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Determinants and Equity Evaluation for Health Expenditure Among Patients with Rare Diseases in China.

Chin Med J (Engl). 2016 Jun 20;129(12):1387-93

Authors: Xin XX, Zhao L, Guan XD, Shi LW

Abstract
BACKGROUND: China has not established social security system for rare diseases. Rare diseases could easily impoverish patients and their families. Little research has studied the equity and accessibility of health services for patients with rare diseases in China. This study aimed to explore the factors that influence health expenditure of rare diseases and evaluate its equity.
METHODS: Questionnaire survey about living conditions and cost burden of patients with rare diseases was conducted. Individual and family information, health expenditure and reimbursement in 2014 of 982 patients were collected. The impact of medical insurance, individual sociodemographic characteristics, family characteristics, and healthcare need on total and out-of-pocket (OOP) health expenditures was analyzed through the generalized linear model. Equity of health expenditure was evaluated by both concentration index and Lorenz curve.
RESULTS: Of all the surveyed patients, 11.41% had no medical insurance and 92.10% spent money to seek medical treatment in 2014. It was suggested female (P = 0.048), over 50 years of age (P = 0.062), high-income group (P = 0.021), hospitalization (P = 0.000), and reimbursement ratio (RR) (P = 0.000) were positively correlated with total health expenditure. Diseases not needing long-term treatment (P = 0.000) was negatively correlated with total health expenditure. Over 50 years of age (P = 0.065), high-income group (P = 0.018), hospitalization (P = 0.000) and having Urban Employee Basic Medical Insurance (UEBMI) (P = 0.022) were positively correlated with OOP health expenditure. Patient or the head of the household having received higher education (P = 0.044 and P = 0.081) and reimbursement ratio (P = 0.078) were negatively correlated with OOP health expenditure. The equity evaluation found concentration indexes of health expenditure before and after reimbursement were 0.0550 and 0.0539, respectively.
CONCLUSIONS: OOP health expenditure of patients with UEBMI was significantly more than that of patients without medical insurance. However, for any other medical insurance, there was no difference between OOP health expenditure of the insured patients and patients without insurance. The current reimbursement policies have increased the equity of health expenditure, but are biased toward high-income people.

PMID: 27270531 [PubMed - indexed for MEDLINE]

Risk for molecular contamination of tissue samples evaluated for targeted anti-cancer therapy.

PLoS One. 2017;12(3):e0173760

Authors: Asor E, Stav MY, Simon E, Fahoum I, Sabo E, Ben-Izhak O, Hershkovitz D

Abstract
With the increasing usage of sensitive PCR technology for pharmacogenetics, cross contamination becomes a significant concern. Researchers employed techniques which basically include replacing laboratory equipment after each sample preparation; however, there are no recommended guidelines. In the present work we wanted to evaluate the risk of cross contamination during tissue processing using the routine precaution measures. Twenty-one surgical samples of lung adenocarcinoma were used, of which 7 contained EGFR exon 19 mutation, 7 contained EGFR exon 21 mutation (p.L858R) and 7 were EGFR wild-type. The samples were ordered by alternating the mutation group to maximize the potential for cross contamination and underwent tissue sectioning and de-paraffinization. The entire process was performed using the same tools. Following DNA extraction all samples underwent PCR amplification and were scrutinized for small fractions of EGFR mutation using deep sequencing with the Ion torrent PGM technology. Twenty samples yielded results. The fraction of mutated copies was 41 ± 23% (range 11-66) for the cases with known exon 19 mutation and 48±24% (range 0-65) for the cases with known exon 21 mutations. No in-frame exon 19 deletion mutations were identified in the wild-type (WT) and exon 21 groups. The fraction of EGFR exon 21 (codon 858) mutations was 0.018±0.014% (range 0-0.05%) in the WT and exon 19 groups, which was not statistically different than the background sequencing artifact noise for the same base-pair alteration (p = 0.21). Our results suggest that standard precautions are sufficient for molecular pathology diagnosis of surgical samples and are not associated with increased risk of cross contamination.

PMID: 28288198 [PubMed - in process]

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Aucubin and its hydrolytic derivative attenuate activation of hepatic stellate cells via modulation of TGF-β stimulation.

