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"systems biology"

These pubmed results were generated on 2018/05/08

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

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

These pubmed results were generated on 2018/05/08

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Towards a map of cis-regulatory sequences in the human genome.

Nucleic Acids Res. 2018 May 04;:

Authors: Niu M, Tabari E, Ni P, Su Z

Abstract
Accumulating evidence indicates that transcription factor (TF) binding sites, or cis-regulatory elements (CREs), and their clusters termed cis-regulatory modules (CRMs) play a more important role than do gene-coding sequences in specifying complex traits in humans, including the susceptibility to common complex diseases. To fully characterize their roles in deriving the complex traits/diseases, it is necessary to annotate all CREs and CRMs encoded in the human genome. However, the current annotations of CREs and CRMs in the human genome are still very limited and mostly coarse-grained, as they often lack the detailed information of CREs in CRMs. Here, we integrated 620 TF ChIP-seq datasets produced by the ENCODE project for 168 TFs in 79 different cell/tissue types and predicted an unprecedentedly completely map of CREs in CRMs in the human genome at single nucleotide resolution. The map includes 305 912 CRMs containing a total of 1 178 913 CREs belonging to 736 unique TF binding motifs. The predicted CREs and CRMs tend to be subject to either purifying selection or positive selection, thus are likely to be functional. Based on the results, we also examined the status of available ChIP-seq datasets for predicting the entire regulatory genome of humans.

PMID: 29733395 [PubMed - as supplied by publisher]

Is the pharmaceutical industry's preoccupation with the monotherapy drug model stifling the development of effective new drug therapies?

Inflammopharmacology. 2018 May 07;:

Authors: Cock IE

Abstract
Drug discovery and development is heavily biased towards the development of monotherapies. Screening, testing, and evaluation of mono-entity drugs are generally much simpler than drug combinations, and are generally easier to get approval from the regulatory authorities for their clinical use. However, monotherapy drugs may not have optimal activity, may have associated toxicities, or may lose activity over time as their target develops resistance. Drug combinations, often developed from existing monotherapies, may have improved efficacy and/or be less toxic. Furthermore, the existing drugs which have lost efficacy due to the development of resistance can often be re-activated by combining them with other chemical entities. Thus, whilst the current climate for drug approval, registration, and clinical use drives the majority of drug development research towards the development of monotherapies, combinations are often a substantial improvement on the original drug. This commentary examines monotherapy and combinational therapy models and discusses the benefits and limitations of each model.

PMID: 29736688 [PubMed - as supplied by publisher]

Clustering based drug-drug interaction networks for possible repositioning of drugs against EGFR mutations: Clustering based DDI networks for EGFR mutations.

Comput Biol Chem. 2018 Apr 27;75:24-31

Authors: Munir A, Elahi S, Masood N

Abstract
EGFRs are a vast group of receptor tyrosine kinases playing an important role in a number of tumors, including lungs, head and neck, breast, and esophageal cancers. A couple of techniques are being used in the process of drug design. Drug repositioning or repurposing is a rising idea that consists of distinguishing modern remedial indications for officially existing dynamic pharmaceutical compounds. Here, a novel approach of analyzing drug-drug interaction networks, based on clustering methodology is used to reposition effective compounds against mutant EGFR having G719X, exon 19 deletions/insertions, L858R, and L861Q mutations. Data about 2062 drugs are obtained, and mining is performed to filter only those drugs which fulfill Lipinski rule of five. Clustering is performed, and DDIs are built on the clusters to identify effective drug compounds. Only 1052 compounds fulfill Lipinski rule. 12 clusters are formed for 1052 drugs compounds. DDIs are developed for each cluster. Only 15 drugs are suggested to be more effective assuming strong interactions in a DDI.

PMID: 29730365 [PubMed - as supplied by publisher]

Repurposing drugs for glioblastoma: from bench to bedside.

Cancer Lett. 2018 May 02;:

Authors: Basso J, Miranda A, Sousa J, Pais A, Vitorino C

Abstract
Glioblastoma multiforme is the most common, aggressive and lethal type of brain tumour. It is a stage IV cancer disease with a poor prognosis, as the current therapeutic options (surgery, radiotherapy and chemotherapy) are not able to eradicate tumour cells. The approach to treat glioblastoma has not suffered major changes over the last decade and temozolomide (TMZ) remains the mainstay for chemotherapy. However, resistance mechanisms to TMZ and other chemotherapeutic agents are becoming more frequent. The lack of effective options is a reality that may be counterbalanced by repositioning known and commonly used drugs for other diseases. This approach takes into consideration the available pharmacokinetic, pharmacodynamic, toxicity and safety data, and allows a much faster and less expensive drug and product development process. In this review, an extensive literature search is conducted aiming to list drugs with repurposing usage, based on their preferential damage in glioblastoma cells through various mechanisms. Some of these drugs have already entered clinical trials, exhibiting favourable outcomes, which sparks their potential application in glioblastoma treatment.

