Related Articles

Nanomedicine and personalised medicine: understanding the personalisation of health care in the molecular era.

Sociol Health Illn. 2017 May;39(4):547-565

Authors: Noury M, López J

Abstract
Globally supported by public policy and investment, nanomedicine is presented as an ongoing medical revolution that will radically change the practice of health care from diagnostic to therapeutic, and everything in between. One of nanomedicine's major promises is that of personalised medicine, enabling diagnostics and therapeutics tailored to individual needs and developing a truly 'patient-friendly' medical approach. Based on qualitative interviews with nanomedicine researchers in Canada, this article explores the emerging concept of personalised medicine as it becomes entangled with nanomedical research. More precisely, drawing on insights from science studies and the sociology of expectations, it analyses researchers' perceptions of personalised medicine in the cutting edge of current nanomedicine research. Two perceptions of personalisation are identified; a molecular conception of individuality and a technical conception of personalisation. The article concludes by examining the relationship between the two conceptions and contrasts them with the normative reflex of a more expansive conception of personalised medicine.

PMID: 27782304 [PubMed - indexed for MEDLINE]

An Interventionalist's Guide to Hemoptysis in Cystic Fibrosis.

Radiographics. 2018 Mar-Apr;38(2):624-641

Authors: Monroe EJ, Pierce DB, Ingraham CR, Johnson GE, Shivaram GM, Valji K

Abstract
Massive hemoptysis occurs in a minority of patients with cystic fibrosis, with an annual incidence of 1%. Although rare, massive hemoptysis can be a severe and potentially fatal complication of this disease. Beyond the acute life-threatening event, hemoptysis in patients with cystic fibrosis has been associated with faster decline in lung function, accelerated need for lung transplant, and increased mortality. The bronchial arteries are the culprit vessels in over 90% of cases of hemoptysis. This normally quiescent vascular system undergoes remarkable hypertrophy, collateralization, and angiogenesis before the onset of hemoptysis, introducing numerous pitfalls for the interventionalist. However, in experienced hands, bronchial artery embolization is a safe and potentially lifesaving therapy. Preprocedural noninvasive imaging, specifically computed tomographic angiography, has been repeatedly validated for helping to localize the likely site of bleeding, characterizing pertinent arterial anatomy, and promoting efficient and effective intervention; it has been recommended for all stable patients with hemoptysis. Success in the angiographic suite requires a thorough understanding of normal and variant bronchial arterial anatomy, appropriate patient selection, and a meticulous embolization technique. A meticulous approach to imaging and intervention, conscientious of both visualized and nonvisualized collateral pathways and nontarget vessels, can minimize potentially devastating complications. This review summarizes the current literature, modern procedural techniques, and emerging controversies, serving to guide an evolving approach to management of patients with cystic fibrosis and hemoptysis. ©RSNA, 2018.

PMID: 29528824 [PubMed - in process]

Difficult conversations: Discussing prognosis with children with cystic fibrosis.

Pediatr Pulmonol. 2018 Mar 12;:

Authors: Farber JG, Prieur MG, Roach C, Shay R, Walter M, Borowitz D, Dellon EP

Abstract
Background Despite the chronic, progressive, and life-threatening nature of cystic fibrosis (CF), there are no guidelines for when and how to communicate prognosis to children with CF.
METHODS: Semi-structured interviews with young adults with CF, parents of young adults with CF, and multidisciplinary CF health care providers assessed recall of and practices for communicating about prognosis. Recommendations for improvements were also solicited.
RESULTS: Young adults with CF recalled learning that life expectancy is limited by CF between the ages of 8 and 16 years, and that CF is a progressive disease between the ages of 7 and 19 years. They reported that the information often came from CF physicians or from online resources. Patients and parents reported earlier knowledge of prognosis than providers assumed. While learning about prognosis caused sadness and stress for some patients and families, others denied negative feelings. Interestingly, most patients reported that disclosure of prognosis had minimal impact on their adherence and treatment goals. Patients and parents reported wanting physicians to be involved in conversations about prognosis. However, providers noted several barriers to discussing prognosis, including their own reluctance, time limitations, and uncertainty about appropriate timing and content of communication.
CONCLUSIONS: Communication about prognosis is important but also difficult for providers, patients, and families. Appropriately timed conversations, using tools to facilitate communication, could ensure patients receive timely, accurate information.

