Validation of the binary designation 'Symbiodinium thermophilum' (Dinophyceae).

J Phycol. 2018 Jul 07;:

Authors: Hume BCC, D'Angelo C, Smith EG, Stevens JR, Burt JA, Wiedenmann J

Abstract
The binary designation 'Symbiodinium thermophilum' was invalid due to the absence of an illustration as required by Article 44.2 of the ICN. Herein, it is validated. This species is the most common symbiont in reef corals in the southern Persian/Arabian Gulf (PAG), the world's hottest body of water sustaining reef coral growth. This article is protected by copyright. All rights reserved.

PMID: 29981276 [PubMed - as supplied by publisher]

A Critical Comparison of Rejection-Based Algorithms for Simulation of Large Biochemical Reaction Networks.

Bull Math Biol. 2018 Jul 06;:

Authors: Thanh VH

Abstract
The rejection-based simulation technique has been applying to improve the computational efficiency of the stochastic simulation algorithm (SSA) in simulating large reaction networks, which are required for a thorough understanding of biological systems. We compare two recently proposed simulation methods, namely the composition-rejection algorithm (SSA-CR) and the rejection-based SSA (RSSA), aiming for this purpose. We discuss the right interpretation of the rejection-based technique used in these algorithms in order to make an informed choice when dealing with different aspects of biochemical networks. We provide the theoretical analysis as well as the detailed runtime comparison of these algorithms on concrete biological models. We highlight important factors that are omitted in previous analysis of these algorithms. The numerical comparison shows that for reaction networks where the search cost is expensive then SSA-CR is more efficient, and for reaction networks where the update cost is dominant, often the case in practice, then RSSA should be the choice.

PMID: 29981002 [PubMed - as supplied by publisher]

Advanced tools for the safety assessment of nanomaterials.

Nat Nanotechnol. 2018 Jul;13(7):537-543

Authors: Fadeel B, Farcal L, Hardy B, Vázquez-Campos S, Hristozov D, Marcomini A, Lynch I, Valsami-Jones E, Alenius H, Savolainen K

Abstract
Engineered nanomaterials (ENMs) have tremendous potential to produce beneficial technological impact in numerous sectors in society. Safety assessment is, of course, of paramount importance. However, the myriad variations of ENM properties makes the identification of specific features driving toxicity challenging. At the same time, reducing animal tests by introducing alternative and/or predictive in vitro and in silico methods has become a priority. It is important to embrace these new advances in the safety assessment of ENMs. Indeed, remarkable progress has been made in recent years with respect to mechanism-based hazard assessment of ENMs, including systems biology approaches as well as high-throughput screening platforms, and new tools are also emerging in risk assessment and risk management for humans and the environment across the whole life-cycle of nano-enabled products. Here, we highlight some of the key advances in the hazard and risk assessment of ENMs.

PMID: 29980781 [PubMed - in process]

Imaging the Vascular Bone Marrow Niche During Inflammatory Stress.

Circ Res. 2018 Jul 06;:

Authors: Vandoorne K, Rohde D, Kim HY, Courties G, Wojtkiewicz GR, Honold L, Hoyer FF, Frodermann V, Nayar R, Herisson FE, Jung Y, Désogère P, Vinegoni C, Caravan P, Weissleder R, Sosnovik DE, Lin CP, Swirski FK, Nahrendorf M

Abstract
Rationale: Inflammatory stress induced by exposure to bacterial lipopolysaccharide (LPS) causes hematopoietic stem cell (HSC) expansion in the bone marrow niche, generating a cellular immune response. As an integral component of the hematopoietic stem cell niche, the bone marrow vasculature regulates the production and release of blood leukocytes, which protect the host against infection but also fuel inflammatory diseases. Objective: We aimed to develop imaging tools to explore vascular changes in the bone marrow niche during acute inflammation. Methods and Results: Using the Toll-like receptor ligand LPS as a prototypical danger signal, we applied multi-parametric, -modality and -scale imaging to characterize how the bone marrow vasculature adapts when hematopoiesis boosts leukocyte supply. In response to LPS, ex vivo flow cytometry and histology showed vascular changes to the bone marrow niche. Specifically, proliferating endothelial cells gave rise to new vasculature in the bone marrow during hypoxic conditions. We studied these vascular changes with complementary intravital microscopy and PET/MR imaging. Fluorescence and PET integrin αVβ3 imaging signal increased during LPS-induced vascular remodeling. Vascular leakiness, quantified by albumin-based in vivo microcopy and MRI, rose when neutrophils departed and hematopoietic stem and progenitor cells (HSPC) proliferated more vigorously. Conclusions: Introducing a tool set to image bone marrow either with cellular resolution or non-invasively within the entire skeleton, this work sheds light on angiogenic responses that accompany emergency hematopoiesis. Understanding and monitoring bone marrow vasculature may provide a key to unlock therapeutic targets regulating systemic inflammation.

