408,862 results match your criteria Regulatory Toxicology and Pharmacology [Journal]


Developmental mutant mouse models for external genitalia formation.

Congenit Anom (Kyoto) 2018 Nov 22. Epub 2018 Nov 22.

Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), Wakayama, Japan.

Development of external genitalia and perineum is the subject of developmental biology as well as toxicology and teratology researches. Cloaca forms in the lower (caudal) end of endoderm. Such endodermal epithelia and surrounding mesenchyme interact with various signals to form the external genitalia. Read More

View Article
November 2018

Ambient geochemical baselines for trace elements in Chernozems-approximation of geochemical soil transformation in an agricultural area.

Environ Monit Assess 2018 Dec 15;191(1):19. Epub 2018 Dec 15.

Wrocław University of Environmental and Life Sciences, Institute of Soil Science and Environmental Protection, Grunwaldzka 53, 50-357, Wrocław, Poland.

The legal regulatory/action levels of trace elements in soils are established at high concentrations, at which the crucial functions of soil are at risk or are eliminated. However, concentrations below these action levels, but above presumed natural levels, may also limit particular ecosystem services, including organic food production. Thus, defining the (ambient) background concentrations is an essential part of environmental or health risk assessment, e. Read More

View Article
December 2018

Evidence for Weak Selective Constraint on Human Gene Expression.

Genetics 2018 Dec 15. Epub 2018 Dec 15.

Stanford University

Gene expression variation is a major contributor to phenotypic variation in human complex traits. Selection on complex traits may therefore be reflected in constraint on gene expression. Here, we explore the effects of stabilizing selection on -regulatory genetic variation in humans. Read More

View Article
December 2018

Long noncoding RNA CRNDE promotes non-small cell lung cancer progression via sponging microRNA-338-3p.

Biomed Pharmacother 2018 Dec 13;110:825-833. Epub 2018 Dec 13.

Department of Respiratory Medicine, The First Hospital of Jilin University, Changchun, Jilin, 130021, China. Electronic address:

Background: The long noncoding RNA colorectal neoplasia differentially expressed (CRNDE) was reported to be involved in the initiation and development of multiple cancers. However, the detailed biological role of CRNDE in non-small cell lung cancer (NSCLC) remains largely unclear. Herein, we aimed to explore the biological function and underlying molecular mechanism of CRNDE in NSCLC. Read More

View Article
December 2018

Uranium distribution in groundwater and assessment of age dependent radiation dose in Amritsar, Gurdaspur and Pathankot districts of Punjab, India.

Chemosphere 2018 Dec 7;219:607-616. Epub 2018 Dec 7.

Department of Physics, Guru Nanak Dev University, Amritsar, Punjab, 143005, India. Electronic address:

A comprehensive study of seasonal variation of uranium distribution in groundwater of Amritsar, Gurdaspur and Pathankot districts of Punjab, India and assessment of associated radiological risks, chemical risks and effective radiation dose for different age groups, was conducted to determine its health impact on humans residing in these regions. Physicochemical parameters such as pH, EC, TDS, total hardness and contents of various anions such as carbonates/bicarbonates, chlorides, fluorides, nitrates, sulphates and phosphates in groundwater were also analysed to determine correlation between groundwater chemistry and uranium distribution. The average values of uranium concentration in ground water samples of Amritsar, Gurdaspur and Pathankot districts were found to be 8. Read More

View Article
December 2018

miRNA-185 regulates retained fetal membranes of cattle by targeting STIM1.

Theriogenology 2018 Nov 27;126:166-171. Epub 2018 Nov 27.

College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China. Electronic address:

Retained fetal membranes (RFM) of cows is an important reproductive disturbance, and is related to miRNA-185. Stromal interaction molecule 1 (STIM1), a potential target gene of miRNA-185, could influence placenta release via regulating Ca concentration intracellular. The aim of this study was to explore the mechanism of RFM by investigating the regulatory relationship between miRNA-185 and STIM1 in primary uterine caruncel epithelial (UCE) cells. Read More

View Article
November 2018

Suppressive effects of iron chelation in clear cell renal cell carcinoma and their dependency on VHL inactivation.

Free Radic Biol Med 2018 Dec 13. Epub 2018 Dec 13.

Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263; Department of Cancer Genetics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263; Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14214. Electronic address:

Background And Objectives: Accumulating data implicate iron accumulation in tumorigenesis of the kidney, particularly the clear cell renal cell carcinoma (ccRCC) subtype. The von Hippel Lindau (VHL)/hypoxia inducible factor-α (HIF-α) axis is uniquely dysregulated in ccRCC and is a major regulator and regulatory target of iron metabolism, yet the role of iron in ccRCC tumorigenesis and its potential interplay with VHL inactivation remains unclear. We investigated whether ccRCC iron accumulation occurs due to increased cell dependency on iron for growth and survival as a result of VHL inactivation. Read More

View Article
December 2018

CellMinerCDB for Integrative Cross-Database Genomics and Pharmacogenomics Analyses of Cancer Cell Lines.

iScience 2018 Nov 30. Epub 2018 Nov 30.

Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

CellMinerCDB provides a web-based resource (https://discover.nci.nih. Read More

View Article
November 2018

Studying Transcriptional Enhancers: The Founder Fallacy, Validation Creep, and Other Biases.

Authors:
Marc S Halfon

Trends Genet 2018 Dec 12. Epub 2018 Dec 12.

Department of Biochemistry, University at Buffalo-State University of New York, Buffalo, NY, USA; NY State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, USA; Department of Biological Sciences, University at Buffalo-State University of New York, Buffalo, NY, USA; Department of Biomedical Informatics, University at Buffalo-State University of New York, Buffalo, NY, USA; Department of Molecular and Cellular Biology and Program in Cancer Genetics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Electronic address:

Transcriptional enhancers play a major role in regulating metazoan gene expression. Recent developments in genomics and next-generation sequencing have accelerated and revitalized the study of this important class of sequence elements. Increased interest and attention, however, has also led to troubling trends in the enhancer literature. Read More

View Article
December 2018

An expression quantitative trait locus variant for LKB1 gene predicts the clinical outcomes of chemotherapy in patients with non-small cell lung cancer.

Cancer Genet 2018 Dec 16;228-229:73-82. Epub 2018 Oct 16.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Lung Cancer Center, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

Background: We conducted this study to identify regulatory variants in cancer-related pathway genes which can predict clinical outcomes of chemotherapy in advanced NSCLC, using a comprehensive list of regulatory SNPs prioritized by RegulomeDB.

Methods: A total of 509 potentially functional SNPs in cancer-related pathway genes were evaluated. The SNPs were analyzed in a discovery set (n = 198), and an independent validation set (n = 181). Read More

View Article
December 2018

Identification of key genes and construction of microRNA-mRNA regulatory networks in non-small cell lung cancer.

Cancer Genet 2018 Dec 27;228-229:47-54. Epub 2018 Aug 27.

School of Clinical Medicine, Dali University, Xue-ren Road, Xia guang District, Dali, Yunnan 671000, China. Electronic address:

Non-small cell lung cancer (NSCLC) is the most common type of lung tumor. Deregulation of microRNA may be involved in the occurrence of NSCLC and we aimed to find the potential prognostic biomarkers for NSCLC. The microRNA microarray expression profiles were downloaded from GEO dataset and then generated by applying robust multi-array average (RMA). Read More

View Article
December 2018

MicroRNA-506 inhibits the proliferation and invasion of mantle cell lymphoma cells by targeting B7H3.

Biochem Biophys Res Commun 2018 Dec 12. Epub 2018 Dec 12.

Department of Hematology and Lymphoma Research Center, Peking University Third Hospital, Beijing, 100191, PR China. Electronic address:

Background: Aberrant expression of B7 homologue 3 (B7H3) has been observed in various malignancies. Our previous study demonstrated that knocking down of B7H3 inhibited cell proliferation, invasion and enhanced the therapeutic efficacy of chemotherapy in mantle cell lymphoma (MCL). However, the mechanism regulating of B7H3 expression remains unknown. Read More

View Article
December 2018

Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.

Biochem Biophys Res Commun 2018 Dec 13. Epub 2018 Dec 13.

Department of Chemistry, High Point University, High Point, NC, 27268, USA. Electronic address:

Ataxia-telangiectasia mutated (ATM) is a serine-threonine kinase that is integral in the response to DNA double-stranded breaks (DSBs). Cells and tissues lacking ATM are prone to tumor development and enhanced tumor cell migration and invasion. Interestingly, ATM-deficient cells exhibit high levels of oxidative stress; however, the direct mechanism whereby ATM-associated oxidative stress may contribute to the cancer phenotype remains largely unexplored. Read More

View Article
December 2018

Low molecule weight fucoidan mitigates atherosclerosis in ApoE (-/-) mouse model through activating multiple signal pathway.