Environ Toxicol Pharmacol. 2017 Mar;50:234-239

Authors: Lv PY, Feng H, Huang WH, Tian YY, Wang YQ, Qin YH, Li XH, Hu K, Zhou HH, Ouyang DS

Abstract
Eucommia ulmoides is an important traditional Chinese medicine and has been used as a tonic with a long history. Aucubin is an active component extracted from Eucommia ulmoides, which has liver-protection effects. However the mechanisms are still unclear. To investigate the inhibitory effects and the underlying mechanisms of aucubin on TGF-β1-induced activation of hepatic stellate cells and ECM deposition, Human hepatic stellate cells (LX-2 cells) were incubated with TGF-β1 to evaluate the anti-fibrotic effect of aucubin. Western blot was used to investigate the expression of α-SMA, Col I, Col III, MMP-2 and TIMP-1. ROS production was monitored using DCFH-DA probe, and NOX4 expression was detected by Real-time PCR. Results indicated that TGF-β1 stimulated the activation and ECM deposition of LX-2 cells. Compared with the control group, aucubin and aucubigenin both reduced the protein expression of α-SMA, Col I, Col III and MMP-2 in LX-2 cells. Aucubin and aucubigenin also suppressed the generation of ROS and down-regulated the NOX4 mRNA expression. Taken together, aucubin and aucubigenin both inhibit the activation and ECM deposition of LX-2 cells activated by TGF-β1. Aucubin and aucubigenin are potential therapeutic candidate drugs for liver fibrosis.

PMID: 28199906 [PubMed - indexed for MEDLINE]

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No association between non-bullous skin reactions from lamotrigine and heterozygosity of UGT1A4 genetic variants *2(P24T) or *3(L48V) in Norwegian patients.

Seizure. 2017 Feb;45:169-171

Authors: Shirzadi M, Reimers A, Helde G, Sjursen W, Brodtkorb E

Abstract
PURPOSE: High initial serum concentrations increase the risk of cutaneous adverse reactions. Genetic variants of the main metabolizing isoenzyme, uridine diphosphate glucuronosyltransferase (UGT) 1A4 influence the elimination of lamotrigine (LTG). Our aim was to investigate the potential association between the two best studied variants, *2 (P24T) and *3 (L48V), and the occurrence non-bullous skin reactions from LTG.
METHOD: The study included 29 patients of Caucasian ethnicity with a history of non-bullous skin reactions from LTG. 184 subjects tolerant to LTG for at least three months were used as controls. UGT1A4 genotyping was performed in all patients and controls by sequencing of the first part of exon 1. Six controls were excluded due to rare genetic variants.
RESULTS: Two of 29 subjects (7%) with rash from LTG were heterozygous for UGT1A4 *2, compared to 23 of 178 (13%) tolerant controls (p=0.54). Four of 29 subjects (14%) with rash from LTG were heterozygous for UGT1A4 *3 compared to 25 of 178 (14%) tolerant controls (p=0.97).
CONCLUSION: It is unlikely that heterozygosity of the UGT1A4 genetic variants *2(P24T) or *3(L48V) influences the risk of non-bullous skin reactions in patients treated with LTG.

PMID: 28068583 [PubMed - indexed for MEDLINE]

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Integrated Approaches to Drug Discovery for Oxidative Stress-Related Retinal Diseases.

Oxid Med Cell Longev. 2016;2016:2370252

Authors: Nishimura Y, Hara H

Abstract
Excessive oxidative stress induces dysregulation of functional networks in the retina, resulting in retinal diseases such as glaucoma, age-related macular degeneration, and diabetic retinopathy. Although various therapies have been developed to reduce oxidative stress in retinal diseases, most have failed to show efficacy in clinical trials. This may be due to oversimplification of target selection for such a complex network as oxidative stress. Recent advances in high-throughput technologies have facilitated the collection of multilevel omics data, which has driven growth in public databases and in the development of bioinformatics tools. Integration of the knowledge gained from omics databases can be used to generate disease-related biological networks and to identify potential therapeutic targets within the networks. Here, we provide an overview of integrative approaches in the drug discovery process and provide simple examples of how the approaches can be exploited to identify oxidative stress-related targets for retinal diseases.

PMID: 28053689 [PubMed - indexed for MEDLINE]

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The challenges of pharmacokinetic variability of first-line anti-TB drugs.