PMID: 29528566 [PubMed - as supplied by publisher]

The timing and extent of acute physiotherapy involvement following lung transplantation: An observational study.

Physiother Res Int. 2018 Mar 12;:

Authors: Tarrant BJ, Holland A, Le Maitre C, Robinson R, Corbett M, Bondarenko J, Button B, Thompson B, Snell G

Abstract
BACKGROUND AND PURPOSE: Physiotherapy "standard care" for the acute post lung transplant recipient has not yet been documented. We aimed to analyse how soon patients commence exercise and how much time is dedicated to this during physiotherapy sessions acutely post lung transplantation.
METHODS: Prospective observational study of bilateral sequential and single lung transplant recipients for any indication, ≥18 years. Participants were observed during 6 physiotherapy sessions: 3 initial and 3 prior to acute inpatient discharge. Duration and content of each session was recorded, consisting of physical exercise and non-exercise tasks.
RESULTS: Thirty participants, 20 male, median age 58.5 (interquartile range 54.5-65.0) were observed over 173 sessions. Chronic obstructive pulmonary disease was the most common transplant indication (n = 12, 40%). Bilateral lung transplant was performed in 90% (n = 27) of participants. First time to mobilise was 2 (2-3) days. Participants received 14 (12.8-23.8) sessions over 18 (17-31) days. The mean duration of physiotherapy in the initial phase was 107.8 (standard deviation 21.8) min, with 22.9 (7.5) min spent exercising. In the final phase, exercise time increased to 28.1 (11.4) min out of 84.1 (24.6) min. Assessment was the most common non-exercise component, at 26.6 (7.9) and 22.1 (12.5) min across the three initial and final sessions.
IMPLICATIONS FOR PHYSIOTHERAPY PRACTICE: Lung transplant recipients spent 21-34% of observed sessions performing physical exercise beginning 48 hr following surgery. Remaining physiotherapist time was spent on assessment, respiratory interventions, education, and patient-specific duties. The use of physiotherapy assistants, structured, progressive exercise programs, and continued workplace innovation may enable a higher percentage of physiotherapist supervised physical exercise in the future.

PMID: 29528538 [PubMed - as supplied by publisher]

Survival After Lung Transplantation of Cystic Fibrosis Patients Infected with Burkholderia dolosa (Genomovar VI).

Clin Transplant. 2018 Mar 12;:

Authors: Wang R, Welsh SK, Budev M, Goldberg H, Noone PG, Zaas D, Boyer D

Abstract
Cystic fibrosis (CF) with severe lung disease is a well-recognized indication for lung transplantation. Colonization with various organisms in CF patients may impact post-transplant morbidity and mortality. Burkholderia cepacia complex (BCC) is made up of distinct genomovars with significant morbidity and mortality associated with B. cenocepacia (genomovar III) following lung transplant. The outcomes of patients infected with genomovar B. dolosa (genomovar VI) have yet to be described in the literature. We performed a retrospective chart review of all cystic fibrosis patients colonized with B. dolosa from our center who underwent lung transplantation (n=11) at various medical centers across the U.S between 2000 and 2014. Survival rates were 73%, 53%, and 30% for 1-year, 3-years, and 5-years, respectively. Median survival was 44 months (95% CI = 11.1-76.8). CF patients with B. dolosa that have undergone lung transplantation have decreased 1-year survival when compared to all patients transplanted with cystic fibrosis. Conditional 5-year survival for B. dolosa infected patients was 43% in patients that survived the first year post transplant, suggesting that this first year is crucial in managing the infection. Importantly, the survival of the B. dolosa patients was higher than compared to previously reported survival rates of B. cenocepacia patients post transplant. This article is protected by copyright. All rights reserved.

PMID: 29528522 [PubMed - as supplied by publisher]

Exhaled NO as a predictor of exercise-induced asthma in cold air.