Carbohydr Polym 2019 Feb 31;206:110-120. Epub 2018 Oct 31.

Institute of Cerebrovascular Diseases, Affiliated Hospital of Qingdao University, Qingdao 266003, China. Electronic address:

Atherosclerosis (AS) is a chronic inflammatory disease, and many factors are implicated in its progression. This work aims to study the preventive effects and the regulatory mechanism of low-molecular-weight fucoidan (LMWF), which is obtained from Saccharina japonica, on the development of AS. Serum biochemical indices and pathological analyses were determined via ELISA, hematoxylin and eosin (HE) and Oil Red O staining. Read More

View Article
February 2019

C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in pancreatic cancer.

Mol Cancer 2018 Dec 15;17(1):174. Epub 2018 Dec 15.

The Institute of Cell Metabolism, Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 200080, China.

Background: Chromatin modification at mitosis is closely related to transcriptional reactivation in the subsequent cell cycle. We reasoned this process is deregulated by oncogenic signals, which would contribute to mitotic stress resistance in pancreatic cancer. Here, we show DMAP1/Bub3 complex mediates mitotic stress-induced cellular apoptosis, while this effect is counteracted by c-Src in pancreatic cancer cells. Read More

View Article
December 2018

Enhanced remedial effects for vitamin D and calcium co-supplementation against pre-existing lead nephrotoxicity in mice: The roles of renal calcium homeostatic molecules.

Biochim Biophys Acta Mol Basis Dis 2018 Dec 12. Epub 2018 Dec 12.

Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia. Electronic address:

Background: Lead (Pb) is a toxic heavy metal and nephropathy is common with chronic exposure. Although vitamin D (VD) and calcium (Ca) showed promising protections, their co-administration was not previously investigated in Pb nephrotoxicity. This study measured the potential interactions and remedial effects of VD and/or Ca on established Pb nephropathy. Read More

View Article
December 2018

Anthriscus sylvestris root extract reduces allergic lung inflammation by regulating interferon regulatory factor 4-mediated Th2 cell activation.

J Ethnopharmacol 2018 Dec 12. Epub 2018 Dec 12.

Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, 34054, Korea; Department of Pathology, College of Korean Medicine, Sangji University, Wonju-si, Gangwon-do, 26339, Korea. Electronic address:

Ethnopharmacological Relevance: Anthriscus sylvestris L. Hoffmann (AS) is a perennial plant that grows in Asia and Eastern Europe. Its dried root is used to treat conditions such as asthma, bronchitis, and cough. Read More

View Article
December 2018
1 Read

A potential regulatory network among WDR86-AS1, miR-10b-3p, and LITAF is possibly involved in preeclampsia pathogenesis.

Cell Signal 2018 Dec 12. Epub 2018 Dec 12.

Department of Obstetrics and Gynecology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, PR China.

Preeclampsia (PE), a pregnancy-specific disorder, is a leading cause of perinatal maternal and fetal mortality and morbidity. Impaired migration and invasion of trophoblastic cells and an imbalanced systemic maternal inflammatory response have been proposed as possible causes of pathogenesis of PE. Comparative analysis of PE-affected placentas and healthy placentas has uncovered differentially expressed long noncoding RNAs, microRNAs, and mRNAs. Read More

View Article
December 2018

FH535 inhibits proliferation and migration of colorectal cancer cells by regulating CyclinA2 and Claudin1 gene expression.

Gene 2018 Dec 12. Epub 2018 Dec 12.

Wenzhou Medical University School of Laboratory Medicine and Life Sciences, Wenzhou 325000, China. Electronic address:

Wnt signaling pathway plays a major role in the progression of colorectal cancer (CRC). Small molecules which can cut off this signal transduction can be promising anti-cancer drugs for CRC therapy. Therefore, we aimed to investigate the mechanisms of FH535, an inhibitor of the Wnt signaling pathway, on inhibiting proliferation and migration of colorectal cancer cells DLD-1 and SW620. Read More

View Article
December 2018
1 Read

Protocol for evaluation of topical ophthalmic drug products in different compartments of fresh eye tissues in a rabbit model.

