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Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDA-approved compounds.

Tue, 01/30/2018 - 14:04
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Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDA-approved compounds.

Oncotarget. 2016 Sep 13;7(37):58743-58758

Authors: Carrella D, Manni I, Tumaini B, Dattilo R, Papaccio F, Mutarelli M, Sirci F, Amoreo CA, Mottolese M, Iezzi M, Ciolli L, Aria V, Bosotti R, Isacchi A, Loreni F, Bardelli A, Avvedimento VE, di Bernardo D, Cardone L

Abstract
The discovery of inhibitors for oncogenic signalling pathways remains a key focus in modern oncology, based on personalized and targeted therapeutics. Computational drug repurposing via the analysis of FDA-approved drug network is becoming a very effective approach to identify therapeutic opportunities in cancer and other human diseases. Given that gene expression signatures can be associated with specific oncogenic mutations, we tested whether a "reverse" oncogene-specific signature might assist in the computational repositioning of inhibitors of oncogenic pathways. As a proof of principle, we focused on oncogenic PI3K-dependent signalling, a molecular pathway frequently driving cancer progression as well as raising resistance to anticancer-targeted therapies. We show that implementation of "reverse" oncogenic PI3K-dependent transcriptional signatures combined with interrogation of drug networks identified inhibitors of PI3K-dependent signalling among FDA-approved compounds. This led to repositioning of Niclosamide (Niclo) and Pyrvinium Pamoate (PP), two anthelmintic drugs, as inhibitors of oncogenic PI3K-dependent signalling. Niclo inhibited phosphorylation of P70S6K, while PP inhibited phosphorylation of AKT and P70S6K, which are downstream targets of PI3K. Anthelmintics inhibited oncogenic PI3K-dependent gene expression and showed a cytostatic effect in vitro and in mouse mammary gland. Lastly, PP inhibited the growth of breast cancer cells harbouring PI3K mutations. Our data indicate that drug repositioning by network analysis of oncogene-specific transcriptional signatures is an efficient strategy for identifying oncogenic pathway inhibitors among FDA-approved compounds. We propose that PP and Niclo should be further investigated as potential therapeutics for the treatment of tumors or diseases carrying the constitutive activation of the PI3K/P70S6K signalling axis.

PMID: 27542212 [PubMed - indexed for MEDLINE]

Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease.

Tue, 01/30/2018 - 14:04
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Brain Serotonergic and Noradrenergic Deficiencies in Behavioral Variant Frontotemporal Dementia Compared to Early-Onset Alzheimer's Disease.

J Alzheimers Dis. 2016 Jun 15;53(3):1079-96

Authors: Vermeiren Y, Janssens J, Aerts T, Martin JJ, Sieben A, Van Dam D, De Deyn PP

Abstract
Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer's disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) 6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α1/2/β1-blockers, seem to have a rationale and should be considered.

PMID: 27314528 [PubMed - indexed for MEDLINE]

Phenotypes of organ involvement in sarcoidosis.

Sat, 01/27/2018 - 13:41
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Phenotypes of organ involvement in sarcoidosis.

Eur Respir J. 2018 Jan;51(1):

Authors: Schupp JC, Freitag-Wolf S, Bargagli E, Mihailović-Vučinić V, Rottoli P, Grubanovic A, Müller A, Jochens A, Tittmann L, Schnerch J, Olivieri C, Fischer A, Jovanovic D, Filipovic S, Videnovic-Ivanovic J, Bresser P, Jonkers R, O'Reilly K, Ho LP, Gaede KI, Zabel P, Dubaniewicz A, Marshall B, Kieszko R, Milanowski J, Günther A, Weihrich A, Petrek M, Kolek V, Keane MP, O'Beirne S, Donnelly S, Haraldsdottir S, Jorundsdottir KB, Costabel U, Bonella F, Wallaert B, Grah C, Peroš-Golubičić T, Luisetti M, Kadija Z, Pabst S, Grohé C, Strausz J, Vašáková M, Sterclova M, Millar A, Homolka J, Slováková A, Kendrick Y, Crawshaw A, Wuyts W, Spencer L, Pfeifer M, Valeyre D, Poletti V, Wirtz H, Prasse A, Schreiber S, Krawczak M, Müller-Quernheim J

Abstract
Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

PMID: 29371378 [PubMed - in process]

Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer's disease.