Nitric Oxide. 2018 Mar 08;:

Authors: Dreßler M, Salzmann-Manrique E, Zielen S, Schulze J

Abstract
PURPOSE: Physical activity is an important part of life, and exercise-induced asthma (EIA) can reduce the quality of life. A standardized exercise challenge is needed to diagnose EIA, but this is a time consuming, effortful and expensive method. Exhaled nitric oxide (eNO) as a marker of eosinophil inflammation is determined rapidly and easily. The aim of this study was to investigate eNO as surrogate marker for predicting a positive reaction in an exercise challenge in a cold chamber (ECC).
METHODS: A total of 143 subjects aged 6-45 years with suspected EIA were recruited for the study. The subjects underwent an eNO measurement, an ECC and a skin prick test (SPT). To define the sensitivity and specificity of eNO as predictor, a receiver-operating characteristic (ROC) curve was plotted. The individual probability of the occurrence of a positive reaction after ECC based on an eNO value was calculated using a logistic regression model.
RESULTS: An eNO cut-off value of 18.5 ppb (area under the curve (AUC) 0.71, p < 0.001) showed the best combination of sensitivity and specificity for a positive reaction (forced expiratory volume in 1 s (FEV1) decrease ≥ 10% after ECC) for the whole group. An eNO cut-off value of 46.0 ppb had a specificity of 100.0% to predict a significant FEV1 decrease and may save exercise testing in 22.4% of patients. A negative predictive level with a high sensitivity and negative predictive value (NPV) could not be defined. In the subgroup that was house dust might (HDM) allergy positive (HDM pos; n = 68, 45.5% of all subjects), an eNO cut-off value of 35.5 ppb (AUC 0.79, p < 0.01) showed the best combination of sensitivity and specificity for a positive reaction after the ECC with a specificity 100.0% and may save exercise testing in 45.6% of HDM pos patients. Using logistic regression, a 95% probability for a positive FEV1 decrease after ECC was estimated at 53 ppb for the whole group and at 47 ppb for the HDM pos subgroup.
CONCLUSIONS: Exhaled NO measurement is a screening tool for EIA, especially in HDM pos subjects. In a real-life setting, a cut-off value of 46.0 ppb detects EIA at 100% in all suspected patients, and a cut-off level of 35.5 ppb is valuable marker of EIA in patients with an HDM allergy. These levels can save time and costs in a large proportion of patients and will be helpful for clinicians.

PMID: 29526567 [PubMed - as supplied by publisher]

Attenuation of quorum sensing controlled virulence factors and biofilm formation in Pseudomonas aeruginosa by pentacyclic triterpenes, betulin and betulinic acid.

Microb Pathog. 2018 Mar 08;:

Authors: Rajkumari J, Borkotoky S, Murali A, Suchiang K, Mohanty SK, Busi S

Abstract
The production of virulence determinants and biofilm formation in numerous pathogens is regulated by the cell-density-dependent phenomenon, Quorum sensing (QS). The QS system in multidrug resistant opportunistic pathogen, P. aeruginosa constitutes of three main regulatory circuits namely Las, Rhl, and Pqs which are closely linked to its pathogenicity and establishment of chronic infections. In spite intensive antibiotic therapy, P. aeruginosa continue to be an important cause of nosocomial infections and also the major cause of mortality in Cystic Fibrosis patients with 80% of the adults suffering from chronic P. aeruginosa infection. Hence, targeting QS circuit offers an effective intervention to the ever increasing problem of drug resistant pathogens. In the present study, the pentacyclic triterpenes i.e. Betulin (BT) and Betulinic acid (BA) exhibited significant attenuation in production of QS-regulated virulence factors and biofilm formation in P. aeruginosa, at the sub-lethal concentration. The test compound remarkably interfered in initial stages of biofilm development by decreasing the exopolysaccharide production and cell surface hydrophobicity. Based on the in vivo studies, the test compounds notably enhanced the survival of Caenorhabditis elegans infected with P. aeruginosa. Furthermore, molecular docking analysis revealed that BT and BA can act as a strong competitive inhibitor for QS receptors, LasR and RhlR. The findings suggest that BT and BA can serve as potential anti-infectives in the controlling chronic infection of P. aeruginosa.

PMID: 29526565 [PubMed - as supplied by publisher]

[Impact of Cystic Fibrosis Transmembrane Conductance Regulator on Malignant
 Properties of KRAS Mutant Lung Adenocarcinoma A549 Cells].

