A modular yeast biosensor for low-cost point-of-care pathogen detection.

Sci Adv. 2017 Jun;3(6):e1603221

Authors: Ostrov N, Jimenez M, Billerbeck S, Brisbois J, Matragrano J, Ager A, Cornish VW

Abstract
The availability of simple, specific, and inexpensive on-site detection methods is of key importance for deployment of pathogen surveillance networks. We developed a nontechnical and highly specific colorimetric assay for detection of pathogen-derived peptides based on Saccharomyces cerevisiae-a genetically tractable model organism and household product. Integrating G protein-coupled receptors with a visible, reagent-free lycopene readout, we demonstrate differential detection of major human, plant, and food fungal pathogens with nanomolar sensitivity. We further optimized a one-step rapid dipstick prototype that can be used in complex samples, including blood, urine, and soil. This modular biosensor can be economically produced at large scale, is not reliant on cold-chain storage, can be detected without additional equipment, and is thus a compelling platform scalable to global surveillance of pathogens.

PMID: 28782007 [PubMed - in process]

Functional proteomic characterization of cancer cell lines.

Oncoscience. 2017 May;4(5-6):41-42

Authors: Zhao W, Li J, Mills GB

PMID: 28781984 [PubMed]

New frontiers in metabolomics: from measurement to insight.

F1000Res. 2017;6:1148

Authors: Riekeberg E, Powers R

Abstract
Metabolomics is the newest addition to the "omics" disciplines and has shown rapid growth in its application to human health research because of fundamental advancements in measurement and analysis techniques. Metabolomics has unique and proven advantages in systems biology and biomarker discovery. The next generation of analysis techniques promises even richer and more complete analysis capabilities that will enable earlier clinical diagnosis, drug refinement, and personalized medicine. A review of current advancements in methodologies and statistical analysis that are enhancing and improving the performance of metabolomics is presented along with highlights of some recent successful applications.

PMID: 28781759 [PubMed]

Heterogeneity of Stop Codon Readthrough in Single Bacterial Cells and Implications for Population Fitness.

Mol Cell. 2017 Aug 01;:

Authors: Fan Y, Evans CR, Barber KW, Banerjee K, Weiss KJ, Margolin W, Igoshin OA, Rinehart J, Ling J

Abstract
Gene expression noise (heterogeneity) leads to phenotypic diversity among isogenic individual cells. Our current understanding of gene expression noise is mostly limited to transcription, as separating translational noise from transcriptional noise has been challenging. It also remains unclear how translational heterogeneity originates. Using a transcription-normalized reporter system, we discovered that stop codon readthrough is heterogeneous among single cells, and individual cells with higher UGA readthrough grow faster from stationary phase. Our work also revealed that individual cells with lower protein synthesis levels exhibited higher UGA readthrough, which was confirmed with ribosome-targeting antibiotics (e.g., chloramphenicol). Further experiments and mathematical modeling suggest that varied competition between ternary complexes and release factors perturbs the UGA readthrough level. Our results indicate that fluctuations in the concentrations of translational components lead to UGA readthrough heterogeneity among single cells, which enhances phenotypic diversity of the genetically identical population and facilitates its adaptation to changing environments.

PMID: 28781237 [PubMed - as supplied by publisher]

Cardiac Function Improvement and Bone Marrow Response -: Outcome Analysis of the Randomized PERFECT Phase III Clinical Trial of Intramyocardial CD133(+) Application After Myocardial Infarction.

EBioMedicine. 2017 Jul 29;:

Authors: Steinhoff G, Nesteruk J, Wolfien M, Kundt G, PERFECT Trial Investigators Group, Börgermann J, David R, Garbade J, Große J, Haverich A, Hennig H, Kaminski A, Lotz J, Mohr FW, Müller P, Oostendorp R, Ruch U, Sarikouch S, Skorska A, Stamm C, Tiedemann G, Wagner FM, Wolkenhauer O

