Identification of the B-Raf/Mek/Erk MAP kinase pathway as a target for all-trans retinoic acid during skin cancer promotion

<p>Abstract</p> <p>Background</p> <p>Retinoids have been studied extensively for their potential as therapeutic and chemopreventive agents for a variety of cancers, including nonmelanoma skin cancer (NMSC). Despite their use for many years, the mechanism of action of retinoids in the prevention of NMSC is still unclear. In this study we have attempted to understand the chemopreventive mechanism of all-<it>trans </it>retinoic acid (ATRA), a primary biologically active retinoid, in order to more efficiently utilize retinoids in the clinic.</p> <p>Results</p> <p>We have used the 2-stage dimethylbenzanthracene (DMBA)/12-<it>O</it>-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis model to investigate the chemopreventive effects of ATRA. We have compared the gene expression profiles of control skin to skin subjected to the 2-stage protocol, with or without ATRA, using Affymetrix 430 2.0 DNA microarrays. Approximately 49% of the genes showing altered expression with TPA treatment are conversely affected when ATRA is co-administered. The activity of these genes, which we refer to as 'counter-regulated', may contribute to chemoprevention by ATRA. The counter-regulated genes have been clustered into functional categories and bioinformatic analysis has identified the B-Raf/Mek/Erk branch of the MAP kinase pathway as one containing several genes whose upregulation by TPA is blocked by ATRA. We also show that ATRA blocks signaling through this pathway, as revealed by immunohistochemistry and Western blotting. Finally, we found that blocking the B-Raf/Mek/Erk pathway with a pharmacological inhibitor, Sorafenib (BAY43-9006), induces squamous differentiation of existing skin SCCs formed in the 2-stage model.</p> <p>Conclusion</p> <p>These results indicate that ATRA targets the B-Raf/Mek/Erk signaling pathway in the 2-stage mouse skin carcinogenesis model and this activity coincides with its chemopreventive action. This demonstrates the potential for targeting the B-Raf/Mek/Erk pathway for chemoprevention and therapy of skin SCC in humans. In addition our DNA microarray results provide the first expression signature for the chemopreventive effect of ATRA in a mouse skin cancer model. This is a potential source for novel targets for ATRA and other chemopreventive and therapeutic agents that can eventually be tested in the clinic.</p

GatewayNet: a form of sequential rule mining

Abstract Background The gateway hypothesis (and particularly the prediction of developmental stages in drug abuse) has been a subject of protracted debate since the 1970s. Extensive research has gone into this subject, but has yielded contradictory findings. We propose an algorithm for detecting both association and causation relationships given a discrete sequence of events, which we believe will be useful in addressing the validity of the gateway hypothesis. To assess the gateway hypothesis, we developed the GatewayNet algorithm, a refinement of sequential rule mining called initiation rule mining. After a brief mathematical definition, we describe how to perform initiation rule mining and how to infer causal relationships from its rules (“gateway rules”). We tested GatewayNet against data for which relationships were known. After constructing a transaction database using a first-order Markov chain, we mined it to produce a gateway network. We then discuss various incarnations of the gateway network. We then evaluated the performance of GatewayNet on urine drug screening data collected from the emergency department at LSU Health Sciences Center in Shreveport. A de-identified database of urine drug screenings ordered by the department between August 1998 and June 2011 was collected and then restricted to patients having at least one screening succeeding their first positive drug screening result. Results In the synthetic data, a chain of gateway rules was found in the network which demonstrated causation. We did not find any evidence of gateway rules in the empirical data, but we were able to isolate two documented transitions into benzodiazepine use. Conclusions We conclude that GatewayNet may show promise not only for substance use data, but other data involving sequences of events. We also express future goals for GatewayNet, including optimizing it for speed

Trends in drug use among young adult females: a 22-year retrospective analysis

AbstractLouisiana State University Health Sciences Center at Shreveport (LSUHSC-S) serves a largely minority-based, urban population. This study aims to identify trends in urine drug screen (UDS) results among females aged 18–35 visiting State University during 1998–2011 and 2012–2019. Using two databases extracted from the electronic medical record system, we performed statistical analysis of demographics and UDS results. Young females aged 18–35 mostly tested positive for cannabinoids and opiates during both periods, 1998–2011 and 2012–2019. African-American females had a higher percentage of positive UDS for illicit drugs, such as cannabinoids and cocaine, while Caucasian females had a higher rate for prescription drugs such as opiates, benzodiazepines, and amphetamine. Between 1998–2011 and 2012–2019, trends in drug screen results changed in both populations, with Caucasian females showing a drastic increase in amphetamines and African-American females showing increase in opiates and cannabinoids during 2012–2019. GatewayNet analysis (sequential-rule mining for inducing causation) for 2012–2019 indicated that a positive screen for amphetamines is likely preceded by a positive screen for cannabinoids, and benzodiazepines may be preceded by opiates. Our results emphasize the importance of drug use monitoring among young females of childbearing age. GatewayNet analysis implies a sequential nature to drug positivity on urine drug screening in this population

Trends in Drug Tests among Children: A 22-Year Retrospective Analysis

There are several pathophysiological outcomes associated with substance abuse including metabolic disbalance, neurodegeneration, and disordered redox. Drug use in pregnant women is a topic of great concern due to developmental harm which may occur during gestation and the associated complications in the neonate after delivery. We sought to determine what the trajectory of drug use is like in children aged 0–4 years and mothers of neonates. Urine drug screen (UDS) results were obtained of our target demographic during 1998–2011 and 2012–2019 from LSU Health Sciences Center in Shreveport (LSUHSC-S). Statistical analysis was performed using R software. We observed an increase in cannabinoid-positive UDS results in both Caucasian (CC) and African American (AA) groups between 1998–2011 and 2012–2019 periods. Cocaine-positive UDS results decreased in both cohorts. CC children had higher UDS positive results for opiates, benzodiazepines, and amphetamines, while AA children had a higher percentage for illicit drugs such as cannabinoids and cocaine. Neonate’s mothers had similar UDS trends to that in children during 2012–2019. Overall, while percentage of positive UDS results for both AA and CC 0–4 year old children started to decline for opiate, benzodiazepine, and cocaine during 2012–2019, cannabinoid- and amphetamine (CC)-positive UDS steadily increased. These results suggest a shift in the type of drug use by mothers from opiates, benzodiazepines, and cocaine to cannabinoids and/or amphetamines. We also observed that 18-year-old females who tested positive for opiates, benzodiazepine, or cocaine had higher than average chances of testing positive for cannabinoids later in life