Zhongguo Fei Ai Za Zhi. 2018 Feb 20;21(2):89-98

Authors: Li H, Wang Y, Yang J, Liu X, Shi J

Abstract
BACKGROUND: The incidence of lung cancer is gradually increased, and the cystic fibrosis transmembrane conductance regulator (CFTR) has recently demonstrated to have an implication in the deoncogenesis and malignant transformation of many types of cancers. The aim of this study is to investigate impacts of CFTR on the malignant features of lung adenocarcinoma A549 cells.
METHODS: The capacity of cell proliferation, migration, invasion and clonogenicity of non-small cell lung cancer A549 cells were detected by CCK8 cell proliferation assay, cell scratch assay, Transwell cell invasion assay and clone formation assay, respectively. Meanwhile, the effect of CFTR gene on the expression of cancer stem cell related transcriptional factors was also detected by immunoblotting (Western blot) assay.
RESULTS: An overexpression of CFTR gene in A549 cells significantly inhibited the malignant capacity of A549 cells, including potencies of cell proliferation, migration, invasion and colony formation; while knockdown of CFTR gene expression by RNA interference in A549 cells resulted in an opposite effect seen in above cells overexpressing CFTR gene. Mechanistically, immunoblotting assay further revealed that the ectopic expression of CFTR gene led an inhibitory expression of stem cell-related transcriptional factors SOX2 and OCT3/4, and cancer stem cell surface marker CD133 in A549 cells, while a knockdown of CFTR expression yielded a moderately increased expression of these gene. However, an alteration of CFTR gene expression had neither effect on the expression of putative lung cancer stem cell marker aldehyde dehydrogenase1 (ALDH1), nor the frequency of ALDH1A-positive cells in A549 cells, as ascertained by the immunoblotting assay and cytometry analysis, respectively.
CONCLUSIONS: The CFTR exhibited an inhibitory role in the malignancy of lung adenocarcinoma A549 cells, suggesting that it may be a novel potential target for lung cancer treatment. However, its functions in other lung adenocarcinoma cell lines and its underlying molecular mechanisms require further investigation.

PMID: 29526175 [PubMed - in process]

Related Articles

Effect of freezing sputum on Pseudomonas aeruginosa population heterogeneity.

J Cyst Fibros. 2017 May;16(3):353-357

Authors: Poonja A, Heirali A, Workentine M, Storey DG, Somayaji R, Rabin HR, Surette MG, Parkins MD

Abstract
Pseudomonas aeruginosa develops profound population heterogeneity in CF airways. How changes in these populations relate to clinical status is unknown. In order to facilitate this understanding, frequent sampling of this community is required. To determine if the collection and storage of sputum at home may pose a viable option, we collected sputum from ten patients. Sputum samples were partitioned in two, with half immediately processed on MacConkey agar and half assessed after freezing for one week in a home-freezer. From each sample, 88 isolates were assessed for antibiotic susceptibility and virulence factor production. Freezing resulted in a 103CFU/ml drop in P. aeruginosa. However, across 1760 isolates, no consistent difference in either antibiotic susceptibility nor virulence factors was observed suggesting freezing induced indiscriminate killing. Home collection and freezing of sputum will enable frequent and convenient assessment of P. aeruginosa population dynamics in CF.

PMID: 28126444 [PubMed - indexed for MEDLINE]

Related Articles

Classification of CFTR mutation classes.

Lancet Respir Med. 2016 08;4(8):e37-e38

Authors: Marson FAL, Bertuzzo CS, Ribeiro JD

PMID: 27377414 [PubMed - indexed for MEDLINE]

Related Articles

Classification of CFTR mutation classes - Authors' reply.

Lancet Respir Med. 2016 08;4(8):e39

Authors: De Boeck K, Amaral MD

PMID: 27377413 [PubMed - indexed for MEDLINE]

A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia.

Eur J Neurol. 2018 Mar 12;:

Authors: Rydning SL, Dudesek A, Rimmele F, Funke C, Krüger S, Biskup S, Vigeland MD, Hjorthaug HS, Sejersted Y, Tallaksen C, Selmer KK, Kamm C

Abstract
BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSP) are clinically and genetically heterogenous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families.
METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function predicted by bioinformatic prediction tools.
RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease.
CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, we describe the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP. This article is protected by copyright. All rights reserved.

PMID: 29528531 [PubMed - as supplied by publisher]

Related Articles

Hereditary kidney cancer syndromes: Genetic disorders driven by alterations in metabolism and epigenome regulation.