Abstract
OBJECTIVE: The phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133(+) bone marrow stem cell treatment combined with CABG for induction of cardiac repair.
DESIGN: Multicentre, double-blinded, randomised placebo controlled trial.
SETTING: The study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015.
PARTICIPANTS: Post-infarction patients with chronic ischemia and reduced LVEF (25-50%).
INTERVENTIONS: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5ml placebo or a suspension of 0.5-5×10(6) CD133(+).
OUTCOME: Primary endpoint was delta (∆) LVEF at 180days (d) compared to baseline measured in MRI.
FINDINGS (PRESPECIFIED): Safety (n=77): 180d survival was 100%, MACE n=2, SAE n=49, without difference between placebo and CD133(+). Efficacy (n=58): The LVEF improved from baseline LVEF 33.5% by +9.6% at 180d, p=0.001 (n=58). Treatment groups were not different in ∆LVEF (ANCOVA: Placebo +8.8% vs. CD133(+) +10.4%, ∆CD133(+)vs placebo +2.6%, p=0.4).
FINDINGS (POST HOC): Responders (R) classified by ∆LVEF≥5% after 180d were 60% of the patients (35/58) in both treatment groups. ∆LVEF in ANCOVA was +17.1% in (R) vs. non-responders (NR) (∆LVEF 0%, n=23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133(+) EPC (RvsNR: p=0.005) and thrombocytes (p=0.004) in contrast to increased Erythropoeitin (p=0.02), and SH2B3 mRNA expression (p=0.073). Actuarial computed mean survival time was 76.9±3.32months (R) vs. +72.3±5.0months (NR), HR 0.3 [Cl 0.07-1.2]; p=0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation.
INTERPRETATION: The PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133+ EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature.
TRIAL REGISTRATION: ClinicalTrials.govNCT00950274.

PMID: 28781130 [PubMed - as supplied by publisher]

Plant-Pathogen Maneuvering over Apoplastic Sugars.

Trends Plant Sci. 2017 Aug 02;:

Authors: Naseem M, Kunz M, Dandekar T

Abstract
The nutrient-rich extracellular plant compartment, the apoplast, is an attractive niche for attacks by microbial pathogens. Here, we highlight recent trends in plant-pathogen competition for apoplastic sugars in the context of innate immune responses in various plant-pathogen interaction systems.

PMID: 28779901 [PubMed - as supplied by publisher]

The advantage of channeling nucleotides for very processive functions.

F1000Res. 2017;6:724

Authors: Zala D, Schlattner U, Desvignes T, Bobe J, Roux A, Chavrier P, Boissan M

Abstract
Nucleoside triphosphate (NTP)s, like ATP (adenosine 5'-triphosphate) and GTP (guanosine 5'-triphosphate), have long been considered sufficiently concentrated and diffusible to fuel all cellular ATPases (adenosine triphosphatases) and GTPases (guanosine triphosphatases) in an energetically healthy cell without becoming limiting for function. However, increasing evidence for the importance of local ATP and GTP pools, synthesised in close proximity to ATP- or GTP-consuming reactions, has fundamentally challenged our view of energy metabolism. It has become evident that cellular energy metabolism occurs in many specialised 'microcompartments', where energy in the form of NTPs is transferred preferentially from NTP-generating modules directly to NTP-consuming modules. Such energy channeling occurs when diffusion through the cytosol is limited, where these modules are physically close and, in particular, if the NTP-consuming reaction has a very high turnover, i.e. is very processive. Here, we summarise the evidence for these conclusions and describe new insights into the physiological importance and molecular mechanisms of energy channeling gained from recent studies. In particular, we describe the role of glycolytic enzymes for axonal vesicle transport and nucleoside diphosphate kinases for the functions of dynamins and dynamin-related GTPases.

PMID: 28663786 [PubMed]

Evidence and decision algorithm for the withdrawal of antipsychotic treatment in the elderly with dementia and neuropsychiatric symptoms.