Sat, 01/27/2018 - 13:41
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Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer's disease.

Alzheimers Res Ther. 2018 Jan 15;10(1):5

Authors: Duits FH, Brinkmalm G, Teunissen CE, Brinkmalm A, Scheltens P, Van der Flier WM, Zetterberg H, Blennow K

Abstract
BACKGROUND: We investigated whether a panel of 12 potential novel biomarkers consisting of proteins involved in synapse functioning and immunity would be able to distinguish patients with Alzheimer's disease (AD) and patients with mild cognitive impairment (MCI) from control subjects.
METHODS: We included 40 control subjects, 40 subjects with MCI, and 40 subjects with AD from the Amsterdam Dementia Cohort who were matched for age and sex (age 65 ± 5 years, 19 [48%] women). The mean follow-up of patients with MCI was 3 years. Two or three tryptic peptides per protein were analyzed in cerebrospinal fluid using parallel reaction monitoring mass spectrometry. Corresponding stable isotope-labeled peptides were added and used as reference peptides. Multilevel generalized estimating equations (GEEs) with peptides clustered per subject and per protein (as within-subject variables) were used to assess differences between diagnostic groups. To assess differential effects of individual proteins, we included the diagnosis × protein interaction in the model. Separate GEE analyses were performed to assess differences between stable patients and patients with progressive MCI (MCI-AD).
RESULTS: There was a main effect for diagnosis (p < 0.01) and an interaction between diagnosis and protein (p < 0.01). Analysis stratified according to protein showed higher levels in patients with MCI for most proteins, especially in patients with MCI-AD. Chromogranin A, secretogranin II, neurexin 3, and neuropentraxin 1 showed the largest effect sizes; β values ranged from 0.53 to 0.78 for patients with MCI versus control subjects or patients with AD, and from 0.67 to 0.98 for patients with MCI-AD versus patients with stable MCI. In contrast, neurosecretory protein VGF was lower in patients with AD than in patients with MCI (ß = -0.93 [SE 0.22]) and control subjects (ß = 0.46 [SE 0.19]).
CONCLUSIONS: Our results suggest that several proteins involved in vesicular transport and synaptic stability are elevated in patients with MCI, especially in patients with MCI progressing to AD dementia. This may reflect early events in the AD pathophysiological cascade. These proteins may be valuable as disease stage or prognostic markers in an early symptomatic stage of the disease.

PMID: 29370833 [PubMed - in process]

Prognostic Value of the VHL, HIF-1α, and VEGF Signaling Pathway and Associated MAPK (ERK1/2 and ERK5) Pathways in Clear-Cell Renal Cell Carcinoma. A Long-Term Study.

Sat, 01/27/2018 - 13:41
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Prognostic Value of the VHL, HIF-1α, and VEGF Signaling Pathway and Associated MAPK (ERK1/2 and ERK5) Pathways in Clear-Cell Renal Cell Carcinoma. A Long-Term Study.

Clin Genitourin Cancer. 2017 Dec;15(6):e923-e933

Authors: Salinas-Sánchez AS, Serrano-Oviedo L, Nam-Cha SY, Roche-Losada O, Sánchez-Prieto R, Giménez-Bachs JM