PMID: 29980569 [PubMed - as supplied by publisher]

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Outcome of inflammatory breast cancer in Moroccan patients: clinical, molecular and pathological characteristics of 219 cases from the National Oncology Institute (INO).

BMC Cancer. 2018 Jul 05;18(1):713

Authors: Slaoui M, Zoure AA, Mouh FZ, Bensouda Y, El Mzibri M, Bakri Y, Amrani M

Abstract
BACKGROUND: Usually misdiagnosed, Inflammatory Breast Cancer (IBC) is the most aggressive form of non-metastatic breast cancer. This orphan disease is more frequent in North Africa. Despite intensive treatment, the survival rate remains very low.
METHODS: We have retrospectively studied all breast cancer cases diagnosed at the National Oncology Institute (INO), Rabat between 2005 and 2010. We have collected 219 cases of women with metastatic and non-metastatic IBC. Data have been obtained from patients' personal medical files over a follow-up period of 5 years. We have described IBC's clinicopathological features and analyzed its clinical outcome using SPSS software. HR (hazard Ratio) was calculated using Cox regression analysis.
RESULTS: The frequency of IBC cases is 4.05%. The majority of our patients (65.3%) were under 50 years old. The most prevalent molecular subtype was Luminal A (38.7%) followed by Luminal B HER2+ (27.9%) and Triple negative (21.6%). During the follow-up period, 72 patients (32.9%) had recurrence and 40 patients (18.3%) died. The 3-year OS (Overall Survival) and EFS (Event Free Survival) of non-metastatic patients were 70.4 and 46.5% respectively, while in the metastatic disease, the 3-year OS was only 41.9%. In non-metastatic women, we observed a higher rate of EFS associated to Selective estrogen receptor modulation treatment (p = 0.01), and a lower rate EFS in triple negative breast cancer patients (p = 0.02). In univariate analysis, we found that EFS rate is lower in patients presenting Triple Negative tumors when compared to other molecular subtypes (HR: 3.54; 95%CI: 1.13-11.05; p = 0.02). We also found that Selective estrogen receptor modulation treatment is associated with higher EFS rate (HR: 0.48; 95%CI: 0.07-0.59; p = 0.01).
CONCLUSIONS: IBC in Morocco shows similar characteristics to those in North African countries; however, survival rates are still the highest when compared with neighboring countries. Collaborative studies with prospective aspects are warranted to establish the epidemiological profile and understand the high frequencies of IBC in North Africa. More studies on molecular markers are also needed to improve IBC patients' management and eventually their survival rate.

PMID: 29976157 [PubMed - in process]

Sequence variants in nine different genes underlying rare skin disorders in 10 consanguineous families.

Int J Dermatol. 2017 Dec;56(12):1406-1413

Authors: Shah K, Mehmood S, Jan A, Abbe I, Hussain Ali R, Khan A, Chishti MS, Lee K, Ahmad F, Ansar M, University of Washington Center for Mendelian Genomics, Shahzad S, Nickerson DA, Bamshad MJ, Coucke PJ, Santos-Cortez RLP, Spritz RA, Leal SM, Ahmad W

Abstract
BACKGROUND: Genodermatoses represent genetic anomalies of skin tissues including hair follicles, sebaceous glands, eccrine glands, nails, and teeth. Ten consanguineous families segregating various genodermatosis phenotypes were investigated in the present study.
METHODS: Homozygosity mapping, exome, and Sanger sequencing were employed to search for the disease-causing variants in the 10 families.
RESULTS: Exome sequencing identified seven homozygous sequence variants in different families, including: c.27delT in FERMT1; c.836delA in ABHD5; c.2453C>T in ERCC5; c.5314C>T in COL7A1; c.1630C>T in ALOXE3; c.502C>T in PPOX; and c.10G>T in ALDH3A2. Sanger sequencing revealed three homozygous variants: c.1718 + 2A>G in FERMT1; c.10459A>T in FLG; and c.92delT in the KRT14 genes as the underlying genetic cause of skin phenotypes.
CONCLUSION: This study supports the use of exome sequencing as a powerful, efficient tool for identifying genes that underlie rare monogenic skin disorders.