J Pharmacol Toxicol Methods 2018 Dec 12. Epub 2018 Dec 12.

Office of Translational Science, Office of Clinical Pharmacology, Division of Applied Regulatory Science, U.S. Food and Drug Administration, Center for Drug Evaluation and Research, White Oak Federal Research Center, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA. Electronic address:

Topical ophthalmic drugs are the most commonly used dosage form to treat diseases of the anterior segment of the eye. Although this dosage form has the advantages of ease of application, small volume dose, and rapid action and is largely devoid of systemic adverse effects, the bioavailability is low due to pre-corneal anatomical barriers and the nature of the drug formulation itself. Some complex generic formulations (suspensions, ointments, gels) for topical ophthalmic products face impediments to rapid regulatory approval because of the complex nature of the formulations and difficulties in determining bioequivalence with the innovator product. Read More

View Article
December 2018

Nano-based smart pesticide formulations: Emerging opportunities for agriculture.

J Control Release 2018 Dec 12. Epub 2018 Dec 12.

Department of Civil & Environmental Engineering, Hanyang University, 222 Wangsimni-Ro, Seoul 04763, Republic of Korea. Electronic address:

The incorporation of nanotechnology as a means for nanopesticides is in the early stage of development. The main idea behind this incorporation is to lower the indiscriminate use of conventional pesticides to be in line with safe environmental applications. Nanoencapsulated pesticides can provide controlled release kinetics, while efficiently enhancing permeability, stability, and solubility. Read More

View Article
December 2018

The insulin-like growth factor-1 system in the adult mammalian brain and its implications in central maternal adaptation.

Front Neuroendocrinol 2018 Dec 12. Epub 2018 Dec 12.

MTA-ELTE Laboratory of Molecular and Systems Neurobiology, Department of Physiology and Neurobiology, Hungarian Academy of Sciences and Eötvös Loránd University, Budapest, Hungary; Laboratory of Neuromorphology, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary. Electronic address:

Our knowledge on the bioavailability and actions of insulin-like growth factor-1 (IGF-1) has markedly expanded in recent years as novel mechanisms were discovered on IGF binding proteins (IGFBPs) and their ability to release IGF-1. The new discoveries allowed a better understanding of the endogenous physiological actions of IGF-1 and also its applicability in therapeutics. The focus of the present review is to summarize novel findings on the neuronal, neuroendocrine and neuroplastic actions of IGF-1 in the adult brain. Read More

View Article
December 2018
2 Reads

MicroRNA-212 promotes the recovery function and vascular regeneration of endothelial progenitor cells in mice with ischemic stroke through inactivation of the notch signaling pathway via downregulating MMP9 expression.

J Cell Physiol 2018 Dec 15. Epub 2018 Dec 15.

Department of Neurology, Cangzhou Central Hospital, Cangzhou, China.

Ischemic stroke is a refractory disease caused by cerebral ischemic injury, which results in brain dysfunction. This study intends to investigate the effects of microRNA-212 (miR-212) on the recovery function and vascular regeneration of endothelial progenitor cells (EPCs) by inactivation of the Notch signaling pathway by binding to matrix metallopeptidase 9 (MMP9) in mice with ischemic stroke. According to the results of database retrieval systems and data analysis, MMP9 was predicted as a gene related to ischemic stroke and miR-212 is a potential regulating mRNA of MMP9. Read More

View Article
December 2018

NF-YB1-YC12-bHLH144 complex directly activates Wx to regulate grain quality in rice (Oryza sativa L.).

Plant Biotechnol J 2018 Dec 15. Epub 2018 Dec 15.

State Key Lab of Rice Biology, China National Rice Research Institute, Hangzhou, 311400, P.R. China.

Identification of seed development regulatory genes is the key for the genetic improvement of rice grain quality. NF-Ys are important transcription factors, but their roles in rice grain quality control and the underlying molecular mechanism remains largely unknown. Here, we report the functional characterization a rice NF-Y heterotrimer complex NF-YB1-YC12-bHLH144, which is formed by the binding of NF-YB1 to NF-YC12 and then bHLH144 in a sequential order. Read More

View Article
December 2018

Mosaic modularity: an updated perspective and research agenda for the evolution of vascular cambial growth.

New Phytol 2018 Dec 15. Epub 2018 Dec 15.