Eur J Clin Pharmacol. 2017 Aug 05;:

Authors: Miarons M, Cabib C, Barón FJ, Rofes L

Abstract
PURPOSE: Antipsychotics (APs) are commonly used to manage neuropsychiatric symptoms (NPS) in elderly patients with dementia, even though several large studies have demonstrated an association between AP treatment and increased morbidity and mortality in people with dementia. The aim of this study is to review the scientific literature of the use of AP in the elderly with dementia and to propose an algorithm to assist in decision-making regarding the withdrawal of APs.
METHODS: A computerized literature search (MEDLINE: 1966 to December 2016, EMBASE: 1982 to December 2016) was used to locate relevant literature. Keywords in the search included terms from Medical Subject Headings (MESH) and EMBASE thesaurus (EMTREE). The following terms were used in the MESH database and EMTREE thesaurus: Aged, Antipsychotic Agents, Behavioral Symptoms and Dementia.
RESULTS: Earlier studies of APs used in elderly patients with dementia suggest that, in most elderly demented patients, APs can be withdrawn with no effect on behaviour. These patients are likely to benefit from the algorithm we propose to assist clinicians in the withdrawal of APs.
CONCLUSIONS: In this paper, we review the potential risks and benefits of discontinuing AP treatment in elderly demented patients with NPS and propose an algorithm to assist in decision-making regarding AP withdrawal.

PMID: 28780696 [PubMed - as supplied by publisher]

[Comparative relevance of declaration of side effects by patients and health professionals].

Therapie. 2017 Jul 08;:

Authors: Lagneau A, Vigier C, Marianna A, Serfaty R, Rocher F, Spreux A, Drici MD

Abstract
INTRODUCTION: Drug-induced adverse events have been accessible to patient's spontaneous reporting in France and such notifications have been steadily increasing since 2011. However, these notifications are still shrouded with medical perplexity and are sometimes subjected to partial caution in their interpretation by the patient's physician. We aimed to evaluate and compare prospectively the relevance of such spontaneous notifications with those provided by healthcare professionals to the French Pharmacovigilance Center of Nice-Alpes-Côte d'Azur.
METHODS: Spontaneous reporting of drug adverse events notified by patients and health care professionals were compared in terms of critical (name, date, effect, drug involved, chronological compatibility) and non-critical (posology, dosage) information, whereas the plausibility of the cases were assessed in weekly multispecialty staffs. Each patient's notification was matched with the immediate pre- and post-notifications declared by health care providers.
RESULTS: Spontaneous notifications from 61 patients were compared with 122 notifications from health care providers. Neither the critical information necessary for declaring the case in the national database (7/61 versus 16/122, P=0.75), nor the uncritical elements allowing to assess the case (30/61 versus 51/122, P=0.22), its plausibility or the causality of the drug (P=0.10) differed significantly between the two groups. 107 cases out of 122 (88%) notified by health care providers were classified as serious, as compared with 19 out of 61 (15%) of patient's ones (P<0.001).
CONCLUSION: Despite concerns from pharmacovigilance specialists in France, the medical relevance of spontaneous reported drug-associated adverse events does not differ from that of health care providers.

PMID: 28780021 [PubMed - as supplied by publisher]

Pharmacology and drug development in rare diseases: the attractiveness and expertise of the French medical pharmacology.

Fundam Clin Pharmacol. 2017 Aug 05;:

Authors: Micallef J, Boutouyrie P, Blin O

Abstract
Developing drugs for rare disease can be challenging due to specific rare disease characteristics. The French Medical Pharmacology is structured and positioned to play a major role in Orphan Drug Research and Development due to the required expertise concentrated into pharmacology departments, exclusively implemented within the French University Hospitals, public hospitals that are linked to a medical school (and often a pharmacy school) with numerous INSERM or CNRS labelled research units. In addition, these structures allow a close collaboration between researchers, academic institutions and biotech start-up (most of them being spin-off of the academic structures). Also, within University Hospitals are located the Clinical investigation Centres, linking to the FCRIN network and also to Inserm and hospitals, that enable care staff and researchers to be associated and clinical research protocols to be carried out on site, in full respect with ethic and regulatory aspects. As a consequence, this intra and multidisciplinary expertise offers all resource to elaborate a tailored approach for orphan drug development, in new entities as well as in repositioning. For preclinical development: drug screening, candidate selection (taking into account PK, metabolism, variability, potential toxicity), preclinical models (iPS, animal models) that could allow a better translation to human research. For clinical development, we will mention here dose determination, safety evaluation, Orphan Drug Designation and Protocol Assistance preparation and submission. For post marketing evaluation and surveys, the pharmacovigilance, addictovigilance and pharmacoepidemiology expertise, combined with access to large databases allow a better approach to orphan drug use and safety. As outlined through two success stories (Charcot Marie Tooth, vascular Ehlers-Danlos syndrome), the added value of French Medical Pharmacology structures and expertise has been evidenced in the know-how, multidimensional and multidisciplinary approaches, allowing the development of numerous drugs that have been granted with Orphan Drug Designation and later Market Approval. Even if specific and possibly even more, the field of Orphan Drugs requires the respect of highest standards of safety and quality. French Medical Pharmacology intends to continue on this way and constantly improve his involvement in this field, committed to a single objective: answer the unmet medical need of patients with rare diseases. This article is protected by copyright. All rights reserved.