Abstract
BACKGROUND: The prognostic value of molecular markers in renal cell carcinoma has been investigated in several studies. Although their value is still not confirmed, various proteins are important. We describe the effect on long-term survival of the status of the von Hippel-Lindau (VHL) hypoxia-inducible factor 1-α (HIF1-α) signaling pathway as well as associated mitogen-activated protein kinase (extracellular signal-regulated kinase [ERK]1/2 and ERK5).
PATIENTS AND METHODS: A prospective, longitudinal cohort study was conducted with 50 patients diagnosed with clear-cell renal cell carcinoma to analyze VHL mutations and hypermethylation as well as VHL, HIF1-α, vascular endothelial growth factor (VEGF), ERK1/2, and ERK5 protein expression. Overall survival (OS), disease-specific survival (DSS), and progression- or recurrence-free survival (PFS) were analyzed using the Kaplan-Meier method. Mantel-Haenszel was used for comparisons, and Cox proportional risk models were also constructed.
RESULTS: Follow-up was 66.9 months. There were 23 (46.0%) deaths, of which 17 (73.9%) were caused by the tumor. Mean periods were 85.6 months for OS and 94.3 months for DSS. A total of 22 (44.0%) patients showed progression (PFS, 78.1 months). VHL expression (P = .045) and > 10% of HIF1-α expression (P = .034) were associated with greater OS. DSS was greater in patients without VHL methylation (P = .012), with > 10% HIF1-α expression (P = .037), or with ERK5 protein underexpression. Greater PFS was associated with absence of VHL methylation (P = .045), presence of VHL expression (P < .0001), HIF1-α expression > 10% (P = .04), and ERK5 protein underexpression (P = .011). The presence of VHL mutation and/or methylation and VEGF expression had no prognostic value. Fuhrman nuclear grade and Tumor, Node, Metastases (TNM) stage were the only variables that remained in the Cox model.
CONCLUSION: The HIF1-α and ERK5 pathway has prognostic value. Patients with no VHL or HIF1-α expression and ERK5 overexpression had a worse course of disease. VHL or VEGF status had no prognostic value. Only TNM stage and Fuhrman nuclear grade remained in the Cox model and, therefore, are still essential in prognostic biomarker panels.

PMID: 28624320 [PubMed - indexed for MEDLINE]

Overview of ongoing cohort and dietary studies in the Arctic.

Sat, 01/27/2018 - 13:41
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Overview of ongoing cohort and dietary studies in the Arctic.

Int J Circumpolar Health. 2016;75:33803

Authors: Weihe P, Bjerregaard P, Bonefeld-Jørgensen E, Dudarev A, Halling J, Hansen S, Muckle G, Nøst T, Odland JØ, Petersen MS, Rautio A, Veyhe AS, Wennberg M, Bergdahl I

Abstract
This article gives an overview of the ongoing cohort and dietary studies underlying the assessment of population health in the Arctic. The emphasis here is on a description of the material, methods and results or preliminary results for each study. Detailed exposure information is available in an article in this journal, whereas another paper describes the effects associated with contaminant exposure in the Arctic. The cohort descriptions have been arranged geographically, beginning in Norway and moving east to Finland, Sweden, Russia and the other Arctic countries and ultimately to the Faroe Islands. No cohort studies have been reported for Alaska or Iceland.

PMID: 27974135 [PubMed - indexed for MEDLINE]

Patient-derived Mammosphere and Xenograft Tumour Initiation Correlates with Progression to Metastasis.

Sat, 01/27/2018 - 13:41
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Patient-derived Mammosphere and Xenograft Tumour Initiation Correlates with Progression to Metastasis.

J Mammary Gland Biol Neoplasia. 2016 Dec;21(3-4):99-109

Authors: Eyre R, Alférez DG, Spence K, Kamal M, Shaw FL, Simões BM, Santiago-Gómez A, Sarmiento-Castro A, Bramley M, Absar M, Saad Z, Chatterjee S, Kirwan C, Gandhi A, Armstrong AC, Wardley AM, O'Brien CS, Farnie G, Howell SJ, Clarke RB