Pacific Southwest Research Station, USDA Forest Service, Davis, CA, 95618.

Secondary growth from a vascular cambium, present today only in seed plants and isoetalean lycophytes, has a 400-million-year evolutionary history that involves considerably broader taxonomic diversity, most of it hidden in the fossil record. Approaching vascular cambial growth as a complex developmental process, we review data from living plants and fossils that reveal diverse modes of secondary growth. These are consistent with a modular nature of secondary growth, when considered as a tracheophyte-wide structural feature. Read More

View Article
December 2018

Gene expression signatures for HOXA4, HOXA9, and HOXD10 reveal alterations in transcriptional regulatory networks in colon cancer.

J Cell Physiol 2018 Dec 14. Epub 2018 Dec 14.

Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Newark, Delaware.

We previously reported that HOXA4, HOXA9, and HOXD10 are selectively expressed in colonic stem cells (SCs) and their overexpression contributes to colorectal cancer (CRC). Our goals here were to determine how these HOX genes are transcriptionally regulated and whether transcriptional dysregulation of HOX genes occurs in CRC. Accordingly, we used correlation analysis to identify genes that are expression-correlated or anticorrelated with HOXA4, HOXA9, and HOXD10. Read More

View Article
December 2018

BRD4 interacts with PML/RARα in acute promyelocytic leukemia.

Front Med 2018 Dec 14;12(6):726-734. Epub 2018 Dec 14.

State Key Laboratory of Medical Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Bromodomain-containing 4 (BRD4) has been considered as an important requirement for disease maintenance and an attractive therapeutic target for cancer therapy. This protein can be targeted by JQ1, a selective small-molecule inhibitor. However, few studies have investigated whether BRD4 influenced acute promyelocytic leukemia (APL), and whether BRD4 had interaction with promyelocytic leukemia-retinoic acid receptor α (PML/RARα) fusion protein to some extent. Read More

View Article
December 2018

Anatomy of Risk Evaluation and Mitigation Strategies (REMS).

Cancer Treat Res 2019 ;171:93-105

Center for Pharmacoepidemiology and Pharmacoeconomic Research, College of Pharmacy, University of Illinois, Chicago, Illinois, USA.

This Chapter provides an introduction and overview of the U.S. FDA REMS program and applicable regulatory aspects. Read More

View Article
January 2019

The Drug Shortage Crisis in the United States: Impact on Cancer Pharmaceutical Safety.

Cancer Treat Res 2019 ;171:75-92

University of Colorado Denver, Denver, CO, USA.

Drug shortages pose a significant public health concern in the United States, and cancer drugs are among those most affected. Shortages present serious safety risks for patients and substantial burden on providers and the healthcare system. Multifaceted drivers of this complex problem include manufacturing disruptions, raw material shortages, regulatory issues, market dynamics, and limited financial incentives that reward quality and production of off-patent drugs. Read More

View Article
January 2019

Biosimilars: Are They Really Safe?

Cancer Treat Res 2019 ;171:61-73

Robert H. Lurie Comprehensive Cancer Center Northwestern University, Chicago, IL, USA.

An increasing availability of biosimilars is an important step in the process of delivering optimal care while improving access for patients with cancer. Evolving regulatory mechanisms deal with biosimilars with different approaches within major regulatory agencies. We discuss some of the specific properties of biosimilars that merit attention in terms of optimizing their safety, delivering on appropriate related cost savings, and ensuring that appropriate premiums on innovative research are available to ensure ongoing progress in anticancer therapy. Read More

View Article
January 2019
1 Read

Key Elements in Adverse Drug Reactions Safety Signals: Application of Legal Strategies.

Cancer Treat Res 2019 ;171:47-59

University of South Carolina, Columbia, SC, USA.

Adverse drug reactions, or unintended and harmful outcomes related to the administration of a pharmaceutical product, are a major public health concern, particularly for cancer patients. If counted as a separate cause of death, adverse drug reactions would represent the fourth leading cause of death in the United States. Several legal strategies are available to help mitigate their occurrences and to compensate victims for the harm that results from adverse events. Read More

View Article
January 2019
1 Read

Impact of Cost on the Safety of Cancer Pharmaceuticals.

Cancer Treat Res 2019 ;171:1-20

Economics Department, DePaul University, Chicago, IL, USA.