PMID: 29130490 [PubMed - indexed for MEDLINE]

SteeringWheel: A Locality-Preserving Magnification Interface for Low Vision Web Browsing.

Proc SIGCHI Conf Hum Factor Comput Syst. 2018 Apr;2018:

Authors: Billah SM, Ashok V, Porter DE, Ramakrishnan IV

Abstract
Low-vision users struggle to browse the web with screen magnifiers. Firstly, magnifiers occlude significant portions of the webpage, thereby making it cumbersome to get the webpage overview and quickly locate the desired content. Further, magnification causes loss of spatial locality and visual cues that commonly define semantic relationships in the page; reconstructing semantic relationships exclusively from narrow views dramatically increases the cognitive burden on the users. Secondly, low-vision users have widely varying needs requiring a range of interface customizations for different page sections; dynamic customization in extant magnifiers is disruptive to users' browsing. We present SteeringWheel, a magnification interface that leverages content semantics to preserve local context. In combination with a physical dial, supporting simple rotate and press gestures, users can quickly navigate different webpage sections, easily locate desired content, get a quick overview, and seamlessly customize the interface. A user study with 15 low-vision participants showed that their web-browsing efficiency improved by at least 20 percent with SteeringWheel compared to extant screen magnifiers.

PMID: 29978857 [PubMed]

Genetic polymorphisms of organic cation transporter 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes: A systematic review.

Medicine (Baltimore). 2018 Jul;97(27):e11349

Authors: Mofo Mato EP, Guewo-Fokeng M, Essop MF, Owira PMO

Abstract
BACKGROUND: Metformin is one of the most commonly used drugs for the treatment of type 2 diabetes mellitus (T2DM). Despite its widespread use, there are considerable interindividual variations in metformin response, with about 35% of patients failing to achieve initial glycemic control. These variabilities that reflect phenotypic differences in drug disposition and action may indeed be due to polymorphisms in genes that regulate pharmacokinetics and pharmacodynamics of metformin. Moreover, interethnic differences in drug responses in some cases correspond to substantial differences in the frequencies of the associated pharmacogenomics risk allele.
AIM: This study aims to highlight and summarize the overall effects of organic cation transporter 1(OCT1) polymorphisms on therapeutic responses to metformin and to evaluate the potential role of such polymorphisms in interethnic differences in metformin therapy.
METHODS: We conducted a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We searched for PubMed/MEDLINE, Embase, and CINAHL, relevant studies reporting the effects of OCT1 polymorphisms on metformin therapy in T2DM individuals. Data were extracted on study design, population characteristics, relevant polymorphisms, measure of genetic association, and outcomes. The presence of gastrointestinal side effects, glycated hemoglobin A1 (HbA1c) levels, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) concentrations after treatment with metformin were chosen as measures of the metformin responses. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO).
RESULTS: According to the data extracted, a total of 34 OCT1 polymorphisms were identified in 10 ethnic groups. Significant differences in the frequencies of common alleles were observed among these groups. Met408Val (rs628031) variant was the most extensively explored with metformin responses. Although some genotypes and alleles have been associated with deleterious effects on metformin response, others indeed, exhibited positive effects.
CONCLUSION: Genetic effects of OCT1 polymorphisms on metformin responses were population specific. Further investigations in other populations are required to set ethnicity-specific reference for metformin responses and to obtain a solid basis to design personalized therapeutic approaches for T2DM treatment.

PMID: 29979413 [PubMed - in process]

A Common mdr1 Gene Polymorphism is Associated with Changes in Linezolid Clearance.

Ther Drug Monit. 2018 Jul 03;:

Authors: Allegra S, Di Paolo A, Cusato J, Fatiguso G, Arrigoni E, Danesi R, Corcione S, D'Avolio A