Expert Rev Clin Pharmacol. 2017 Jan;10(1):47-58

Authors: Devaleenal Daniel B, Ramachandran G, Swaminathan S

Abstract
INTRODUCTION: Inter-individual variations in the pharmacokinetics (PK) of anti-TB drugs are known to occur, which could have important therapeutic implications in patient management. Areas covered: We compiled factors responsible for PK variability of anti-TB drugs reported from different settings that would give a better understanding about the challenges of PK variability of anti-TB medications. We searched PubMed data base and Google scholar from 1976 to the present using the key words 'Pharmacokinetics', 'pharmacokinetic variability', 'first-line anti-TB therapy', 'Rifampicin', 'Isoniazid', 'Ethambutol', 'Pyrazinamide', 'food', 'nutritional status', 'HIV', 'diabetes', 'genetic polymorphisms' and 'pharmacokinetic interactions'. We also included abstracts from scientific meetings and review articles. Expert commentary: A variety of host and genetic factors can cause inter-individual variations in the PK of anti-TB drugs. PK studies conducted in various settings have adopted different designs, PK sampling time points, drug estimation methodologies. Hence comparison and interpretation of these results should be done with caution More phamacogenomic studies in different patient populations are needed for further understanding.

PMID: 27724114 [PubMed - indexed for MEDLINE]

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A Single Dose of the Anti-Resorptive Peptide Human Calcitonin Paradoxically Augments Particle- and Endotoxin-Mediated Pro-Inflammatory Cytokine Production In Vitro.

Horm Metab Res. 2016 Sep;48(9):607-12

Authors: Jablonski H, Wedemeyer C, Bachmann HS, Schlagkamp M, Bernstein A, Jäger M, Kauther MD

Abstract
The peptide hormone calcitonin (CT) is known to inhibit bone resorption and has previously been shown also to prevent particle-induced osteolysis, the leading cause of revision arthroplasty. In the present study, the influence of human CT on the initial inflammatory response to particulate wear debris or bacterial endotoxins, ultimately leading to osteoclast-mediated bone resorption, was analysed in human THP-1 macrophage-like cells. The cells were activated with either ultra-high molecular weight polyethylene (UHMWPE) particles or bacterial lipopolysaccharides (LPS) in order to simulate an osteolysis-associated inflammatory response. The cells were simultaneously treated with human CT (10(-9) M). Cytokine production of tumour necrosis factor (TNF)-α was quantified on both RNA and protein levels while interleukins (IL)-1β and IL-6 were measured as secreted protein only. Stimulation of the cells with either particles or LPS led to a dose- and time-dependent increase of TNF-α mRNA production and protein secretion of TNF-α, IL-1β, and IL-6. Application of CT mostly enhanced cytokine production as elicited by UHMWPE particles while a pronounced transient inhibitory effect on LPS-induced inflammation became evident at 24 h of incubation. Human CT displayed ambivalent effects on the wear- and LPS-induced production of pro-inflammatory cytokines. Thereby, the peptide primarily upregulated particle-induced inflammation while LPS-induced cytokine secretion was temporarily attenuated in a distinct manner. It needs to be evaluated whether the pro- or anti-inflammatory action of CT contributes to its known anti-resorptive effects. Thus, the therapeutic potential of the peptide in the treatment of either particle- or endotoxin-mediated bone resorption could be determined.

PMID: 27258971 [PubMed - indexed for MEDLINE]

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Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects.

Int J Mol Sci. 2016 May 14;17(5):

Authors: Granata S, Dalla Gassa A, Carraro A, Brunelli M, Stallone G, Lupo A, Zaza G

Abstract
Sirolimus (SRL) and everolimus (EVR) are mammalian targets of rapamycin inhibitors (mTOR-I) largely employed in renal transplantation and oncology as immunosuppressive/antiproliferative agents. SRL was the first mTOR-I produced by the bacterium Streptomyces hygroscopicus and approved for several medical purposes. EVR, derived from SRL, contains a 2-hydroxy-ethyl chain in the 40th position that makes the drug more hydrophilic than SRL and increases oral bioavailability. Their main mechanism of action is the inhibition of the mTOR complex 1 and the regulation of factors involved in a several crucial cellular functions including: protein synthesis, regulation of angiogenesis, lipid biosynthesis, mitochondrial biogenesis and function, cell cycle, and autophagy. Most of the proteins/enzymes belonging to the aforementioned biological processes are encoded by numerous and tightly regulated genes. However, at the moment, the polygenic influence on SRL/EVR cellular effects is still not completely defined, and its comprehension represents a key challenge for researchers. Therefore, to obtain a complete picture of the cellular network connected to SRL/EVR, we decided to review major evidences available in the literature regarding the genetic influence on mTOR-I biology/pharmacology and to build, for the first time, a useful and specific "SRL/EVR genes-focused pathway", possibly employable as a starting point for future in-depth research projects.

