Related Articles

Safety and Immunogenicity of a 9-Valent Human Papillomavirus Vaccine Administered to 9- to 15-Year-Old Japanese Girls.

Jpn J Infect Dis. 2017 Jul 24;70(4):368-373

Authors: Iwata S, Murata S, Rong Han S, Wakana A, Sawata M, Tanaka Y

Abstract
A 9-valent human papillomavirus (HPV 6/11/16/18/31/33/45/52/58) virus-like particle vaccine (9vHPV) has been proven highly efficacious in preventing anogenital diseases related to HPV, in a pivotal phase III study for women aged 16-26 years. Here, we report the results of an open-label phase III study conducted to bridge the gap between the findings in women aged 16-26 years and Japanese girls aged 9-15 years. All subjects (n = 100) received a 3-dose regimen of 9vHPV vaccine on day 1 and at months 2 and 6. Anti-HPV serological assays were performed on day 1 and at months 7, 12, 24, and 30. At month 7 (4 weeks after the third dose), 100% of the subjects exhibited seroconversion for each type of HPV. Increases in geometric mean of the titers for anti-HPV 6/11/16/18/31/33/45/52/58 in the subjects were similar to those in Japanese women aged 16-26 years in a previous phase III study. Persistence of the anti-HPV response was observed for 2 years after administration of the third dose. In addition, administration of the 9vHPV vaccine was generally well-tolerated in Japanese girls.

PMID: 28003597 [PubMed - indexed for MEDLINE]

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[MODERN ASPECTS OF THE SAFE USE OF EXTENSION QT INTERVAL MEDICINES.]

Anesteziol Reanimatol. 2016 Sep;61(5):386-390

Authors: Shikh EV, Ismaailov AD, Dorofeeva MN, Sizava ZM

Abstract
Prolongation of QTinterval is apredictor offatal cardiac arrhythmias and sudden death. In clinical practice, medicines with possible and conditional risk of QTprolongation are combine. The danger of such interactions could be enhanced if medi- cines interact themselves at metabolic rate. The interaction of drugs with possible and conditional risk of QTprolongation and interaction of these drugs with drugs that can influence the metabolic activity of cytochrome P450 isoenzymes require specific attention from physicians. Predictability of QTprolongation by drug-drug interactions at metabolic rate in drug administration will increase the safety of pharmacotherapy of drugs with possible and conditional risk of QTprolongation.

PMID: 29489109 [PubMed - indexed for MEDLINE]

Notice NOT-HL-18-610 from the NIH Guide for Grants and Contracts

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pharmacogenomics

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(exome OR "exome sequencing") AND disease

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("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

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Funding Opportunity PA-18-720 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages research grant applications from institutions/organizations that propose to conduct exploratory/developmental clinical studies that will accelerate the development of effective interventions for prevention or treatment of overweight or obesity in adults and/or children. Exploratory epidemiological research with a goal of informing translational/clinical research will also be supported within this program.

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Comparative oncology approach to drug repurposing in osteosarcoma.

PLoS One. 2018;13(3):e0194224

Authors: Parrales A, McDonald P, Ottomeyer M, Roy A, Shoenen FJ, Broward M, Bruns T, Thamm DH, Weir SJ, Neville KA, Iwakuma T, Fulbright JM

Abstract
BACKGROUND: Osteosarcoma is an orphan disease for which little improvement in survival has been made since the late 1980s. New drug discovery for orphan diseases is limited by the cost and time it takes to develop new drugs. Repurposing already approved FDA-drugs can help overcome this limitation. Another limitation of cancer drug discovery is the lack of preclinical models that accurately recapitulate what occurs in humans. For OS using dogs as a model can minimize this limitation as OS in canines develops spontaneously, is locally invasive and metastasizes to the lungs as it does in humans.
METHODS: In our present work we used high-throughput screens to identify drugs from a library of 2,286 FDA-approved drugs that demonstrated selective growth inhibition against both human and canine OS cell lines. The identified lead compound was then tested for synergy with 7 other drugs that have demonstrated activity against OS. These results were confirmed with in vitro assays and an in vivo murine model of OS.
RESULTS: We identified 13 drugs that demonstrated selective growth inhibition against both human and canine OS cell lines. Auranofin was selected for further in vitro combination drug screens. Auranofin showed synergistic effects with vorinostat and rapamycin on OS viability and apoptosis induction. Auranofin demonstrated single-agent growth inhibition in both human and canine OS xenografts, and cooperative growth inhibition was observed in combination with rapamycin or vorinostat. There was a significant decrease in Ki67-positive cells and an increase in cleaved caspase-3 levels in tumor tissues treated with a combination of auranofin and vorinostat or rapamycin.
CONCLUSIONS: Auranofin, alone or in combination with rapamycin or vorinostat, may be useful new treatment strategies for OS. Future studies may evaluate the efficacy of auranofin in dogs with OS as a prelude to human clinical evaluation.