Cancer care drug costs are rising due to a variety of factors, and safety concerns account for some of the cost. At the same time, clinical and economic concerns drive drug safety improvements. This chapter examines pressures on drug costs due to the complexity of care and drug therapies, marked structure in which care is provided, and regulatory requirements driving safety. Read More

View Article
January 2019

In Schizophrenia, Increased Plasma IgM/IgA Responses to Gut Commensal Bacteria Are Associated with Negative Symptoms, Neurocognitive Impairments, and the Deficit Phenotype.

Neurotox Res 2018 Dec 15. Epub 2018 Dec 15.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Increased gut permeability (leaky gut) with increased translocation of Gram-negative bacteria plays a role in the gut-brain axis through effects on systemic immune-inflammatory processes. Deficit schizophrenia is characterized by an immune-inflammatory response combined with a deficit in natural IgM antibodies to oxidative-specific epitopes (OSEs), which are a first-line defense against bacterial infections. This study measured plasma IgA/IgM responses to 5 Gram-negative bacteria in association with IgM responses to malondialdehyde (MDA) and azelaic acid in 80 schizophrenia patients (40 with the deficit syndrome and 40 without) and in 38 healthy controls. Read More

View Article
December 2018

Variance based global sensitivity analysis of physiologically based pharmacokinetic absorption models for BCS I-IV drugs.

J Pharmacokinet Pharmacodyn 2018 Dec 14. Epub 2018 Dec 14.

Centre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.

Regulatory agencies have a strong interest in sensitivity analysis for the evaluation of physiologically-based pharmacokinetic (PBPK) models used in pharmaceutical research and drug development and regulatory submissions. One of the applications of PBPK is the prediction of fraction absorbed and bioavailability for drugs following oral administration. In this context, we performed a variance based global sensitivity analysis (GSA) on in-house PBPK models for drug absorption, with the aim of identifying key parameters that influence the predictions of the fraction absorbed and the bioavailability for neutral, acidic and basic compounds. Read More

View Article
December 2018

Ex vivo conditioning with IL-12 protects tumor-infiltrating CD8 T cells from negative regulation by local IFN-γ.

Cancer Immunol Immunother 2018 Dec 14. Epub 2018 Dec 14.

Department of Inflammation and Immunity, Cleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue NE40, Cleveland, OH, 44195, USA.

Optimal ex vivo expansion protocols for adoptive cell therapy (ACT) must yield T cells able to effectively home to tumors and survive the inhospitable conditions of the tumor microenvironment (TME), while simultaneously exerting persistent anti-tumor effector functions. Our previous work has shown that ex vivo activation in the presence of IL-12 can induce optimal expansion of murine CD8 T cells, thus resulting in significant tumor regression after ACT mostly via sustained secretion of IFN-γ. In this report, we further elucidate the mechanism of this potency, showing that IL-12 additionally counteracts the negative regulatory effects of autocrine IFN-γ. Read More

View Article
December 2018
2 Reads

A novel role for E2F3b in regulating cocaine action in the prefrontal cortex.

Neuropsychopharmacology 2018 Dec 14. Epub 2018 Dec 14.

Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Drug abuse is a multifaceted disorder that involves maladaptive decision making. Long-lasting changes in the addicted brain are mediated by a complex circuit of brain reward regions. The prefrontal cortex (PFC) is one region in which chronic drug exposure changes expression and function of upstream transcriptional regulators to alter drug responses and aspects of the addicted phenotype. Read More

View Article
December 2018

Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9.

Nat Commun 2018 Dec 14;9(1):5319. Epub 2018 Dec 14.

Murdoch Children's Research Institute, Melbourne, 3052, VIC, Australia.

Disorders of sex development (DSDs) are conditions affecting development of the gonads or genitalia. Variants in two key genes, SRY and its target SOX9, are an established cause of 46,XY DSD, but the genetic basis of many DSDs remains unknown. SRY-mediated SOX9 upregulation in the early gonad is crucial for testis development, yet the regulatory elements underlying this have not been identified in humans. Read More

View Article
December 2018
1 Read

Transcriptome 3'end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma.

Nat Commun 2018 Dec 14;9(1):5331. Epub 2018 Dec 14.

Posttranscriptional Gene Regulation, Cancer Research and Experimental Haemostasis, University Medical Centre Mainz, Mainz, 55131, Germany.