PMID: 27187382 [PubMed - indexed for MEDLINE]

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Quercetin induces caspase-dependent extrinsic apoptosis through inhibition of signal transducer and activator of transcription 3 signaling in HER2-overexpressing BT-474 breast cancer cells.

Oncol Rep. 2016 Jul;36(1):31-42

Authors: Seo HS, Ku JM, Choi HS, Choi YK, Woo JK, Kim M, Kim I, Na CH, Hur H, Jang BH, Shin YC, Ko SG

Abstract
Flavonoids are assumed to exert beneficial effects in different types of cancers at high concentrations. Yet, their molecular mechanisms of action remain unknown. The present study aimed to examine the effect of quercetin on proliferation and apoptosis in HER2-expressing breast cancer cells. The anti-proliferative effects of quercetin were examined by proliferation, MTT and clonogenic survival assays. The effect of quercetin on expression of apoptotic molecules was determined by western blotting. Luciferase reporter assay was performed to measure signal transducer and activator of transcription 3 (STAT3) transcriptional activity. ELISA assay was performed to measure intracellular MMP-9 levels. Immunocytochemistry was performed to evaluate the nuclear STAT3 level. The results revealed that quercetin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Quercetin also inhibited clonogenic survival (anchorage-dependent and -independent) of BT-474 cells in a dose-dependent manner. These growth inhibitions were accompanied with an increase in sub-G0/G1 apoptotic populations. Quercetin induced caspase-dependent extrinsic apoptosis upregulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly(ADP‑ribose) polymerase (PARP). In contrast, quercetin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease the mitochondrial membrane potential and did not affect the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Quercetin reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in the BT-474 cells. Quercetin inhibited MMP-9 secretion and decreased the nuclear translocation of STAT3. Our study indicates that quercetin induces apoptosis at concentrations >20 µM through inhibition of STAT3 signaling and could serve as a useful compound to prevent or treat HER2-overexpressing breast cancer.

PMID: 27175602 [PubMed - indexed for MEDLINE]

Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study.

Ann Intern Med. 2017 Mar 14;:

Authors: Stephenson AL, Sykes J, Stanojevic S, Quon BS, Marshall BC, Petren K, Ostrenga J, Fink AK, Elbert A, Goss CH

Abstract
Background: In 2011, the median age of survival of patients with cystic fibrosis reported in the United States was 36.8 years, compared with 48.5 years in Canada. Direct comparison of survival estimates between national registries is challenging because of inherent differences in methodologies used, data processing techniques, and ascertainment bias.
Objective: To use a standardized approach to calculate cystic fibrosis survival estimates and to explore differences between Canada and the United States.
Design: Population-based study.
Setting: 42 Canadian cystic fibrosis clinics and 110 U.S. cystic fibrosis care centers.
Patients: Patients followed in the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) between 1990 and 2013.
Measurements: Cox proportional hazards models were used to compare survival between patients followed in the CCFR (n = 5941) and those in the CFFPR (n = 45 448). Multivariable models were used to adjust for factors known to be associated with survival.
Results: Median age of survival in patients with cystic fibrosis increased in both countries between 1990 and 2013; however, in 1995 and 2005, survival in Canada increased at a faster rate than in the United States (P < 0.001). On the basis of contemporary data from 2009 to 2013, the median age of survival in Canada was 10 years greater than in the United States (50.9 vs. 40.6 years, respectively). The adjusted risk for death was 34% lower in Canada than the United States (hazard ratio, 0.66 [95% CI, 0.54 to 0.81]). A greater proportion of patients in Canada received transplants (10.3% vs. 6.5%, respectively [standardized difference, 13.7]). Differences in survival between U.S. and Canadian patients varied according to U.S. patients' insurance status.
Limitation: Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results.
Conclusion: Differences in cystic fibrosis survival between Canada and the United States persisted after adjustment for risk factors associated with survival, except for private-insurance status among U.S. patients. Differential access to transplantation, increased posttransplant survival, and differences in health care systems may, in part, explain the Canadian survival advantage.
Primary Funding Source: U.S. Cystic Fibrosis Foundation.