Abstract
BACKGROUND: Several factors contribute to the high variability of linezolid plasma exposure in patients. Very recently, it has been suggested that linezolid could be an ABCB1 substrate. Therefore, the present clinical study was aimed at investigating whether ABCB1 polymorphisms could predict linezolid pharmacokinetics in 27 critically ill patients.
METHODS: Genotypes were assessed through a real-time polymerase chain reaction allelic discrimination system, and linezolid plasma concentrations, considering trough concentration (Ctrough) and area under the time concentration curve (AUC), were analyzed through a nonlinear mixed-effects modeling approach.
RESULTS: A significant effect of abcb1 c.3435C>T polymorphism on linezolid clearance was found, whose values accounted for 13.19L/h in wild-type homozygotes and 7.82 L/h in the remaining individuals. That difference was statistically significant despite the large interindividual variability (60.8%). Terminal half-life and volume of distribution values significantly differed between c.3435CC and c.3435CT/TT patients (2.78 vs. 5.45 h and 37.43 vs. 46.71L, respectively). On the contrary, a modest trend was observed for the difference in AUC and Ctrough based on c.3435C>T genotypes. Simulation according to the final model revealed that the cumulative response fraction for the AUC/MIC parameter was better for .3435CC individuals compared to individuals carrying at least one c.3435T allele with respect to MSSA, MRSA, and S. pneumoniae species.
CONCLUSIONS: The obtained results suggest the possible influence of ABCB1 in linezolid pharmacokinetics, bringing new interest for pharmacogenetic analyses in antimicrobial chemotherapy. These analyses could be incorporated in therapeutic protocols for precision medicine, including a combined use of genetic evaluation (for starting dose) and follow-up TDM.

PMID: 29979333 [PubMed - as supplied by publisher]

The Ethical, Legal and Regulatory Issues Associated with Pharmacogenomics: Systematically Quantifying the Literature.

J Law Med. 2018 Apr;25(3):782-793

Authors: Hewitt JE

Abstract
Since the human genome was successfully mapped much academic attention has been given to ethical, legal and regulatory issues associated with the integration and application of genomics in health care. In line with the recent political commitment to promoting precision medicine that relies heavily on omic knowledge, it is timely to review the issues that this body of literature has addressed. Focusing on pharmacogenomics, this review quantifies the issues identified in this body of academic work. It reveals that, after nearly two decades, interest in the regulatory and legal issues associated with pharmacogenomics continues to generate significant attention. The ethical issues, while not as predominant, also persist. The analyses highlights that there is a dearth of empirical research exploring the impact that these issues have had.

PMID: 29978667 [PubMed - in process]

PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5.

Autophagy. 2018 Jul 06;:

Authors: Lee DH, Kim D, Kim ST, Jeong S, Kim JL, Shim SM, Heo AJ, Song X, Guo ZS, Bartlett DL, Oh SC, Lee J, Saito Y, Kim BY, Kwon YT, Lee YJ

Abstract
Macroautophagy is induced under various stresses to remove cytotoxic materials, including misfolded proteins and their aggregates. These protein cargoes are collected by specific autophagic receptors such as SQSTM1/p62 (sequestosome 1) and delivered to phagophores for lysosomal degradation. To date, little is known about how cells sense and react to diverse stresses by inducing the activity of SQSTM1. Here, we show that the peroxiredoxin-like redox sensor PARK7/DJ-1 modulates the activity of SQSTM1 and the targeting of ubiquitin (Ub)-conjugated proteins to macroautophagy under oxidative stress caused by TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10). In this mechanism, TNFSF10 induces the N-terminal arginylation (Nt-arginylation) of the endoplasmic reticulum (ER)-residing molecular chaperone HSPA5/BiP/GRP78, leading to cytosolic accumulation of Nt-arginylated HSPA5 (R-HSPA5). In parallel, TNFSF10 induces the oxidation of PARK7. Oxidized PARK7 acts as a co-chaperone-like protein that binds the ER-derived chaperone R-HSPA5, a member of the HSPA/HSP70 family. By forming a complex with PARK7 (and possibly misfolded protein cargoes), R-HSPA5 binds SQSTM1 through its Nt-Arg, facilitating self-polymerization of SQSTM1 and the targeting of SQSTM1-cargo complexes to phagophores. The 3-way interaction among PARK7, R-HSPA5, and SQSTM1 is stabilized by the Nt-Arg residue of R-HSPA5. PARK7-deficient cells are impaired in the targeting of R-HSPA5 and SQSTM1 to phagophores and the removal of Ub-conjugated cargoes. Our results suggest that PARK7 functions as a co-chaperone for R-HSPA5 to modulate autophagic removal of misfolded protein cargoes generated by oxidative stress.

PMID: 29976090 [PubMed - as supplied by publisher]

Pharmacoproteomic characterisation of human colon and rectal cancer.