PMID: 28779530 [PubMed - as supplied by publisher]

Depression and Hypersomnia: A Complex Association.

Sleep Med Clin. 2017 Sep;12(3):395-405

Authors: Lopez R, Barateau L, Evangelista E, Dauvilliers Y

Abstract
Hypersomnolence is a clinically defined syndrome characterized by the association of prolonged nocturnal sleep, impaired arousal quality, and sleep inertia. Hypersomnolence is the major feature of central hypersomnias and is frequently reported in various mood disorders, such as major depressive disorder, bipolar disorder, or seasonal affective disorder. Assessment of hypersomnolence is challenging in depressed patients, with objective tests often in the normal range despite a high level of sleepiness complaint. On the other hand, many patients with central hypersomnias reported depressive symptoms. The self-assessment of mood symptoms in patients with central hypersomnias may overdiagnose depression with an overlap between both conditions.

PMID: 28778237 [PubMed - in process]

MTHFR gene variants and non-MALT lymphoma development in primary Sjogren's syndrome.

Sci Rep. 2017 Aug 04;7(1):7354

Authors: Fragkioudaki S, Nezos A, Souliotis VL, Chatziandreou I, Saetta AA, Drakoulis N, Tzioufas AG, Voulgarelis M, Sfikakis PP, Koutsilieris M, Crow MK, Moutsopoulos HM, Mavragani CP

Abstract
Primary Sjogren's syndrome (pSS) confers increased risk for non-Hodgkin lymphoma (NHL) development. Two common polymorphisms, the c. 677C > T and c. 1298A > C, of the methylene-tetrahydrofolate reductase (MTHFR) gene, an enzyme essential in DNA synthesis and methylation, have been associated with susceptibility to NHL. Herein, we tested the hypothesis that MTHFR variants contribute to pSS-related lymphomagenesis. 356 pSS patients, of whom 75 had MALT and 19 non-MALT NHL and 600 healthy controls were genotyped for the detection of MTHFR polymorphisms. DNA methylation levels were assessed by pyrosequencing of the LINE-1 retroelement promoter in DNA from 55 salivary gland tissues from pSS patients. DNA double-strand breaks were determined in peripheral blood mononuclear cells from 13 pSS patients, using comet assay. Αnalysis according to lymphoma subtype revealed increased frequency of c. 677C > T TT genotype and T allele, as well as reduced prevalence of the c. 1298A > C C allele in the pSS non-MALT group compared to controls and patients without NHL. MTHFR c. 677C > T TT genotype was associated with reduced DNA methylation levels, while MTHFR c. 1298A > C AC genotype with reduced DNA double-strand breaks levels. MTHFR variants may be involved in SS non-MALT NHL development, through contribution to defective DNA methylation and genomic instability.

PMID: 28779180 [PubMed - in process]

Utility of gene methylation analysis, cytological examination, and HPV-16/18 genotyping in triage of high-risk human papilloma virus-positive women.

Oncotarget. 2017 Jul 22;:

Authors: Tian Y, Wu NY, Liou YL, Yeh CT, Cao L, Kang YN, Wang HJ, Li Y, Chu TY, Li W, Liu X, Zhang Y, Zhou H, Zhang Y