PMID: 29579058 [PubMed - in process]

Related Articles

Do investors value the FDA orphan drug designation?

Orphanet J Rare Dis. 2017 Jun 19;12(1):114

Authors: Miller KL

Abstract
BACKGROUND: The Orphan Drug Act is an important piece of legislation that uses financial incentives to encourage the development of drugs that treat rare diseases. This analysis studies the effects of a portion of the Orphan Drug Act, the orphan drug designation. Specifically, it studies the value that investors place on the orphan drug designation, by investigating how investors react to companies' announcing that their product has received the designation.
RESULTS: The results, on average, show that the stock price of a company increases by 3.36% after the announcement of the designation, increasing the value of the company. The results are more pronounced for oncology drugs, and drugs being developed by the smallest companies.
CONCLUSION: The orphan designation appears to be successful at generating positive value for companies, as seen by the positive and significant average increases in stock price.

PMID: 28629392 [PubMed - indexed for MEDLINE]

Related Articles

Open issues in Mucopolysaccharidosis type I-Hurler.

Orphanet J Rare Dis. 2017 Jun 15;12(1):112

Authors: Parini R, Deodato F, Di Rocco M, Lanino E, Locatelli F, Messina C, Rovelli A, Scarpa M

Abstract
Mucopolysaccharidosis I-Hurler (MPS I-H) is the most severe form of a metabolic genetic disease caused by mutations of IDUA gene encoding the lysosomal α-L-iduronidase enzyme. MPS I-H is a rare, life-threatening disease, evolving in multisystem morbidity including progressive neurological disease, upper airway obstruction, skeletal deformity and cardiomyopathy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the gold standard for the treatment of MPS I-H in patients diagnosed and treated before 2-2.5 years of age, having a high rate of success. Beyond the child's age, other factors influence the probability of treatment success, including the selection of patients, of graft source and the donor type employed. Enzyme replacement therapy (ERT) with human recombinant laronidase has also been demonstrated to be effective in ameliorating the clinical conditions of pre-transplant MPS I-H patients and in improving HSCT outcome, by peri-transplant co-administration. Nevertheless the long-term clinical outcome even after successful HSCT varies considerably, with a persisting residual disease burden. Other strategies must then be considered to improve the outcome of these patients: one is to pursue early pre-symptomatic diagnosis through newborn screening and another one is the identification of novel treatments. In this perspective, even though newborn screening can be envisaged as a future attractive perspective, presently the best path to be pursued embraces an improved awareness of signs and symptoms of the disorder by primary care providers and pediatricians, in order for the patients' timely referral to a qualified reference center. Furthermore, sensitive new biochemical markers must be identified to better define the clinical severity of the disease at birth, to support clinical judgement during the follow-up and to compare the effects of the different therapies. A prolonged neuropsychological follow-up of post-transplant cognitive development of children and residual disease burden is needed. In this perspective, the reference center must guarantee a multidisciplinary follow-up with an expert team. Diagnostic and interventional protocols of reference centers should be standardized whenever possible to allow comparison of clinical data and evaluation of results. This review will focus on all these critical issues related to the management of MPS I-H.

PMID: 28619065 [PubMed - indexed for MEDLINE]

Related Articles

Deep mining heterogeneous networks of biomedical linked data to predict novel drug-target associations.