Mol Syst Biol. 2017 Nov 03;13(11):951

Authors: Frejno M, Zenezini Chiozzi R, Wilhelm M, Koch H, Zheng R, Klaeger S, Ruprecht B, Meng C, Kramer K, Jarzab A, Heinzlmeir S, Johnstone E, Domingo E, Kerr D, Jesinghaus M, Slotta-Huspenina J, Weichert W, Knapp S, Feller SM, Kuster B

Abstract
Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome-guided pre-clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,074 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data as a resource to the community to, for example, facilitate the design of innovative prospective clinical trials.

PMID: 29101300 [PubMed - indexed for MEDLINE]

Impact of glutathione transferases genes polymorphisms in nevirapine adverse reactions: a possible role for GSTM1 in SJS/TEN susceptibility.

Eur J Clin Pharmacol. 2017 Oct;73(10):1253-1259

Authors: Ciccacci C, Latini A, Politi C, Mancinelli S, Marazzi MC, Novelli G, Palombi L, Borgiani P

Abstract
PURPOSE: Nevirapine (NVP) is used in developing countries as first-line treatment of HIV infection. Unfortunately, its use is associated with common serious adverse drug reactions, such as liver toxicity and the most severe and rare Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). GSTT1 and GSTM1 genes code for enzymes involved in the metabolism of a wide range of drugs. We hypothesized that this gene variability could be implicated in NVP adverse reactions.
METHODS: We analyzed the GSTM1 and GSTT1 null genotypes by multiplex PCR in a population of 181 patients from Mozambique, treated with NVP. A case/control association study was performed. We also counted the number of risk alleles in SJS/TEN patients and in controls, including the GSTM1 null genotype and four previously identified risk alleles in CYP2B6, HCP5, and TRAF3IP2 genes.
RESULTS: Among patients, 27 had developed SJS/TEN and 76 had developed hepatotoxicity during the treatment. The GSTM1 null genotype was more frequent in the cases with SJS/TEN than in the controls (OR = 2.94, P = 0.027). This association is also observed when other risk factors are taken into account, by a multivariate analysis (P = 0.024 and OR = 3.58). The risk allele counting analysis revealed a significantly higher risk for SJS/TEN in patients carrying three or four risk alleles. Moreover, all subjects with five or six risk alleles developed SJS/TEN, while subjects without any risk alleles were present only in the control group.
CONCLUSIONS: We observed an association between GSTM1 and SJS/TEN susceptibility. Moreover, GSTM1 contributes to the definition of a genetic risk profile for SJS/TEN susceptibility.

PMID: 28689274 [PubMed - indexed for MEDLINE]

Add on DPP-4 inhibitor alogliptin alone or in combination with pioglitazone improved β-cell function and insulin sensitivity in metformin treated PCOS.

Endocr Res. 2017 Nov;42(4):261-268

Authors: Jensterle M, Goricar K, Janez A

Abstract
PURPOSE: Impaired β-cell function remains unaddressed in PCOS. The aim of the study was to evaluate whether dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin (ALO) alone or in combination with pioglitazone (PIO) improves β-cell function along with insulin resistance (IR) in metformin (MET) treated obese women with PCOS with persistent IR.
MATERIALS AND METHODS: In 12-week randomized study, ALO 25 mg QD (n=15) or ALO 25 mg QD and PIO 30 mg QD (n=15) was added to MET 1000 mg BID in PCOS women (aged 34.4 ± 6.5 years, BMI 39.0 ± 4.9 kg/m2, HOMA-IR 4.82 ± 2.52, mean ± SD). Model derived parameters of glucose homeostasis from the meal tolerance test (MTT) were determined. The ability of the β-cell function was assessed by the adaptation index (AI).
RESULTS: MET-ALO and MET-ALO-PIO resulted in a significant decrease of HOMA-IR (by 1.6±2.3 (p=0.039) and 2.9±3.3 (p=0.001), respectively) and an increase in insulin sensitivity (IS) after meal ingestion (oral glucose IS) by 31.4±97.5 ml·min-1·m-2 (p=0.007) vs 39.0±58.1 ml·min-1·m-2 (p=0.039), respectively. AI across the entire group was significantly improved from 329.6±200.6 to 442.5±303.9 (p=0.048).
CONCLUSIONS: ALO alone and in combination with PIO improved IR along with dynamic IS and meal related β-cell function when added to MET treated PCOS.

PMID: 28323503 [PubMed - indexed for MEDLINE]

Maternal Smoking Induces Acquired CFTR Dysfunction in Neonatal Rats.