Abstract
In 2015, the American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology issued interim guidance for the use of a human papillomavirus (HPV) test for primary screening, suggesting triage of women positive for high-risk human papillomavirus (hrHPV) by HPV-16/18 genotyping and cytology for women positive for non-16/18 hrHPV. The design of the present study was based on this interim guidance and analysis of the methylation status of specific candidate genes, which has been proposed as a tool to reduce unnecessary referral following primary HPV screening for cervical cancer. We performed a hospital-based case-control study including 312 hrHPV-positive women. hrHPV genotyping was performed by nested multiplex PCR assay with type-specific primers.Residual cervical cells from liquid-based cytology were used for extraction of genomic DNA for assessment of the methylation status of PAX1, ZNF582, SOX1, and NKX6-1 and HPV genotyping. Combined with HPV-16/18 genotyping, both a dual methylation test for PAX1/ZNF582 and testing for ZNF582 methylation demonstrated 100% association of methylation with pathology results, indicating carcinoma in situ or squamous cell carcinoma. The sensitivity and specificity of the dual methylation test for PAX1/ZNF582 as a reflex test for identification of CIN3+ lesions were 78.85% and 73.55% (odds ratio = 10.37, 95% confidence interval = 4.76-22.58), respectively. This strategy could reduce the number of patients referred for colposcopic examination by 31.3% compared with cytology, and thus provide a feasible follow-up solution in regions where colposcopy is not readily available. This strategy could also prevent unnecessary anxiety in women with hrHPV infection.

PMID: 28779032 [PubMed - as supplied by publisher]

Respiratory viruses in healthy infants and infants with cystic fibrosis: a prospective cohort study.

Thorax. 2017 Aug 04;:

Authors: Korten I, Kieninger E, Klenja S, Mack I, Schläpfer N, Barbani MT, Regamey N, Kuehni CE, Hilty M, Frey U, Gorgievski M, Casaulta C, Latzin P, SCILD and BILD study groups

Abstract
RATIONALE: Acute viral respiratory tract infections in children with cystic fibrosis (CF) are known causes of disease exacerbation. The role of viral infections during infancy is, however, less known, although early infancy is thought to be a crucial period for CF disease development.We prospectively assessed symptomatic and asymptomatic viral detection in the first year of life in infants with CF and healthy controls.
METHODS: In a prospective cohort study, we included 31 infants with CF from the Swiss Cystic Fibrosis Infant Lung Development Cohort and 32 unselected, healthy infants from the Basel Bern Infant Lung Development Cohort and followed them throughout the first year of life. Respiratory symptoms were assessed by weekly telephone interviews. Biweekly nasal swabs were analysed for 10 different viruses and two atypical bacteria with real-time seven duplex PCR (CF=561, controls=712).
MEASUREMENTS AND RESULTS: Infants with CF and healthy controls showed similar numbers of swabs positive for virus (mean 42% vs 44%; OR 0.91, 95% CI 0.66 to 1.26, p=0.6). Virus-positive swabs were less often accompanied by respiratory symptoms in infants with CF (17% vs 23%; OR 0.64, 95% CI 0.43 to 0.95, p=0.026). This finding was pronounced for symptomatic human rhinovirus detection (7% vs 11%; OR 0.52, 95% CI 0.31 to 0.9, p=0.02).
CONCLUSIONS: Viral detection is not more frequent in infants with CF and respiratory symptoms during viral detection occur even less often than in healthy controls. It is likely an interplay of different factors such as local epithelial properties and immunological mechanisms that contribute to our findings.

PMID: 28778921 [PubMed - as supplied by publisher]

The top 10 research priorities in cystic fibrosis developed by a partnership between people with CF and healthcare providers.

Thorax. 2017 Aug 04;:

Authors: Rowbotham NJ, Smith S, Leighton PA, Rayner OC, Gathercole K, Elliott ZC, Nash EF, Daniels T, Duff AJA, Collins S, Chandran S, Peaple U, Hurley MN, Brownlee K, Smyth AR

Abstract
There remain many treatment uncertainties in cystic fibrosis (CF). With limited resources, research should focus on questions which are most important to the CF community. We conducted a James Lind Alliance Priority Setting Partnership in CF. Research questions were elicited and then prioritised in successive surveys. A workshop agreed the final top 10. Online methods avoided cross infection and widened participation. The elicitation survey had 482 respondents (1080 questions) and prioritisation survey 677 respondents. Participants were drawn equally from the patient and clinical communities globally. We have achieved a consensus on 10 research priorities which will be attractive to funders.

PMID: 28778919 [PubMed - as supplied by publisher]