PMID: 29729291 [PubMed - as supplied by publisher]

Development of minimum standards of care for juvenile localized scleroderma.

Eur J Pediatr. 2018 May 04;:

Authors: Constantin T, Foeldvari I, Pain CE, Pálinkás A, Höger P, Moll M, Nemkova D, Weibel L, Laczkovszki M, Clements P, Torok KS

Abstract
Juvenile localized scleroderma (jLS), also known as morphea, is an orphan disease. Pediatric guidelines regarding diagnosis, assessment, and management are lacking.Our objective was to develop minimum standards of care for diagnosis, assessment, and management of jLS. A systematic review was undertaken to establish the pediatric evidence for assessment and monitoring of jLS. An expert panel, including members of the Pediatric Rheumatology European Society (PRES) Scleroderma Working Group, were invited to a consensus meeting where recommendations were developed based on evidence graded by the systematic review and, where evidence was lacking, consensus opinion. A nominal technique was used where 75% consensus was taken as agreement. Recommendations for diagnosis, assessment, and management were developed. Due to a lack of pediatric evidence, these were primarily consensus driven. Careful assessment for extra-cutaneous manifestations including synovitis, brain involvement, and uveitis were key features together with joint assessments between Dermatology and Rheumatology to improve and standardize care.
CONCLUSION: Management of jLS is varied. These recommendations should help provide standardization of assessment and care for those with this rare and potentially debilitating condition. What is Known: • Children with juvenile localized scleroderma (jLS) are managed by a number of specialties including pediatric rheumatologists and dermatologists, sometimes in shared clinics. Studies have shown that management varies considerably and that there are notable differences between specialties [1]. • There is very little published guidance on management of jLS. What is new: • These recommendations aim to standardize diagnosis, assessment, and management through review of pediatric evidence and consensus agreement. • Joint review of patients by both pediatric rheumatologists and dermatologists is recommended.

PMID: 29728839 [PubMed - as supplied by publisher]

Melorheostosis: a Rare Sclerosing Bone Dysplasia.

Curr Osteoporos Rep. 2017 Aug;15(4):335-342

Authors: Kotwal A, Clarke BL

Abstract
PURPOSE OF REVIEW: Melorheostosis is a rare sclerosing bone dysplasia that affects both cortical bone and adjacent soft tissue structures in a sclerotomal distribution. In this review, we describe the natural history, radiological features, proposed pathogenesis, and management options for this debilitating condition.
RECENT FINDINGS: Since its first description in 1922, about 400 cases of melorheostosis have been reported, either as single reports or in small case series. Melorheostosis affects the appendicular skeleton more commonly than the axial skeleton and usually presents with lower limb deformity. Diagnosis is based on a combination of clinical and radiological features that help differentiate this condition from other sclerosing bone dysplasias. LEM domain-containing protein 3 (LEMD3) gene mutations have been demonstrated in several familial cases, but these have been more strongly correlated with other hereditary dysplasias, such as osteopoikilosis, and are not thought to be the causative gene for melorheostosis. The exact etiology of classic sporadically occurring melorheostosis remains unknown, with possible causes being somatic LEMD3 mutations, somatic mutations in the bone morphogenetic protein/transforming growth factor-beta pathway, mutations in multiple genes, or other non-genetic causes. Management in recent years has involved nitrogen-containing bisphosphonates in addition to traditional orthopedic surgical approaches and physical therapy. Melorheostosis may present as mixed or atypical osseous involvement in addition to the classically described "dripping candle wax" appearance of hyperostosis. Some patients may have overlap with osteopoikilosis or Buschke-Ollendorff syndrome. In the future, better characterization of genetic and developmental factors predisposing to melorheostosis may lead to the development of targeted therapy for this condition, as well as for more commonly encountered skeletal abnormalities.

PMID: 28676968 [PubMed - indexed for MEDLINE]

[Liver Transplantation as Treatment for Rare Diseases in Adults].