Diversification at the transcriptome 3'end is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. Here, we identify extensive transcriptome 3'end-alterations in neuroblastoma, a tumour entity with a paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. Utilising extensive RNAi-screening we reveal the landscape and drivers of transcriptome 3'end-diversification, discovering PCF11 as critical regulator, directing alternative polyadenylation (APA) of hundreds of transcripts including a differentiation RNA-operon. Read More

View Article
December 2018

RagC phosphorylation autoregulates mTOR complex 1.

EMBO J 2018 Dec 14. Epub 2018 Dec 14.

School of Life and Environmental Sciences, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia

The mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) controls cell growth, proliferation, and metabolism in response to diverse stimuli. Two major parallel pathways are implicated in mTORC1 regulation including a growth factor-responsive pathway mediated via TSC2/Rheb and an amino acid-responsive pathway mediated via the Rag GTPases. Here, we identify and characterize three highly conserved growth factor-responsive phosphorylation sites on RagC, a component of the Rag heterodimer, implicating cross talk between amino acid and growth factor-mediated regulation of mTORC1. Read More

View Article
December 2018

The ferredoxin-like protein, FerR, regulates PrbP activity in .

Appl Environ Microbiol 2018 Dec 14. Epub 2018 Dec 14.

Microbiology and Cell Science Department, Genetics Institute, Institute of Food and Agricultural Science, University of Florida, Gainesville, Florida, United States

In , PrbP is an important transcriptional accessory protein that regulates gene expression through interactions with the RNA polymerase β-subunit and a specific sequence on the promoter region. The constitutive expression of observed upon chemical inactivation of PrbP/DNA interactions indicated that the expression of was not auto-regulated at the level of transcription. This observation suggested that a modulatory mechanism via protein-protein interactions maybe involved. Read More

View Article
December 2018
1 Read

FDA Approval Summary: Pertuzumab for adjuvant treatment of HER2-positive early breast cancer.

Clin Cancer Res 2018 Dec 14. Epub 2018 Dec 14.

Office of Hematology and Oncology, FDA.

On December 20, 2017, the Food and Drug Administration granted regular approval to pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) at high risk of recurrence. Approval was based on data from the APHINITY trial, which randomized patients to receive pertuzumab or placebo in combination with trastuzumab and chemotherapy. After 45. Read More

View Article
December 2018

Visualization of long-lived proteins reveals age mosaicism within nuclei of postmitotic cells.

J Cell Biol 2018 Dec 14. Epub 2018 Dec 14.

Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA

Many adult tissues contain postmitotic cells as old as the host organism. The only organelle that does not turn over in these cells is the nucleus, and its maintenance represents a formidable challenge, as it harbors regulatory proteins that persist throughout adulthood. Here we developed strategies to visualize two classes of such long-lived proteins, histones and nucleoporins, to understand the function of protein longevity in nuclear maintenance. Read More

View Article
December 2018

Low-dose chidamide restores immune tolerance in ITP patients and mice by modulating nTreg cells and CTLA4 expression.

Blood 2018 Dec 14. Epub 2018 Dec 14.

Department of Hematology, Qilu Hospital, Shandong University, Jinan, China;

Increased macrophage phagocytosis of antibody-coated platelet as well as decreased number and/or impaired function of CD4CD25Foxp3 regulatory T (Treg) cells have been shown to participate in the pathogenesis of immune thrombocytopenia (ITP). Low-dose histone deacetylase inhibitors (HDACi) are anti-inflammatory and immunomodulatory agents that can enhance immunosuppression in graft-versus-host disease by increasing the number and function of Foxp3 T-regulatory cells. Whether low-dose HDACi has potential in promoting immune tolerance and platelet release in ITP is unclear. Read More

View Article
December 2018

Complaints addressed by regulatory authorities in drug advertising targeted at consumers: Cases across three, different countries.

Res Social Adm Pharm 2018 Dec 7. Epub 2018 Dec 7.

Department of Health, Social and Clinical Pharmacy, Chung-Ang University College of Pharmacy, Seoul, South Korea; The Graduate School of Pharmaceutical Industry Management, Chung-Ang University, Seoul, South Korea. Electronic address:

Background: Misleading advertisements can affect behavior of both consumers and prescribers and may lead to inappropriate use of medications.