Abstract
Breast cancer specific mortality results from tumour cell dissemination and metastatic colonisation. Identification of the cells and processes responsible for metastasis will enable better prevention and control of metastatic disease, thus reducing relapse and mortality. To better understand these processes, we prospectively collected 307 patient-derived breast cancer samples (n = 195 early breast cancers (EBC) and n = 112 metastatic samples (MBC)). We assessed colony-forming activity in vitro by growing isolated cells in both primary (formation) and secondary (self-renewal) mammosphere culture, and tumour initiating activity in vivo through subcutaneous transplantation of fragments or cells into mice. Metastatic samples formed primary mammosphere colonies significantly more frequently than early breast cancers and had significantly higher primary mammosphere colony formation efficiency (0.9 % vs. 0.6 %; p < 0.0001). Tumour initiation in vivo was significantly higher in metastatic than early breast cancer samples (63 % vs. 38 %, p = 0.04). Of 144 breast cancer samples implanted in vivo, we established 20 stable patient-derived xenograft (PDX) models at passage 2 or greater. Lung metastases were detected in mice from 14 PDX models. Mammosphere colony formation in vitro significantly correlated with the ability of a tumour to metastasise to the lungs in vivo (p = 0.05), but not with subcutaneous tumour initiation. In summary, the breast cancer stem cell activities of colony formation and tumour initiation are increased in metastatic compared to early samples, and predict metastasis in vivo. These results suggest that breast stem cell activity will predict for poor outcome tumours, and therapy targeting this activity will improve outcomes for patients with metastatic disease.

PMID: 27680982 [PubMed - indexed for MEDLINE]

Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes.

Sat, 01/27/2018 - 13:41
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Integrated multi-omics of the human gut microbiome in a case study of familial type 1 diabetes.

Nat Microbiol. 2016 Oct 10;2:16180

Authors: Heintz-Buschart A, May P, Laczny CC, Lebrun LA, Bellora C, Krishna A, Wampach L, Schneider JG, Hogan A, de Beaufort C, Wilmes P

Abstract
The gastrointestinal microbiome is a complex ecosystem with functions that shape human health. Studying the relationship between taxonomic alterations and functional repercussions linked to disease remains challenging. Here, we present an integrative approach to resolve the taxonomic and functional attributes of gastrointestinal microbiota at the metagenomic, metatranscriptomic and metaproteomic levels. We apply our methods to samples from four families with multiple cases of type 1 diabetes mellitus (T1DM). Analysis of intra- and inter-individual variation demonstrates that family membership has a pronounced effect on the structural and functional composition of the gastrointestinal microbiome. In the context of T1DM, consistent taxonomic differences were absent across families, but certain human exocrine pancreatic proteins were found at lower levels. The associated microbial functional signatures were linked to metabolic traits in distinct taxa. The methodologies and results provide a foundation for future large-scale integrated multi-omic analyses of the gastrointestinal microbiome in the context of host-microbe interactions in human health and disease.

PMID: 27723761 [PubMed - indexed for MEDLINE]

Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk.

Sat, 01/27/2018 - 13:41
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Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk.

Epidemiology. 2016 Nov;27(6):787-96

Authors: Myte R, Gylling B, Schneede J, Ueland PM, Häggström J, Hultdin J, Hallmans G, Johansson I, Palmqvist R, Van Guelpen B