Zentralbl Chir. 2017 Apr;142(2):169-179

Authors: Bauschke A, Malessa C, Rauchfuss F, Zanow J, Settmacher U

Abstract
In addition to the main indications pertaining to 95 % of all patients receiving liver transplantation in Germany, there are numerous other diseases that may become clinically evident in the adult age and may lead to the decision for liver transplantation. These may be metabolic diseases with their main defect located in the liver, malformations of liver cells, hepatic vascular diseases and rare tumours of the liver. Standard exceptions for the listing are in place only for a limited number of diseases. Exact diagnostics and the point in time for transplantation are crucial for the prognosis.

PMID: 24241952 [PubMed - indexed for MEDLINE]

Pseudomonas pharyngitis in a cystic fibrosis patient.

Respirol Case Rep. 2018 Jul;6(5):e00325

Authors: Pradeepan S, Wark P

Abstract
We report a case of Pseudomonas pharyngitis in a cystic fibrosis (CF) patient not known to have prior colonization of Pseudomonas. We believe that this is one of the first cases of pseudomonas pharyngitis in a CF patient.

PMID: 29736241 [PubMed]

Volatile fingerprinting of <i>pseudomonas aeruginosa</i> and respiratory syncytial virus infection in an <i>in vitro</i> cystic fibrosis co-infection model.

J Breath Res. 2018 May 08;:

Authors: Purcaro G, Rees C, Melvin JA, Bomberg JM, Hill JE

Abstract
Volatile molecules in exhaled breath represent potential biomarkers in the setting of infectious diseases, particularly those affecting the respiratory tract. In particular, Pseudomonas aeruginosa is a critically-important respiratory pathogen in specific subsets of the population, such as those with cystic fibrosis. Infections caused by P. aeruginosa can be particularly problematic when co-infection with respiratory syncytial virus (RSV) occurs, as this is correlated with the establishment of chronic P. aeruginosa infection. In the present study, we evaluate the volatile metabolites produced by P. Aeruginosa (PAO1)-infected, RSV-infected, co-infected, or uninfected cystic fibrosis bronchial epithelial (CFBE) cells, in vitro. We identified a volatile metabolic signature that could discriminate between P. aeruginosa-infected and non-P. aeruginosa-infected CFBE with an area under the receiver operating characteristic curve (AUROC) of 0.850, using the machine learning algorithm Random Forest (RF). Although we could not discriminate between RSV-infected and non-RSV-infected CFBE (AUROC = 0.431), we note that sample classification probabilities for RSV-infected cell, generated using RF, were between those of uninfected CFBE and P. aeruginosa-infected CFBE, suggesting that RSV infection may result in a volatile metabolic profile that shares attributes with both of these groups. To more precisely elucidate the biological origins of the volatile metabolites that were discriminatory between P. aeruginosa-infected and non-P. aeruginosa-infected CFBE, we measured the volatile metabolites produced by P. aeruginosa grown in the absence of CFBE. Our findings suggest that the discriminatory metabolites produced likely result from the interaction of P. aeruginosa with the CFBE cells, rather than the metabolism of media components by the bacterium. Taken together, our findings support the notion that P. aeruginosa interacting with CFBE yields a particular volatile metabolic signature. Such a signature may have clinical utility in the monitoring of individuals with cystic fibrosis.

PMID: 29735804 [PubMed - as supplied by publisher]

Apolipoprotein E polymorphism determines vitamin K supplementation effectiveness in cystic fibrosis patients.

J Cyst Fibros. 2018 May 04;:

Authors: Krzyżanowska-Jankowska P, Sobkowiak P, Thalmann O, Drzymała-Czyż S, Glapa A, Hołysz M, Walkowiak D, Rohovyk N, Bober L, Pogorzelski A, Walkowiak J

PMID: 29735383 [PubMed - as supplied by publisher]

Use of a rare disease patient registry in long-term post-authorisation drug studies: a model for collaboration with industry.

Lancet Respir Med. 2018 May 04;:

Authors: Bilton D, Caine N, Cunningham S, Simmonds NJ, Cosgriff R, Carr SB

PMID: 29735358 [PubMed - as supplied by publisher]

Precision Medicine In Action: The Impact Of Ivacaftor On Cystic Fibrosis-Related Hospitalizations.

