ACE s was feasible and identified a trend toward increasing ACE score association with positive prenatal maternal depression screen.

Tumours arising from mesenchymal tissue components such as vascular, fibrous and adipose tissue can manifest in the liver. Although histopathology is often necessary for definitive diagnosis, many of these lesions exhibit characteristic imaging features. The radiologist plays an important role in suggesting the diagnosis, which can direct appropriate immunohistochemical staining at histology. The aim of this review is to present clinical and imaging findings of a spectrum of mesenchymal liver tumours such as haemangioma, epithelioid haemangioendothelioma, lipoma, PEComa, angiosarcoma, inflammatory myofibroblastic tumour, solitary fibrous tumour, leiomyoma, leiomyosarcoma, Kaposi sarcoma, mesenchymal hamartoma, undifferentiated embryonal sarcoma, rhabdomyosarcoma and hepatic metastases. Knowledge of the characteristic features of these tumours will aid in guiding the radiologic diagnosis and appropriate patient management.