Abstract
BACKGROUND: Despite extensive study, the role of folate in colorectal cancer remains unclear. Research has therefore begun to address the role of other elements of the folate-methionine metabolic cycles. This study investigated factors other than folate involved in one-carbon metabolism, i.e., choline, betaine, dimethylglycine, sarcosine, and methionine and relevant polymorphisms, in relation to the risk of colorectal cancer in a population with low intakes and circulating levels of folate.
METHODS: This was a prospective case-control study of 613 case subjects and 1,190 matched control subjects nested within the population-based Northern Sweden Health and Disease Study. We estimated odds ratios (OR) by conditional logistic regression, and marginal risk differences with weighted maximum likelihood estimation using incidence data from the study cohort.
RESULTS: Higher plasma concentrations of methionine and betaine were associated with modest colorectal cancer risk reductions (OR [95% confidence interval {CI}] for highest versus lowest tertile: 0.76 [0.57, 0.99] and 0.72 [0.55, 0.94], respectively). Estimated marginal risk differences corresponded to approximately 200 fewer colorectal cancer cases per 100,000 individuals on average. We observed no clear associations between choline, dimethylglycine, or sarcosine and colorectal cancer risk. The inverse association of methionine was modified by plasma folate concentrations (OR [95% CI] for highest/lowest versus lowest/lowest tertile of plasma methionine/folate concentrations 0.39 [0.24, 0.64], Pinteraction = 0.06).
CONCLUSIONS: In this population-based, nested case-control study with a long follow-up time from baseline to diagnosis (median: 8.2 years), higher plasma concentrations of methionine and betaine were associated with lower colorectal cancer risk.See Video Abstract at http://links.lww.com/EDE/B83.

PMID: 27367522 [PubMed - indexed for MEDLINE]

Clinical applications of ultra-high field magnetic resonance imaging in multiple sclerosis.

Fri, 01/26/2018 - 12:41

Clinical applications of ultra-high field magnetic resonance imaging in multiple sclerosis.

Expert Rev Neurother. 2018 Jan 25;:

Authors: Inglese M, Fleysher L, Oesingmann N, Petracca M

Abstract
INTRODUCTION: Magnetic resonance imaging (MRI) is of paramount importance for the early diagnosis of multiple sclerosis (MS) and MRI findings are part of the MS diagnostic criteria. There is a growing interest in the use of ultra-high-field strength -7 Tesla- (7T) MRI to investigate, in vivo, the pathological substrate of the disease. Areas covered: An overview of 7T MRI applications in MS focusing on increased sensitivity for lesion detection, specificity of the central vein sign and better understanding of MS pathophysiology and discuss the implications for disease diagnosis, monitoring and treatment planning. Expert commentary: 7T MRI provides increased signal-to-noise and contrast-to-noise-ratio that allow higher spatial resolution and better detection of anatomical and pathological features. The high spatial resolution reachable at 7T has been a game changer for neuroimaging applications not only in multiple sclerosis but also in epilepsy, brain tumors, dementia, and neuro-psychiatric disorders. Furthermore, the first 7T device has recently been cleared for clinical use by the food and drug administration.

PMID: 29369733 [PubMed - as supplied by publisher]

Evaluation of a Method for Long-Term Cryopreservation of Fungal Strains.

Fri, 01/26/2018 - 12:41

Evaluation of a Method for Long-Term Cryopreservation of Fungal Strains.

Biopreserv Biobank. 2018 Jan 25;:

Authors: García-Martínez J, López Lacomba D, Castaño Pascual A

Abstract
The conservation of microorganisms is essential for their in-depth study. However, today's most widely used conservation methods, based on the use of distilled water, soil, oils, or silica, do not guarantee the stability of fungal cells, especially dermatophytes. This problem led us to evaluate the conservation capacity of a cryogenic vials system containing glass beads covered in a cryopreservant hypertonic solution as an alternative method of storage of fungal cells at -80°C. Up to 570 strains of fungi belonging to 27 different species, isolated from clinical samples, were inoculated into cryotubes containing 25 glass beads covered in a cryopreserving hypertonic solution. Suspensions were mixed vigorously and the cryopreserving solution was discarded. The tubes were frozen at -80°C for a period of 42 months and periodically, a glass bead was removed from each cryotube and inoculated onto Sabouraud dextrose agar, and incubated at 30°C for 7-14 days to evaluate the number of colonies recovered, their purity, and phenotypic characteristics. All yeast isolates were recovered, unlike 2 isolates (4.4%) of the mold group and 21 (10.7%) of the dermatophytes. Survival rates were close to 100% for yeasts and molds, with expiration times being estimated for almost indefinite stocks, and 62% for dermatophytes, with an average expiration date of 25.5 years. The phenotypic characteristics remained comparable to those of the strains before storage. Conservation at -80°C using cryogenic vials is a reliable and efficient system for the conservation of fungal collections, and although the behavior differs by groups, stratified survival data are obtained to avoid extinction.

