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Significant evidence suggests that misfolded alpha‐synuclein (aSyn), a major component of Lewy bodies, propagates in a prion‐like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha‐synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human‐relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF‐injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human‐relevant pre‐clinical measures and suggest that these pre‐clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease. [ABSTRACT FROM AUTHOR]

Purpose Inpatient drug purchase price trends at an 811-bed academic medical center are described. Summary Recent highly publicized drug price increases by pharmaceutical manufacturers have generated public interest in regulatory solutions to reduce drug costs. Monitoring drug price changes through internal dashboards has been demonstrated to aid in purchasing decisions to reduce the impact of drug price changes on inpatient pharmacy drug budgets. In this research, University of Chicago Medicine created an internal dashboard to detail specific inpatient drug purchase price trends. Dashboard data input included all medications purchased through the organization's group purchasing organization over a 25-month time frame. A total of 69,245 drug purchases of 2,432 unique medications and/or dosage strengths were analyzed in the study. Within the 25-month time period, 706 medications (29%) had a net drug purchase price increase, while 898 (37%) had a net drug purchase price decrease. The range of net price percentage changes for medications with price increases was 0.01% to 733.6%; the range for medications with price decreases was 0.01% to 97.5%. Conclusion Relative to previous purchase prices, drug purchase prices decreased or remained the same more often than they increased over a 25-month time frame. However, drug purchase price percentage changes were far greater for medications whose prices increased rather than decreased. [ABSTRACT FROM AUTHOR]

BACKGROUND: Asparaginase agents are vital in the treatment of acute lymphoblastic leukemia (ALL) and can be delivered via an intravenous (IV) or intramuscular (IM) injection. Hypersensitivity reaction (HSR) rates with these agents are common, multifactorial, and treatment-altering. The specific route of asparaginase administration may lead to disparate rates of HSRs and other adverse events in pediatric patients with ALL. OBJECTIVE: To analyze the role of administration route in the incidence and severity of adverse events in pediatric patients receiving asparaginase therapy. METHODS: This single-center, retrospective analysis evaluated patients receiving pegaspargase or Erwinia asparaginase from January 1, 2008, through September 30, 2015. The primary outcome measured the incidence of HSRs with IV or IM pegaspargase and IV or IM Erwinia asparaginase. Secondary outcomes included the potential role of administration route on the timing and rate of adverse drug events. RESULTS: A total of 368 patients received pegaspargase during the study period. Of this group, 199 received only IV pegaspargase, 138 received only IM pegaspargase, and 31 received both IV and IM pegaspargase. Overall, HSRs occurred in 18.6% of patients who received IV administration and 13.8% who received IM administration (P = .241). Among patients who received both routes during ALL treatment, 9.7% had an HSR. A total of 43 (76.8%) patients had an HSR during the consolidation phase of therapy. A total of 517 Erwinia asparaginase doses were administered, and only 1 patient had an HSR. We found increased antiemetic use in 28 (36.4%) of 77 IV Erwinia asparaginase doses compared with only 28 (6.4%) of 440 IM doses (P <.001). CONCLUSION: Our findings showed no significant difference in HSR rates between patients receiving IV pegaspargase and those receiving IM pegaspargase. Hypersensitivity resulting from Erwinia asparaginase were infrequent, and IV Erwinia asparaginase administration displayed more emetogenicity than the traditional IM route. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). Surveillance in this at-risk population remains challenging. We assessed the methylation status of genes in the non-neoplastic mucosa of UC–CRC patients and controls to identify potential biomarkers of CRC.METHODS:We evaluated the methylation status of 10 genes (p16, p14, runt-related transcript factor-3 (RUNX3), cyclooxygenase-2 (COX-2), E-cadherin, methylated-in-tumor-1 (MINT1), MINT31, HPP1, estrogen receptor, SLC5A8) in UC–CRC tumors and non-neoplastic sections from both UC–CRC cases and UC controls (n=114 for each) using methylation-specific PCR.RESULTS:Amplification was successful for 96 UC controls, 83 tumors, and 66 non-adjacent, non-neoplastic samples. The prevalence of methylation was significantly greater in UC–CRC tumors for p16, RUNX3, MINT1, MINT31, and HPP1. Methylation of COX-2 and E-cadherin was greater in UC controls than in tumors. Univariate testing of these genes using non-adjacent, non-neoplastic sections from UC–CRC cases indicated that associations between p16, RUNX3, MINT1, MINT31, E-cadherin, and COX-2 and UC–CRC remained significant. In multivariable analysis of the six genes, only RUNX3, MINT1, and COX-2 remained significantly associated with the UC–CRC cases (odds ratio=12.6, 9.0, and 0.2, respectively). The results remained unaffected by the presence of PSC or severity of inflammation. Logistic regression modeling with the three genes showed interactions that increased the odds ratio for each gene.CONCLUSIONS:RUNX3, MINT1, and COX-2 are potential biomarkers for detecting the presence of CRC in patients with UC. These genes should be evaluated as biomarkers for colorectal dysplasia. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Improved treatments for advanced HCC are urgently needed. The recently identified human sulfatase 1 enzyme (SULF1) desulfates cell surface heparan sulfate glycosaminoglycans and down-regulates cell growth signaling in HCC cells in vitro. While investigating the epigenetic regulation of SULF1, we discovered that histone H4 acetylation is up-regulated by SULF1 in HCC cells. Histone deacetylase (HDAC) inhibitors reprogram cellular gene expression through the acetylation of nucleosomal histones and promote cell growth arrest and apoptosis. Hence, they are a promising modality for cancer treatment. Methods: To explore the interaction between SULF1 expression and HDAC inhibitor action, we examined the effects of SULF1 expression on HCC cells and xenografts treated with HDAC inhibitors. Results: (1) Forced expression of SULF1 significantly delayed the growth of Huh7 and Hep3B xenografts in nude mice in vivo. (2) SULF1 increased histone H4 acetylation by modulation of cellular HDAC and histone acetyltransferase activities. (3) SULF1 enhanced the induction of apoptosis by the HDAC inhibitors apicidin and scriptaid. (4) SULF1 enhanced the inhibition of tumor growth, migration, and angiogenesis by HDAC inhibitors. We also demonstrate that knockdown of SULF1 with shRNA constructs up-regulates phosphorylation of AKT and Erk and attenuates apicidin-induced apoptosis. The interaction between SULF1 and apicidin was confirmed in vivo in Huh7 and Hep3B xenografts. Conclusions: These results show that SULF1 promotes histone H4 acetylation, potentiates the effects of HDAC inhibitors, and inhibits HCC tumorigenesis. [Copyright &y& Elsevier]