Health Aff (Millwood). 2018 May;37(5):773-779

Authors: Feng LB, Grosse SD, Green RF, Fink AK, Sawicki GS

Abstract
Cystic fibrosis is a life-threatening genetic disease that causes severe damage to the lungs. Ivacaftor, the first drug that targeted the underlying defect of the disease caused by specific mutations, is a sterling example of the potential of precision medicine. Clinical trial and registry studies showed that ivacaftor improved outcomes and reduced hospitalizations. Our study used US administrative claims data to assess the real-world effectiveness of ivacaftor. Comparing twelve-month rates before and after starting the use of ivacaftor among people who initiated therapy during 2012-2015, we found that overall and cystic fibrosis-related inpatient admissions fell by 55 percent and 81 percent, respectively. There was a comparable reduction in inpatient spending. Ivacaftor appears to be effective for multiple mutations that cause the disease, as suggested by the fact that during the study period, ivacaftor's use was extended to nine additional mutations in 2014. Examination of evidence from clinical trial, clinical care, and administrative data sources is important for understanding the real-world effectiveness of precision medicines such as ivacaftor.

PMID: 29733727 [PubMed - in process]

Small RNA and transcriptome sequencing reveal the role of miR-199a-3p in inflammatory processes in cystic fibrosis airways.

J Pathol. 2018 May 07;:

Authors: Bardin P, Marchal-Duval E, Sonneville F, Blouquit-Laye S, Rousselet N, Le Rouzic P, Corvol H, Tabary O

Abstract
Cystic fibrosis (CF) is the most common lethal genetic disease, caused by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations. CF is characterized by an ionic imbalance and thickened mucus, which impair mucociliary clearance, promote bacterial colonization, and the establishment of infection/inflammation cycles. However, the origin of this inflammation remains unclear, although microRNA (miRNA) are suspected to be involved. MiRNA are small non-coding RNA that bind to the 3'-untranslated regions (UTR) of target gene mRNA, thereby repressing their translation and/or inducing their degradation. The goal of this study was to investigate the role of microRNA associated with pulmonary inflammation in CF patients. Through the analysis of all miRNA (miRNome) in human primary air-liquid interface cultures, we demonstrated that miR-199a-3p is the only miRNA downregulated in CF patients compared to controls. Moreover, through RNA sequencing (transcriptome) analysis, we showed that 50% of all deregulated mRNA are linked directly or indirectly to the NF-κB pathway. To identify a specific target, we used bioinformatics analysis to predict whether miR-199a-3p targets the 3'-UTR of IKBKB which encodes IKKβ, a major protein in the NF-κB pathway. Subsequently, we used bronchial explants from CF patients to show that miR-199a-3p expression is downregulated compared to controls and inversely correlated with increases in expression of IKKβ and IL-8. Through functional studies, we showed that miR-199a-3p modulates the expression of IKBKB through a direct interaction at its 3'-UTR in bronchial epithelial cells from CF patients. In miR-199a-3p overexpression experiments, we demonstrated that for CF cells miR-199a-3p reduced IKKβ protein expression, NF-κB activity, and IL-8 secretion. Taken together, our findings show that miR-199a-3p plays a negative regulatory role in the NF-κB signalling pathway and that its low expression in CF patients contributes to chronic pulmonary inflammation.

PMID: 29732561 [PubMed - as supplied by publisher]

Adrenal Insufficiency in Cystic Fibrosis: A Rare Phenomenon?

Can Respir J. 2018;2018:3629031

Authors: Préville-Ratelle S, Coriati A, Ménard A, Bourdeau I, Tremblay F, Berthiaume Y

Abstract
Background: The prevalence of adrenal insufficiency (AI) in cystic fibrosis (CF) is unknown. The frequent use of glucocorticoids (inhaled or systemic) may induce the long-term suppression of the hypothalamic-pituitary-adrenal axis.
Methods: We reviewed the results of adrenocorticotropic hormone (ACTH) stimulation tests done over a 10-year period to evaluate adrenal function in 69 CF patients of the CHUM CF clinic. Clinical characteristics of AI patients were compared to adrenal-sufficient (AS) patients.
Results: AI was confirmed in 33 of the 69 CF patients. A higher rate of dysglycemia (P=0.022) and of Aspergillus positive culture (P=0.006) was observed in AI patients compared to AS patients. Weight, CFTR genotype, and pulmonary function were comparable between AI and AS patients. The use of systemic corticosteroids (SC) prior to the diagnosis of AI was observed in 42.4% of patients. Compared to AI patients without SC, SC-treated AI patients were older and had a higher rate of allergic bronchopulmonary aspergillosis.
Conclusion: This study is the first to systematically examine the presence of AI in the largest cohort of CF patients studied to date with a prevalence of 8%. Patients treated with corticosteroids and those colonized with Aspergillus have a greater risk of AI.

PMID: 29731953 [PubMed - in process]

Innovative Therapeutic Strategies for Cystic Fibrosis: Moving Forward to CRISPR Technique.