Objective: To analyze the complaints upheld by regulatory authorities in the United Kingdom, Canada, and Australia regarding pharmaceutical advertising directed at consumers.

Methods: Complaints addressed between January 2014 and June 2017 were retrieved from the websites of regulatory authorities. Read More

View Article
December 2018

Outpatient management in plastic and reconstructive head and neck surgery in France.

Eur Ann Otorhinolaryngol Head Neck Dis 2018 Dec 11. Epub 2018 Dec 11.

Service d'ORL et de chirurgie cervico-faciale, centre hospitalier universitaire de Nantes, Hôtel-Dieu, 1, place A. Ricordeau, BP 1005, 44093 Nantes cedex 01, France.

The present review lays out the main principles governing outpatient management in the French health system in 2018, and more specifically in plastic and reconstructive head and neck surgery. The historical regulatory aspects and the changes of the last few years are explained, along with the trends and health authorities' expectations for the years to come. The main limitations to implementing outpatient procedures are the common to all surgical specialities, plastic and reconstructive head and neck surgery being no exception. Read More

View Article
December 2018

Principal component analysis reveals disconnect between regulatory cytokines and disease activity in Systemic Lupus Erythematosus.

Cytokine 2018 Dec 11. Epub 2018 Dec 11.

Rheumatology Group, School of Medicine & Pharmacology, The University of Western Australia, Australia; Department of Rheumatology, Sir Charles Gairdner Hospital, Perth Western, Australia. Electronic address:

Objective: Cytokine dysregulation contributes to inflammation and organ damage in Systemic Lupus Erythematosus (SLE). Principle Component Analysis (PCA) can determine which groups of cytokines have the most influence across disease activity states.

Material And Method: A cross-sectional study of age- and gender-matched SLE patients (n = 100) and controls (n = 31). Read More

View Article
December 2018

Long noncoding RNA H19 promotes vascular remodeling by sponging let-7a to upregulate the expression of cyclin D1.

Biochem Biophys Res Commun 2018 Dec 11. Epub 2018 Dec 11.

Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, 110001, China. Electronic address:

Vascular remodeling is mainly caused by excessive proliferation of vascular smooth muscle cells (VSMCs). Noncoding RNAs (ncRNAs) have emerged as important regulators in diverse pathological processes. Previous work has shown the functions and mechanisms of long noncoding RNA H19 (LncRNA H19) on VSMCs. Read More

View Article
December 2018

Epidemic preparedness: why is there a need to accelerate the development of diagnostics?

Lancet Infect Dis 2018 Dec 11. Epub 2018 Dec 11.

UNICEF-UNDP-World Bank-WHO Special Programme for Research and Training in Tropical Diseases, WHO, Geneva, Switzerland; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address:

Global epidemics of infectious diseases are increasing in frequency and severity. Diagnostics are needed for rapid identification of the cause of the epidemic to facilitate effective control and prevention. Lessons learned from the recent Ebola virus and Zika virus epidemics are that delay in developing the right diagnostic for the right population at the right time has been a costly barrier to disease control and prevention. Read More

View Article
December 2018

Transcriptome analyses identify key genes and potential mechanisms in a rat model of osteoarthritis.

J Orthop Surg Res 2018 Dec 14;13(1):319. Epub 2018 Dec 14.

Department of Orthopaedics, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China.

Background: Osteoarthritis (OA) is one of the most common degenerative diseases of the joints worldwide, but still the pathogenesis of OA is largely unknown. The purpose of our study is to clarify key candidate genes and relevant signaling pathways in a surgical-induced OA rat model.

Methods: The microarray raw data of GSE8077 was downloaded from GEO datasets. Read More

View Article
December 2018

Enhancer Trapping and Annotation in Zebrafish Mediated with Sleeping Beauty, piggyBac and Tol2 Transposons.

Genes (Basel) 2018 Dec 13;9(12). Epub 2018 Dec 13.

Institute of Mobilome and Genome, College of Animal Science & Technology, Yangzhou University, Yangzhou 225009, China.

Although transposon-mediated enhancer trapping (ET) is successfully applied in diverse models, the efficiency of various transposon systems varies significantly, and little information is available regarding efficiency of enhancer trapping by various transposons in zebrafish. Most potential enhancers (Ens) still lack evidence of actual En activity. Here, we compared the differences in ET efficiency between (), () and transposons. Read More

View Article
December 2018
1 Read