PMID: 28288488 [PubMed - as supplied by publisher]

Forskolin-induced Swelling in Intestinal Organoids: An In Vitro Assay for Assessing Drug Response in Cystic Fibrosis Patients.

J Vis Exp. 2017 Feb 11;(120):

Authors: Boj SF, Vonk AM, Statia M, Su J, Vries RR, Beekman JM, Clevers H

Abstract
Recently-developed cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs correct surface expression and/or function of the mutant CFTR channel in subjects with cystic fibrosis (CF). Identification of subjects that may benefit from these drugs is challenging because of the extensive heterogeneity of CFTR mutations, as well as other unknown factors that contribute to individual drug efficacy. Here, we describe a simple and relatively rapid assay for measuring individual CFTR function and response to CFTR modulators in vitro. Three dimensional (3D) epithelial organoids are grown from rectal biopsies in standard organoid medium. Once established, the organoids can be bio-banked for future analysis. For the assay, 30-80 organoids are seeded in 96-well plates in basement membrane matrix and are then exposed to drugs. One day later, the organoids are stained with calcein green, and forskolin-induced swelling is monitored by confocal live cell microscopy at 37 °C. Forskolin-induced swelling is fully CFTR-dependent and is sufficiently sensitive and precise to allow for discrimination between the drug responses of individuals with different and even identical CFTR mutations. In vitro swell responses correlate with the clinical response to therapy. This assay provides a cost-effective approach for the identification of drug-responsive individuals, independent of their CFTR mutations. It may also be instrumental in the development of future CFTR modulators.

PMID: 28287550 [PubMed - in process]

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Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies.

Am J Hum Genet. 2017 Mar 06;:

Authors: Xu M, Xie YA, Abouzeid H, Gordon CT, Fiorentino A, Sun Z, Lehman A, Osman IS, Dharmat R, Riveiro-Alvarez R, Bapst-Wicht L, Babino D, Arno G, Busetto V, Zhao L, Li H, Lopez-Martinez MA, Azevedo LF, Hubert L, Pontikos N, Eblimit A, Lorda-Sanchez I, Kheir V, Plagnol V, Oufadem M, Soens ZT, Yang L, Bole-Feysot C, Pfundt R, Allaman-Pillet N, Nitschké P, Cheetham ME, Lyonnet S, Agrawal SA, Li H, Pinton G, Michaelides M, Besmond C, Li Y, Yuan Z, von Lintig J, Webster AR, Le Hir H, Stoilov P, UK Inherited Retinal Dystrophy Consortium, Amiel J, Hardcastle AJ, Ayuso C, Sui R, Chen R, Allikmets R, Schorderet DF

Abstract
Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

PMID: 28285769 [PubMed - as supplied by publisher]

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Diagnosis with Multiple Epiphyseal Dysplasia Using Whole-exome Sequencing in a Chinese Family.

Chin Med J (Engl). 2017 5th Jan 2017;130(1):104-107

Authors: Liu HY, Xiao JF, Huang J, Wang Y, Wu D, Li T, Wang HD, Guo LJ, Guo QN, Xiao H, Lyu X, Yu ZH

PMID: 28051032 [PubMed - indexed for MEDLINE]

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Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms.

Sci Rep. 2016 Mar 10;6:22760

Authors: Asai T, Hatlen MA, Lossos C, Ndiaye-Lobry D, Deblasio A, Murata K, Fleisher M, Cortizas EM, Verdun RE, Petrini J, Nimer SD

Abstract
Multiple myeloma is a plasma cell neoplasm with an extremely variable clinical course. Animal models are needed to better understand its pathophysiology and for preclinical testing of potential therapeutic agents. Hematopoietic cells expressing the hypermorphic Rad50(s) allele show hematopoietic failure, which can be mitigated by the lack of a transcription factor, Mef/Elf4. However, we find that 70% of Mef(-/-)Rad50(s/s) mice die from multiple myeloma or other plasma cell neoplasms. These mice initially show an abnormal plasma cell proliferation and monoclonal protein production, and then develop anemia and a decreased bone mineral density. Tumor cells can be serially transplanted and according to array CGH and whole exome sequencing, the pathogenesis of plasma cell neoplasms in these mice is not linked to activation of a specific oncogene, or inactivation of a specific tumor suppressor. This model recapitulates the systemic manifestations of human plasma cell neoplasms, and implicates cooperativity between the Rad50(s) and Mef/Elf4 pathways in initiating myelomagenic mutations that promote plasma cell transformation.