Front Pharmacol. 2018;9:396

Authors: Marangi M, Pistritto G

Abstract
One of the most revolutionary technologies in recent years in the field of molecular biology is CRISPR-Cas9. CRISPR technology is a promising tool for gene editing that provides researchers the opportunity to easily alter DNA sequences and modify gene function. Its many potential applications include correcting genetic defects, treating and preventing the spread of diseases. Cystic fibrosis (CF) is one of the most common lethal genetic diseases caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although CF is an old acquaintance, there is still no effective/resolutive cure. Life expectancy has improved thanks to the combination of various treatments, but it is generally below average. Recently, a significant number of additional key medications have become licensed in Europe for the CF treatment including CFTR modulators. But innovative genomically-guided therapies have begun for CF and it is predictable that this will lead to rapid improvements in CF clinical disease and survival in the next decades. In this way, CRISPR-Cas9 approach may represent a valid tool to repair the CFTR mutation and hopeful results were obtained in tissue and animal models of CF disease.

PMID: 29731717 [PubMed]

A Low-Cost and Simple Genetic Screening for Cystic Fibrosis Provided by the Brazilian Public Health System.

J Pediatr. 2018 May 03;:

Authors: Rispoli T, Martins de Castro S, Grandi T, Prado M, Filippon L, Dornelles da Silva CM, Vargas JE, Rossetti LMR

Abstract
Cystic fibrosis newborn screening was implemented in Brazil by the Public Health System in 2012. Because of cost, only 1 mutation was tested - p.Phe508del. We developed a robust low-cost genetic test for screening 11 CFTR gene mutations with potential use in developing countries.

PMID: 29731357 [PubMed - as supplied by publisher]

Severely Impaired Control of Bacterial Infections in a Patient With Cystic Fibrosis Defective in Mucosal-Associated Invariant T Cells.

Chest. 2018 May;153(5):e93-e96

Authors: Pincikova T, Paquin-Proulx D, Moll M, Flodström-Tullberg M, Hjelte L, Sandberg JK

Abstract
Here we report a unique case of a patient with cystic fibrosis characterized by severely impaired control of bacterial respiratory infections. This patient's susceptibility to such infections was much worse than expected from a cystic fibrosis clinical perspective, and he died at age 22 years despite extensive efforts and massive use of antibiotics. We found that this severe condition was associated with a near-complete deficiency in circulating mucosal-associated invariant T (MAIT) cells as measured at several time points. MAIT cells are a large, recently described subset of T cells that recognize microbial riboflavin metabolites presented by the highly evolutionarily conserved MR1 molecules. The MAIT cell deficiency was specific; other T-cell subsets were intact. Even though this is only one unique case, the findings lend significant support to the emerging role of MAIT cells in mucosal immune defense and suggest that MAIT cells may significantly modify the clinical phenotype of respiratory diseases.

PMID: 29731053 [PubMed - in process]

Initiating transitional care for adolescents with cystic fibrosis at the age of 12 is both feasible and promising.

Acta Paediatr. 2018 May 05;:

Authors: Skov M, Teilmann G, Damgaard IN, Nielsen KG, Hertz PG, Holgersen MG, Presfeldt M, Dalager AMS, Brask M, Boisen KA

Abstract
AIM: Adolescence is a vulnerable period in cystic fibrosis, associated with declining lung function. This study described, implemented and evaluated a transition programme for adolescents.
METHODS: We conducted a single centre, non-randomised and non-controlled prospective programme at the cystic fibrosis centre at Copenhagen University Hospital Rigshospitalet from 2010-2011, assessing patients aged 12 to 18 at baseline and after 12 months. Changes implemented included staff training on communication, a more youth friendly feel to the outpatient clinic, the introduction of youth consultations partly alone with the adolescent, and a parents' evening focusing on cystic fibrosis in adolescence. Lung function and body mass index (BMI) were measured monthly and adolescents were assessed for their readiness for transition and quality of life at baseline and 12 months.
RESULTS: We found that 40 (98%) of the eligible patients participated and youth consultations were successfully implemented with no dropouts. The readiness checklist score increased significantly over the one-year study period, indicating increased readiness for transfer and self-care. Overall quality of life, lung function and BMI remained stable during the study period.
CONCLUSION: A well structured transition programme for cystic fibrosis patients as young as 12 years of age proved to be both feasible and sustainable. This article is protected by copyright. All rights reserved.

PMID: 29729195 [PubMed - as supplied by publisher]