Cancer Sci. 2018 Mar;109(3):581-586

Authors: Hasumi H, Yao M

Abstract
Although hereditary kidney cancer syndrome accounts for approximately five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, USA and the first kidney cancer-associated gene, VHL, was identified through kindred analysis of von Hippel-Lindau (VHL) syndrome in 1993. Subsequent molecular studies on VHL function have elucidated that the VHL protein is a component of E3 ubiquitin ligase complex for hypoxia-inducible factor (HIF), which provided the basis for the development of tyrosine kinase inhibitors targeting the HIF-VEGF/PDGF pathway. Recent whole-exome sequencing analysis of sporadic kidney cancer exhibited the recurrent mutations in chromatin remodeling genes and the later study has revealed that several chromatin remodeling genes are altered in kidney cancer kindred at the germline level. To date, more than 10 hereditary kidney cancer syndromes together with each responsible gene have been characterized and most of the causative genes for these genetic disorders are associated with either metabolism or epigenome regulation. In this review article, we describe the molecular mechanisms of how an alteration of each kidney cancer-associated gene leads to renal tumorigenesis as well as denote therapeutic targets elicited by studies on hereditary kidney cancer.

PMID: 29325224 [PubMed - indexed for MEDLINE]

Related Articles

Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate.

Birth Defects Res. 2017 01 20;109(1):27-37

Authors: Liu H, Busch T, Eliason S, Anand D, Bullard S, Gowans LJJ, Nidey N, Petrin A, Augustine-Akpan EA, Saadi I, Dunnwald M, Lachke SA, Zhu Y, Adeyemo A, Amendt B, Roscioli T, Cornell R, Murray J, Butali A

Abstract
BACKGROUND: Recent advances in genomics methodologies, in particular the availability of next-generation sequencing approaches have made it possible to identify risk loci throughout the genome, in particular the exome. In the current study, we present findings from an exome study conducted in five affected individuals of a multiplex family with cleft palate only.
METHODS: The GEnome MINIng (GEMINI) pipeline was used to functionally annotate the single nucleotide polymorphisms, insertions and deletions. Filtering methods were applied to identify variants that are clinically relevant and present in affected individuals at minor allele frequencies (≤1%) in the 1000 Genomes Project single nucleotide polymorphism database, Exome Aggregation Consortium, and Exome Variant Server databases. The bioinformatics tool Systems Tool for Craniofacial Expression-Based Gene Discovery was used to prioritize cleft candidates in our list of variants, and Sanger sequencing was used to validate the presence of identified variants in affected and unaffected relatives.
RESULTS: Our analyses approach narrowed the candidates down to the novel missense variant in ARHGAP29 (GenBank: NM_004815.3, NP_004806.3;c.1654T>C [p.Ser552Pro]. A functional assay in zebrafish embryos showed that the encoded protein lacks the activity possessed by its wild-type counterpart, and migration assays revealed that keratinocytes transfected with wild-type ARHGAP29 migrated faster than counterparts transfected with the p.Ser552Pro ARHGAP29 variant or empty vector (control).
CONCLUSION: These findings reveal ARHGAP29 to be a regulatory protein essential for proper development of the face, identifies an amino acid that is key for this, and provides a potential new diagnostic tool.Birth Defects Research 109:27-37, 2017. © 2016 Wiley Periodicals, Inc.

PMID: 28029220 [PubMed - indexed for MEDLINE]

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Funding Opportunity RFA-FD-18-006 from the NIH Guide for Grants and Contracts. The intended outcome of this program is to advance efforts to improve and develop state drug residue prevention programs. It is necessary to provide assistance to state drug residue programs that need a stronger foundation to promote the prevention of illegal drug residues in animal derived foods through educational outreach and training. This program is intended to ensure drug residue prevention programs are developed to protect consumer exposure to drug residues in the edible products of food animals and support activities related to drug residue prevention. In addition, these awards will assist state agencies to better direct their programs to reduce the outcomes of illegal drug residues in animal derived foods. This cooperative agreement program (CAP) will focus on outreach, education and training. In addition, grantees will focus on performing targeted on-site assessments related to drug residue violations and best practice visits to industry and individuals to communicate proper drug use and promote effective management practices for drug residue prevention.

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"systems biology"

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Pharmacogenetics and the Promise of Personalized Medicine.

JAMA Cardiol. 2018 Mar 11;:

Authors: Sabatine MS

PMID: 29525817 [PubMed - as supplied by publisher]