PMID: 29369693 [PubMed - as supplied by publisher]

Biomarkers for acute kidney injury in decompensated cirrhosis: A Prospective Study.

Fri, 01/26/2018 - 12:41

Biomarkers for acute kidney injury in decompensated cirrhosis: A Prospective Study.

Nephrology (Carlton). 2018 Jan 25;:

Authors: Jaques DA, Spahr L, Berra G, Poffet V, Lescuyer P, Gerstel E, Garin N, Martin PY, Ponte B

Abstract
BACKGROUND: Acute kidney injury (AKI) is a frequent complication in cirrhotic patients. As serum creatinine is a poor marker of renal function in this population, we aimed to study the utility of several biomarkers in this context.
METHODS: A prospective study was conducted in hospitalized patients with decompensated cirrhosis. Serum creatinine (SCr), Cystatin C (CystC), NGAL and urinary NGAL, KIM-1, protein, albumin and sodium were measured on three separate occasions. Renal resistive index (RRI) was obtained. We analyzed the value of these biomarkers to determine the presence of AKI, its etiology [prerenal, acute tubular necrosis (ATN), or hepatorenal (HRS)], its severity and a composite clinical outcome at 30 days (death, dialysis and intensive care admission).
RESULTS: We included 105 patients, of which 55 had AKI. SCr, CystC, NGAL (plasma and urinary), urinary sodium and RRI at inclusion were independently associated with the presence of AKI. SCr, CystC and plasma NGAL were able to predict the subsequent development of AKI. Pre-renal state showed lower levels of SCr, NGAL (plasma and urinary) and RRI. ATN patients had high levels of NGAL (plasma and urinary) as well as urinary protein and sodium. HRS patients presented an intermediate pattern. All biomarkers paralleled the severity of AKI. SCr, CystC and plasma NGAL predicted the development of the composite clinical outcome with the same performance as the MELD score.
CONCLUSIONS: In patients with decompensated cirrhosis, early measurement of renal biomarkers provides valuable information on AKI etiology. It could also improve AKI diagnosis and prognosis.

PMID: 29369449 [PubMed - as supplied by publisher]

PCSK9 inhibition alters the lipidome of plasma and lipoprotein fractions.

Fri, 01/26/2018 - 12:41
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PCSK9 inhibition alters the lipidome of plasma and lipoprotein fractions.

Atherosclerosis. 2018 Jan 12;269:159-165

Authors: Hilvo M, Simolin H, Metso J, Ruuth M, Öörni K, Jauhiainen M, Laaksonen R, Baruch A

Abstract
BACKGROUND AND AIMS: While inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is known to result in dramatic lowering of LDL-cholesterol (LDL-C), it is poorly understood how it affects other lipid species and their metabolism. The aim of this study was to characterize the alterations in the lipidome of plasma and lipoprotein particles after administration of PCSK9 inhibiting antibody to patients with established coronary heart disease.
METHODS: Plasma samples were obtained from patients undergoing a randomized placebo-controlled phase II trial (EQUATOR) for the safe and effective use of RG7652, a fully human monoclonal antibody inhibiting PCSK9 function. Lipoprotein fractions were isolated by sequential density ultracentrifugation, and both plasma and major lipoprotein classes (VLDL-IDL, LDL, HDL) were subjected to mass spectrometric lipidomic profiling.
RESULTS: PCSK9 inhibition significantly decreased plasma levels of several lipid classes, including sphingolipids (dihydroceramides, glucosylceramides, sphingomyelins, ceramides), cholesteryl esters and free cholesterol. Previously established ceramide ratios predicting cardiovascular mortality, or inflammation related eicosanoid lipids, were not altered. RG7652 treatment also affected the overall and relative distribution of lipids in lipoprotein classes. An overall decrease of total lipid species was observed in LDL and VLDL + IDL particles, while HDL-associated phospholipids increased. Following the treatment, LDL displayed reduced lipid cargo, whereas relative lipid proportions of the VLDL + IDL particles were mostly unchanged, and there were relatively more lipids carried in the HDL particles.
CONCLUSIONS: Administration of PCSK9 antibody significantly alters the lipid composition of plasma and lipoprotein particles. These changes further shed light on the link between anti-PCSK9 therapies and cardiovascular risk.

