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Joy E Kirkpatrick, Keith L Kirkwood, Patrick M Woster
Periodontal disease (PD) afflicts 46% of Americans with no effective adjunctive therapies available. While most pharmacotherapy for PD targets bacteria, the host immune response is responsible for driving tissue damage and bone loss in severe disease. Herein, we establish that the histone demethylase KDM4B is a potential drug target for the treatment of PD. Immunohistochemical staining of diseased periodontal epithelium revealed an increased abundance of KDM4B that correlates with inflammation. In murine calvarial sections exposed to Aggregatibacter actinomycetemcomitans lipopolysaccharide (Aa-LPS), immunohistochemical staining revealed a significant increase in KDM4B protein expression...
June 21, 2018: Epigenetics: Official Journal of the DNA Methylation Society
Amy Jewett, Alexis B Peterson, Erin K Sauber-Schatz
INTRODUCTION: Alcohol or drug impaired driving can cause motor vehicle crashes, injuries, and death. Estimates of drug impaired driving are difficult to obtain. This study explores self-reported prevalence of and factors associated with alcohol, marijuana, and prescription opioid use and impaired driving among adults aged 21 years and older in the U.S. METHODS: Self-reported data from 3,383 adults in the 2015 Fall ConsumerStyles survey were analyzed. Respondents were asked about alcohol, marijuana, and prescription opioid use and driving while impaired in the last 30 days...
June 21, 2018: Traffic Injury Prevention
Håvard Furuhaugen, Ragnhild E G Jamt, Galina Nilsson, Vigdis Vindenes, Hallvard Gjerde
OBJECTIVE: To study the use of alcohol and drugs among the general driving population in the south-eastern part of Norway and to compare the findings with the results from a similar roadside survey in 2008-9. METHODS: A roadside survey of drivers of cars, vans, motorcycles and mopeds was performed from April 2016 to April 2017 in collaboration with the Mobile Police Service. Oral fluid was collected using the Quantisal device and analysed for alcohol, illicit drugs and psychoactive medicinal drugs...
June 21, 2018: Traffic Injury Prevention
Herwig P Moll, Klemens Pranz, Monica Musteanu, Beatrice Grabner, Natascha Hruschka, Julian Mohrherr, Petra Aigner, Patricia Stiedl, Luka Brcic, Viktoria Laszlo, Daniel Schramek, Richard Moriggl, Robert Eferl, Judit Moldvay, Katalin Dezso, Pedro P Lopez-Casas, Dagmar Stoiber, Manuel Hidalgo, Josef Penninger, Maria Sibilia, Balázs Győrffy, Mariano Barbacid, Balázs Dome, Helmut Popper, Emilio Casanova
On the basis of clinical trials using first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), it became a doctrine that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( K-RAS ) mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Conversely, we provide evidence that EGFR signaling is engaged in K-RAS-driven lung tumorigenesis in humans and in mice. Specifically, genetic mouse models revealed that deletion of Egfr quenches mutant K-RAS activity and transiently reduces tumor growth...
June 20, 2018: Science Translational Medicine
Guanqun Huang, Hui Jiang, Ye Lin, Wuzheng Xia, Yuanwei Luo, Yanpeng Wu, Weilong Cai, Xinke Zhou, Xianhan Jiang
BACKGROUND: With self-renewal and differentiation properties, liver tumor initiating cells (TICs) are the reasons for tumor initiation, metastasis and drug resistance. G protein coupled receptors (GPCR) are critical modulators in many physiological and pathological processes. While, their roles in liver TICs are unknown. METHODS: An unbiased screening was performed using online-available data dataset. Liver TICs were sorted by FACS with surface marker CD133, or enriched by oncosphere formation...
June 20, 2018: Journal of Experimental & Clinical Cancer Research: CR
Nikita Devnarain, Mahmoud E S Soliman
The global threat of the Zika virus to humanity is real. Innovative and potent anti-Zika virus drugs are still at large, due to the lack of anti-Zika virus drugs that have passed phase 1 trials. Experimental research has revealed novel inhibitors of Zika virus NS5 methyltransferase enzyme. This study has taken a step further to provide insight into the molecular dynamics of Zika virus and inhibitor binding, which have not been established experimentally. Movements of the methyltransferase binding site loops have a large role to play in the methylation of the viral mRNA cap, which is essential for Zika virus replication...