PMID: 26961797 [PubMed - indexed for MEDLINE]

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Dysregulation of BET proteins in levodopa-induced dyskinesia.

Neurobiol Dis. 2017 Mar 09;:

Authors: Figge D, Standaert DG

Abstract
Levodopa (L-DOPA) remains the most effective pharmacological treatment for Parkinson's Disease (PD) but its use is limited by the development of debilitating drug-related side effects, particularly L-DOPA induced dyskinesia (LID). LID is a consequence of long-term L-DOPA use, and in model systems is characterized by a "priming effect", whereby initial administrations of L-DOPA trigger a sensitized biochemical and transcriptional response upon subsequent dopaminergic stimulation. Preliminary studies into the mechanisms underlying this cellular memory have indicated an important role for epigenetic change but many of the downstream mechanisms remain unknown. The family of bromodomain and extraterminal (BET) proteins, which bind acetylated histones, play a critical effector role in the regulation of transcription. BET proteins have been implicated in several forms of neural plasticity, but their potential relevance to LID remains unexplored. Using the 6-OHDA rodent model of LID, we show that dyskinesia development induces alterations in BET protein expression along with enhanced occupation of sites at the promoter and enhancer regions of genes dysregulated during dyskinesia development. When BET function was blocked using the pharmacologic inhibitor JQ1, LID was prevented. In addition, we found that JQ1 treatment blocked the transcriptional upregulation of several immediate-early genes known to participate in the pathogenesis of dyskinesia. Together, these results demonstrate an essential role for BET protein activity as an epigenetic "reader" of the altered histone acetylation required for LID development and suggest that modulation of BET protein function is a potential therapeutic avenue for the treatment prevention or reversal of LID in PD.

PMID: 28286180 [PubMed - as supplied by publisher]

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The insect repellents: A silent environmental chemical toxicant to the health.

Environ Toxicol Pharmacol. 2017 Mar;50:91-102

Authors: Roy DN, Goswami R, Pal A

Abstract
In recent years, a large number of insect repellents have been developed with the idea of consumer benefits. In addition to already known advantageous application of insect repellents, there is increasing concern about the potential toxicity in environment leading to health caused by random use of these compounds. An increasing number of evidence suggests that insect repellents may trigger undesirable hazardous interactions with biological systems with a potential to generate harmful effects including intermediate metabolites. Biotransformation followed by bioaccumulation (vice e versa) may be an important phenomenon for toxic response of this chemicals. In this review, we have summarized the current state of knowledge on the insect repellent toxicity, including biochemical pathway alteration under in vitro and in vivo conditions considering different classes of organisms, from lower to higher vertebrate. Furthermore, we have tried to incorporate the effects of insect repellent in light of some clinical reports. We hope this review would provide useful information on potential side effects of uncontrolled use of insect repellents.

PMID: 28171823 [PubMed - indexed for MEDLINE]

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Antimalarial activity of the terpene nerolidol.

Int J Antimicrob Agents. 2016 Dec;48(6):641-646

Authors: Saito AY, Marin Rodriguez AA, Menchaca Vega DS, Sussmann RA, Kimura EA, Katzin AM

Abstract
Malaria, an infectious disease that kills more than 438,000 people per year worldwide, is a major public health problem. The emergence of strains resistant to conventional therapeutic agents necessitates the discovery of new drugs. We previously demonstrated that various substances, including terpenes, have antimalarial activity in vitro and in vivo. Nerolidol is a sesquiterpene present as an essential oil in several plants that is used in scented products and has been approved by the US Food and Drug Administration as a food-flavouring agent. In this study, the antimalarial activity of nerolidol was investigated in a mouse model of malaria. Mice were infected with Plasmodium berghei ANKA and were treated with 1000 mg/kg/dose nerolidol in two doses delivered by the oral or inhalation route. In mice treated with nerolidol, parasitaemia was inhibited by >99% (oral) and >80% (inhalation) until 14 days after infection (P <0.0001). On Day 30 post-infection, the survival rate of orally treated mice was 90% compared with 16% in controls (P <0.0001). In contrast, inhalation-treated mice showed a survival rate of 50% vs. 42% in controls (P > 0.05). The toxicity of nerolidol administered by either route was not significant, whilst genotoxicity was observed only at the highest dose tested. These results indicate that combined use of nerolidol and other drugs targeting different points of the same isoprenoid pathway may be an effective treatment for malaria.