Bioinformatics. 2017 Aug 01;33(15):2337-2344

Authors: Zong N, Kim H, Ngo V, Harismendy O

Abstract
Motivation: A heterogeneous network topology possessing abundant interactions between biomedical entities has yet to be utilized in similarity-based methods for predicting drug-target associations based on the array of varying features of drugs and their targets. Deep learning reveals features of vertices of a large network that can be adapted in accommodating the similarity-based solutions to provide a flexible method of drug-target prediction.
Results: We propose a similarity-based drug-target prediction method that enhances existing association discovery methods by using a topology-based similarity measure. DeepWalk, a deep learning method, is adopted in this study to calculate the similarities within Linked Tripartite Network (LTN), a heterogeneous network generated from biomedical linked datasets. This proposed method shows promising results for drug-target association prediction: 98.96% AUC ROC score with a 10-fold cross-validation and 99.25% AUC ROC score with a Monte Carlo cross-validation with LTN. By utilizing DeepWalk, we demonstrate that: (i) this method outperforms other existing topology-based similarity computation methods, (ii) the performance is better for tripartite than with bipartite networks and (iii) the measure of similarity using network topology outperforms the ones derived from chemical structure (drugs) or genomic sequence (targets). Our proposed methodology proves to be capable of providing a promising solution for drug-target prediction based on topological similarity with a heterogeneous network, and may be readily re-purposed and adapted in the existing of similarity-based methodologies.
Availability and Implementation: The proposed method has been developed in JAVA and it is available, along with the data at the following URL: https://github.com/zongnansu1982/drug-target-prediction .
Contact: nazong@ucsd.edu.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 28430977 [PubMed - indexed for MEDLINE]

Role of Spdef in the Regulation of Muc5b Expression in the Airways of Naïve and Muco-obstructed Mice.

Am J Respir Cell Mol Biol. 2018 Mar 26;:

Authors: Chen G, Volmer AS, Wilkinson KJ, Deng Y, Jones LC, Yu D, Bustamante-Marin XM, Burns KA, Grubb BR, O'Neal WK, Livraghi-Butrico A, Boucher RC

Abstract
Understanding how airway secretory mucins MUC5B and MUC5AC expression is regulated in health and disease is important to elucidate the pathogenesis of muco-obstructive respiratory diseases. The transcription factor SPDEF is a key regulator of MUC5AC, but its role in regulating MUC5B in health and in muco-obstructive lung diseases is unknown. Characterization of Spdef-deficient mice upper and lower airways demonstrated region-specific, Spdef-dependent regulation of basal Muc5b expression. Neonatal Spdef-deficient mice exhibited reductions in bronchoalveolar lavage (BAL) Muc5ac and Muc5b. Adult Spdef-deficient mice partially phenocopied Muc5b-deficient mice as they exhibited reduced Muc5b in nasopharyngeal and airway epithelia but not in olfactory Bowman glands, 75% incidence of nasopharyngeal hair/mucus plugs, and mild bacterial otitis media, without defective mucociliary clearance (MCC) in the nasopharynx. In contrast, tracheal MCC was reduced in Spdef-deficient mice in the absence of lung disease. To evaluate the role of Spdef in the development and persistence of Muc5b-predominant muco-obstructive lung disease, Spdef-deficient mice were crossed with Scnn1b-Tg mice, which exhibit airway surface dehydration-induced airway mucus obstruction and inflammation. Spdef-deficient Scnn1b-Tg mice exhibited reduced Muc5ac, but not Muc5b, expression and BAL content. Airway mucus obstruction was not decreased in Spdef-deficient Scnn1b-Tg mice, consistent with Muc5b dominant Scnn1b disease, but increased airway neutrophilia was observed compared to Spdef-sufficient Scnn1b-Tg mice. Collectively, these results indicate that Spdef regulates baseline Muc5b expression in respiratory epithelia, but does not contribute to Muc5b regulation in a mouse model of Muc5b-predominant mucus obstruction caused by airway dehydration.

PMID: 29579396 [PubMed - as supplied by publisher]

Related Articles

Maternal chronic hypoxia increases expression of genes regulating lung liquid movement and surfactant maturation in male fetuses in late gestation.