June 20, 2018: Chemical Biology & Drug Design
Loredana Puca, Rohan Bareja, Davide Prandi, Reid Shaw, Matteo Benelli, Wouter R Karthaus, Judy Hess, Michael Sigouros, Adam Donoghue, Myriam Kossai, Dong Gao, Joanna Cyrta, Verena Sailer, Aram Vosoughi, Chantal Pauli, Yelena Churakova, Cynthia Cheung, Lesa Dayal Deonarine, Terra J McNary, Rachele Rosati, Scott T Tagawa, David M Nanus, Juan Miguel Mosquera, Charles L Sawyers, Yu Chen, Giorgio Inghirami, Rema A Rao, Carla Grandori, Olivier Elemento, Andrea Sboner, Francesca Demichelis, Mark A Rubin, Himisha Beltran
A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients...
June 19, 2018: Nature Communications
Sara Charmsaz, Maria Prencipe, Maeve Kiely, Graham P Pidgeon, Denis M Collins
Conventional therapies for cancer such as chemotherapy and radiotherapy remain a mainstay in treatment, but in many cases a targeted approach is lacking, and patients can be vulnerable to drug resistance. In recent years, novel concepts have been emerging to improve the traditional therapeutic options in cancers with poor survival outcomes. New therapeutic strategies involving areas like energy metabolism and extracellular vesicles along with advances in immunotherapy and nanotechnology are driving the next generation of cancer treatments...
June 19, 2018: Cancers
Manuela Alcañiz, Montserrat Guillen, Miguel Santolino
BACKGROUND: In the context of road safety, this study aims to examine the prevalence of drug use in a random sample of drivers. METHODS: A stratified probabilistic sample was designed to represent vehicles circulating on non-urban roads. Random drug tests were performed during autumn 2014 on 521 drivers in Catalonia (Spain). Participation was mandatory. The prevalence of drug driving for cannabis, methamphetamines, amphetamines, cocaine, opiates and benzodiazepines was assessed...
2018: PloS One
Simon McKenzie-Nickson, Jacky Chan, Keyla Perez, Lin W Hung, Lesley Cheng, Amelia Sedjahtera, Lydia Gunawan, Paul A Adlard, David J Hayne, Lachlan E Mcinnes, Paul S Donnelly, David I Finkelstein, Professor Andrew Hill, Kevin J Barnham
Alzheimer's disease (AD) is the leading cause of dementia worldwide accounting around 70% of all cases. There is currently no treatment for AD beyond symptom management and attempts at developing disease-modifying therapies have yielded very little. These strategies have traditionally targeted the peptide Aβ which is thought to drive pathology. However, the lack of clinical translation of these Aβ-centric strategies underscores the need for diverse treatment strategies targeting other aspects of the disease...
June 19, 2018: ACS Chemical Neuroscience
Zengjie Fan, Jie Li, Jianli Liu, Hongjing Jiao, Bin Liu
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, which can cause endless suffering to the patients and severely impact their normal lives. To treat RA, the drugs in use have many serious side effects, high cost or only focus on their anti-inflammatory mechanisms without taking joint lubrication into consideration. Therefore, in this study, we aim to construct a novel anti-RA drug composed of hyaluronic acid/curcumin (HA/Cur) nanomicelle to resolve these problems. Characterizations show that Cur is bound to HA by ester linkages, and self-assembles to form a spherical nanomicelle with a diameter of around 164 nm under the main driving of the hydrophilic and hydrophobic forces...
June 19, 2018: ACS Applied Materials & Interfaces
Shuliang Chen, Yixian Cui, Smriti Parashar, Peter J Novick, Susan Ferro-Novick
The endoplasmic reticulum (ER) forms a contiguous network of tubules and sheets that is predominantly associated with the cell cortex in yeast. Upon treatment with rapamycin, the ER undergoes degradation by selective autophagy. This process, termed ER-phagy, requires Atg40, a selective autophagy receptor that localizes to the cortical ER. Here we report that ER-phagy also requires Lnp1, an ER membrane protein that normally resides at the three-way junctions of the ER network, where it serves to stabilize the network as it is continually remodeled...
June 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
Anne M Rompalo, Neko Castleberry, Lea Widdice, Jay Schulkin, Charlotte A Gaydos
Background: Point-of-care tests (POCTs) for reproductive health conditions have existed for decades. Newer POCTs for syphilis, HIV and trichomonas are currently available and easy to use. We surveyed practicing obstetricians and gynaecologists to determine current POCT use and perceived obstacles to use. Methods: Between June and August 2016, 1000 members of the American College of Obstetricians and Gynecologists were randomly selected and invited to complete a Qualtrics (222 West river Park Drive, Provo, Utah 84604, USA) survey; 600 of these were members of the Collaborative Ambulatory Research Network...