PMID: 27742206 [PubMed - indexed for MEDLINE]

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Assessing Natural Product-Drug Interactions: An End-to-End Safety Framework.

Regul Toxicol Pharmacol. 2016 Apr;76:1-6

Authors: Roe AL, Paine MF, Gurley BJ, Brouwer KR, Jordan S, Griffiths JC

Abstract
The use of natural products (NPs), including herbal medicines and other dietary supplements, by North Americans continues to increase across all age groups. This population has access to conventional medications, with significant polypharmacy observed in older adults. Thus, the safety of the interactions between multi-ingredient NPs and drugs is a topic of paramount importance. Considerations such as history of safe use, literature data from animal toxicity and human clinical studies, and NP constituent characterization would provide guidance on whether to assess NP-drug interactions experimentally. The literature is replete with reports of various NP extracts and constituents as potent inhibitors of drug metabolizing enzymes, and transporters. However, without standard methods for NP characterization or in vitro testing, extrapolating these reports to clinically-relevant NP-drug interactions is difficult. This lack of a clear definition of risk precludes clinicians and consumers from making informed decisions about the safety of taking NPs with conventional medications. A framework is needed that describes an integrated robust approach for assessing NP-drug interactions; and, translation of the data into formulation alterations, dose adjustment, labelling, and/or post-marketing surveillance strategies. A session was held at the 41st Annual Summer Meeting of the Toxicology Forum in Colorado Springs, CO, to highlight the challenges and critical components that should be included in a framework approach.

PMID: 26776752 [PubMed - indexed for MEDLINE]

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Adverse outcome pathways: From research to regulation scientific workshop report.

Regul Toxicol Pharmacol. 2016 Apr;76:39-50

Authors: Kleinstreuer NC, Sullivan K, Allen D, Edwards S, Mendrick DL, Embry M, Matheson J, Rowlands JC, Munn S, Maull E, Casey W

Abstract
An adverse outcome pathway (AOP) helps to organize existing knowledge on chemical mode of action, starting with a molecular initiating event such as receptor binding, continuing through key events, and ending with an adverse outcome such as reproductive impairment. AOPs can help identify knowledge gaps where more research is needed to understand the underlying mechanisms, aid in chemical hazard characterization, and guide the development of new testing approaches that use fewer or no animals. A September 2014 workshop in Bethesda, Maryland considered how the AOP concept could improve regulatory assessments of chemical toxicity. Scientists from 21 countries, representing industry, academia, regulatory agencies, and special interest groups, attended the workshop, titled Adverse Outcome Pathways: From Research to Regulation. Workshop plenary presentations were followed by breakout sessions that considered regulatory acceptance of AOPs and AOP-based tools, criteria for building confidence in an AOP for regulatory use, and requirements to build quantitative AOPs and AOP networks. Discussions during the closing session emphasized a need to increase transparent and inclusive collaboration, especially with disciplines outside of toxicology. Additionally, to increase impact, working groups should be established to systematically prioritize and develop AOPs. Multiple collaborative projects and follow-up activities resulted from the workshop.

PMID: 26774756 [PubMed - indexed for MEDLINE]

Funding Opportunity RFA-FD-17-007 from the NIH Guide for Grants and Contracts. The intended outcome of this FOA is to advance efforts for a nationally integrated food safety system by assisting retail food regulatory programs in achieving conformance with the Voluntary National Retail Food Regulatory Program Standards (VNRFRPS or Retail Program Standards). The Retail Program Standards apply to the operation and management of a retail food regulatory program that is focused on the reduction of risk factors known to cause or contribute to foodborne illness and to the promotion of active managerial control of these risk factors. These cooperative agreements are intended to assist regulatory food retail programs in developing, implementing, and improving the infrastructure necessary to support conformance with the VNRFRPS.