J Physiol. 2017 Jul 01;595(13):4329-4350

Authors: McGillick EV, Orgeig S, Allison BJ, Brain KL, Niu Y, Itani N, Skeffington KL, Kane AD, Herrera EA, Giussani DA, Morrison JL

Abstract
KEY POINTS: Chronic fetal hypoxaemia is a common pregnancy complication associated with intrauterine growth restriction that may influence respiratory outcome at birth. We investigated the effect of maternal chronic hypoxia for a month in late gestation on signalling pathways regulating fetal lung maturation and the transition to air-breathing at birth using isobaric hypoxic chambers without alterations to maternal food intake. Maternal chronic hypoxia in late gestation increases fetal lung expression of genes regulating hypoxia signalling, lung liquid reabsorption and surfactant maturation, which may be an adaptive response in preparation for the successful transition to air-breathing at birth. In contrast to other models of chronic fetal hypoxaemia, late gestation onset fetal hypoxaemia promotes molecular regulation of fetal lung maturation. This suggests a differential effect of timing and duration of fetal chronic hypoxaemia on fetal lung maturation, which supports the heterogeneity observed in respiratory outcomes in newborns following exposure to chronic hypoxaemia in utero.
ABSTRACT: Chronic fetal hypoxaemia is a common pregnancy complication that may arise from maternal, placental and/or fetal factors. Respiratory outcome of the infant at birth likely depends on the duration, timing and severity of the hypoxaemic insult. We have isolated the effect of maternal chronic hypoxia (MCH) for a month in late gestation on fetal lung development. Pregnant ewes were exposed to normoxia (21% O2 ) or hypoxia (10% O2 ) from 105 to 138 days of gestation (term ∼145 days). At 138 days, gene expression in fetal lung tissue was determined by quantitative RT-PCR. Cortisol concentrations were determined in fetal plasma and lung tissue. Numerical density of surfactant protein positive cells was determined by immunohistochemistry. MCH reduced maternal PaO2 (106 ± 2.9 vs. 47 ± 2.8 mmHg) and fetal body weight (4.0 ± 0.4 vs. 3.2 ± 0.9 kg). MCH increased fetal lung expression of the anti-oxidant marker CAT and decreased expression of the pro-oxidant marker NOX-4. MCH increased expression of genes regulating hypoxia signalling and feedback (HIF-3α, KDM3A, SLC2A1, EGLN-3). There was no effect of MCH on fetal plasma/lung tissue cortisol concentrations, nor genes regulating glucocorticoid signalling (HSD11B-1, HSD11B-2, NR3C1, NR3C2). MCH increased expression of genes regulating sodium (SCNN1-B, ATP1-A1, ATP1-B1) and water (AQP-4) movement in the fetal lung. MCH promoted surfactant maturation (SFTP-B, SFTP-D, ABCA3) at the molecular level, but did not alter the numerical density of surfactant positive cells in lung tissue. MCH in late gestation promotes molecular maturation of the fetal lung, which may be an adaptive response in preparation for the successful transition to air-breathing at birth.

PMID: 28318025 [PubMed - indexed for MEDLINE]

Related Articles

Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression.

Proc Natl Acad Sci U S A. 2016 11 01;113(44):12508-12513

Authors: Roy B, Friesen WJ, Tomizawa Y, Leszyk JD, Zhuo J, Johnson B, Dakka J, Trotta CR, Xue X, Mutyam V, Keeling KM, Mobley JA, Rowe SM, Bedwell DM, Welch EM, Jacobson A

Abstract
A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in control, ataluren-treated, and aminoglycoside-treated cells. We find that ataluren's likely target is the ribosome and that it produces full-length protein by promoting insertion of near-cognate tRNAs at the site of the nonsense codon without apparent effects on transcription, mRNA processing, mRNA stability, or protein stability. The resulting readthrough proteins retain function and contain amino acid replacements similar to those derived from endogenous readthrough, namely Gln, Lys, or Tyr at UAA or UAG PTCs and Trp, Arg, or Cys at UGA PTCs. These insertion biases arise primarily from mRNA:tRNA mispairing at codon positions 1 and 3 and reflect, in part, the preferred use of certain nonstandard base pairs, e.g., U-G. Ataluren's retention of similar specificity of near-cognate tRNA insertion as occurs endogenously has important implications for its general use in therapeutic nonsense suppression.

PMID: 27702906 [PubMed - indexed for MEDLINE]