June 19, 2018: Sexual Health
Madeline Collette Evans, Kelly Ann Dougherty
Medial temporal lobe epilepsy (mTLE)-the most common form of focal epilepsy-is defined by recurrent partial seizures originating within the medial temporal lobe. Such seizures are commonly associated with the anterior hippocampus (as opposed to the posterior hippocampus), and refractory to the currently available anti-epileptic drugs (AED) for about one third of patients. Unfortunately, the mechanisms driving seizure generation and AED efficacy along the longitudinal hippocampal axis remain poorly understood...
June 9, 2018: Epilepsy Research
Evelyn M Brosnan, Carey K Anders
One of the most feared sequelae after a diagnosis of advanced breast cancer is development of metastases to the brain as this diagnosis can affect physical function, independence, relationships, quality of life, personality, and ultimately one's sense of self. The propensity to develop breast cancer brain metastases (BCBMs) varies by subtype, occurring in up to one half of those with triple negative breast cancer (TNBC), approximately a third of HER+ breast cancers and 14% in hormone positive disease. Median survival after BCBM diagnosis can be as short as 5 months in TNBC and 10-18 months in the other subtypes...
May 2018: Annals of Translational Medicine
Jessie Peh, Matthew W Boudreau, Hannah M Smith, Paul J Hergenrother
The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Here we demonstrate a general strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL)...
May 18, 2018: Cell Chemical Biology
Claire E H Barber, J Carter Thorne, Vandana Ahluwalia, Jennifer Burt, Diane Lacaille, Deborah A Marshall, Glen S Hazlewood, Dianne Mosher, Lisa Denning, Ildiko Szamjo, Ricky Chin, Sean Hamilton, Susanne Benseler, Marinka Twilt, Natalie J Shiff, Vivian Bykerk, Joanne Homik, Cheryl Barnabe
OBJECTIVE: To test the feasibility of reporting on 4 national performance measures for patients with rheumatoid arthritis (RA) in 5 different models of care. METHODS: The following performance measures were evaluated in 5 models of care: waiting time (WT) to rheumatologist consultation, percentage of patients seen in yearly followup (FU), percentage taking disease-modifying antirheumatic drugs (DMARD), and time to starting DMARD. All models aimed to improve early access and care for patients with RA...
June 15, 2018: Journal of Rheumatology
Gabriele Romano, Serena Reggi, Barbara Kutryb-Zajac, Amanda Facoetti, Elisa Chisci, Mariateresa Pettinato, Maria Rita Giuffrè, Federica Vecchio, Silvia Leoni, Marco De Giorgi, Federica Avezza, Massimiliano Cadamuro, Luca Crippa, Biagio Eugenio Leone, Marialuisa Lavitrano, Ilaria Rivolta, Donatella Barisani, Ryszard Tomasz Smolenski, Roberto Giovannoni
BACKGROUND: Atherosclerosis is a slowly progressing, chronic multifactorial disease characterized by the accumulation of lipids, inflammatory cells, and fibrous tissue that drives to the formation of asymmetric focal thickenings in the tunica intima of large and mid-sized arteries. Despite the high therapeutic potential of ApoA-1 proteins, the purification and delivery into the disordered organisms of these drugs is still limited by low efficiency in these processes. METHODS AND RESULTS: We report here a novel production and delivery system of anti-atherogenic APOA-1Milano muteins (APOA-1M) by means of genetically modified rice plants...
June 11, 2018: International Journal of Cardiology
Berenika Szczęśniak-Sięga, Katarzyna Gębczak, Tomasz Gębarowski, Jadwiga Maniewska
Oxicams (e.g. piroxicam, meloxicam) are widely used nonsteroidal anti-inflammatory drugs (NSAIDs). A large body of evidence from epidemiological and preclinical studies has shown that NSAIDs have a chemopreventive effect on different types of cancer, especially in colorectal cancer. Moreover, mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. What is more, inflammation induces reactive oxygen and nitrogen species, which cause damage to important cellular components (e...
June 15, 2018: Acta Biochimica Polonica
Chiara Scelfo, Carla Galeone, Francesca Bertolini, Marco Caminati, Patrizia Ruggiero, Nicola Facciolongo, Francesco Menzella
Asthma is a chronic obstructive respiratory disease characterised by bronchial inflammation. Its biological and clinical features have been widely explored and a number of pharmacological treatments are currently available. Currently several aspects of asthma pathophysiological background remain unclear, and this is crucial for the traditional asthma phenotype approach as well as for new endotype definition. In this scenario, the identification of new molecular and clinical biomarkers may be helpful in order to better understand the disease, define specific diagnostic tools and highlight relevant novel targets for pharmacology treatments...
2018: F1000Research
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