Am J Respir Crit Care Med. 2018 Jul 06;:

Authors: McCormick LL, Phillips SE, Kaza N, Tang LP, Rasmussen L, Byzek S, Raju SV, Rowe S

PMID: 29979606 [PubMed - as supplied by publisher]

Overcoming psychosocial challenges in cystic fibrosis: Promoting resilience.

Pediatr Pulmonol. 2018 Jul 06;:

Authors: Muther EF, Polineni D, Sawicki GS

Abstract
Individuals living with cystic fibrosis (CF), and their families, have experienced significant improvements in treatment and related research that have enhanced outcomes and survival. Despite such advancement, the burden of living with CF still exists. Many psychosocial stressors and risk factors are associated with the impact of CF. The identification and treatment of such risk factors are discussed throughout this review, with an emphasis on strategies to address psychosocial risk and the importance of promoting resiliency in those touched by CF.

PMID: 29979497 [PubMed - as supplied by publisher]

Reevaluating approaches to cystic fibrosis pulmonary exacerbations.

Pediatr Pulmonol. 2018 Jul 06;:

Authors: Schechter MS

Abstract
Cystic Fibrosis (CF) lung disease is characterized by intermittent acute episodes of worsening signs, symptoms, and pulmonary function; these so-called pulmonary exacerbations (PEx) appear to be important drivers of long-term declines in lung function, quality of life, and life expectancy. Surveillance for development of PEx and their treatment is a fundamental component of chronic CF management, and the merits of novel CF therapies are often judged based on their ability to reduce the frequency of PEx. Given the central role that they play, it is surprising how poorly PEx are understood, how thin is the evidence base for their treatment and how often they are left unrecognized and untreated in clinical practice. This paper reviews what is known and what is unknown regarding the nature of PEx, and discusses the impact of missed recognition and treatment of these episodes as well as the apparent variation in practice across CF care centers. The arguments supporting a liberal, highly sensitive approach to the diagnosis of PEx are presented, as well as recommendation for how care programs can achieve consistency in their early recognition and treatment. A stepwise approach to personalized treatment supported by close follow-up to ensure the successful resolution of all signs and symptoms will lead to the stabilization of patients' lung function and quality of life. Recommendations are made regarding important priorities for research into evidence-based approaches to improving the care of PEx.

PMID: 29979495 [PubMed - as supplied by publisher]

Targeted disruption of the extracellular polymeric network of Pseudomonas aeruginosa biofilms by alginate oligosaccharides.

NPJ Biofilms Microbiomes. 2018;4:13

Authors: Powell LC, Pritchard MF, Ferguson EL, Powell KA, Patel SU, Rye PD, Sakellakou SM, Buurma NJ, Brilliant CD, Copping JM, Menzies GE, Lewis PD, Hill KE, Thomas DW

Abstract
Acquisition of a mucoid phenotype by Pseudomonas sp. in the lungs of cystic fibrosis (CF) patients, with subsequent over-production of extracellular polymeric substance (EPS), plays an important role in mediating the persistence of multi-drug resistant (MDR) infections. The ability of a low molecular weight (Mn = 3200 g mol-1) alginate oligomer (OligoG CF-5/20) to modify biofilm structure of mucoid Pseudomonas aeruginosa (NH57388A) was studied in vitro using scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM) with Texas Red (TxRd®)-labelled OligoG and EPS histochemical staining. Structural changes in treated biofilms were quantified using COMSTAT image-analysis software of CLSM z-stack images, and nanoparticle diffusion. Interactions between the oligomers, Ca2+ and DNA were studied using molecular dynamics (MD) simulations, Fourier transform infrared spectroscopy (FTIR) and isothermal titration calorimetry (ITC). Imaging demonstrated that OligoG treatment (≥0.5%) inhibited biofilm formation, revealing a significant reduction in both biomass and biofilm height (P < 0.05). TxRd®-labelled oligomers readily diffused into established (24 h) biofilms. OligoG treatment (≥2%) induced alterations in the EPS of established biofilms; significantly reducing the structural quantities of EPS polysaccharides, and extracellular (e)DNA (P < 0.05) with a corresponding increase in nanoparticle diffusion (P < 0.05) and antibiotic efficacy against established biofilms. ITC demonstrated an absence of rapid complex formation between DNA and OligoG and confirmed the interactions of OligoG with Ca2+ evident in FTIR and MD modelling. The ability of OligoG to diffuse into biofilms, potentiate antibiotic activity, disrupt DNA-Ca2+-DNA bridges and biofilm EPS matrix highlights its potential for the treatment of biofilm-related infections.

PMID: 29977590 [PubMed]