PMID: 29366988 [PubMed - as supplied by publisher]

ISBER Best Practice-Based Education: ISBER-Canadian Tissue Repository Network Introduction to Biobanking.

Thu, 01/25/2018 - 16:56

ISBER Best Practice-Based Education: ISBER-Canadian Tissue Repository Network Introduction to Biobanking.

Biopreserv Biobank. 2018 Jan 24;:

Authors: O'Donoghue S, Matzke L, Watson P

PMID: 29364000 [PubMed - as supplied by publisher]

Utilizing Fibrin-Alginate and Matrigel-Alginate for Mouse Follicle Development in Three-Dimensional Culture Systems.

Thu, 01/25/2018 - 16:56

Utilizing Fibrin-Alginate and Matrigel-Alginate for Mouse Follicle Development in Three-Dimensional Culture Systems.

Biopreserv Biobank. 2018 Jan 24;:

Authors: Sadr SZ, Fatehi R, Maroufizadeh S, Amorim CA, Ebrahimi B

Abstract
In vitro culture of ovarian follicles is a new technique in reproductive technology, which helps in understanding the process of folliculogenesis. The in vitro culture of follicles could be carried out using three-dimensional (3D) natural scaffolds that mimic the ovarian tissue stroma. Selection of the right matrix and culture media in these scaffolds could increase the survival and maturation of the follicles. In this work, the applicability of matrigel-alginate (MA) and fibrin-alginate (FA) 3D scaffolds for folliculogenesis was assessed. The ovaries of 13-day-old Naval Medical Research Institute (NMRI) mice were isolated and distributed into control and vitrification groups. Preantral follicles (mean diameter: 120-140 μm) were mechanically isolated from control and vitrified-warmed ovaries, encapsulated in MA or FA scaffold and cultured for 12 days. Follicle survival, growth, maturation, and quantitative expression of oocyte maturation genes (Gdf9, Bmp15, Fgf8, KitL, Kit, and Amh) and proteins (GDF9 and BMP15) were assessed. Survival rate of culture preantral follicles in control groups was found to be significantly higher than vitrified follicles. Antrum formation was similar in all groups. Follicle diameters were significantly increased in all groups during culture period. A decreasing pattern of gene expression was seen for all genes in all groups. This trend was verified through evaluation of protein expression, during which there was strong staining in antral follicles from all groups in the last day of in vitro culture. The better survival and maturation rate of follicles in the MA compared to FA scaffold indicates that the MA matrix, being rich in extracellular matrix components, could mimic the ovarian condition better and presents a good environment for follicle development.

PMID: 29363997 [PubMed - as supplied by publisher]

New Approach to Cryopreservation of Primary Noncultivated Human Umbilical Vein Endothelium in Biobanking.

Thu, 01/25/2018 - 16:56

New Approach to Cryopreservation of Primary Noncultivated Human Umbilical Vein Endothelium in Biobanking.

Biopreserv Biobank. 2018 Jan 24;:

Authors: Puzanov MV, Vasilyeva LB, Popova PV, Grineva EN, Dmitrieva RI

Abstract
It is widely accepted that endothelial dysfunction (ED) is a common feature and a risk factor for cardiovascular diseases and metabolic disorders. Cultures of human umbilical vein endothelial cells (HUVECs) are routinely used in cell-based models to study in vitro molecular and cellular mechanisms of development of different aspects of ED. The methods of the HUVEC extraction and expansion are well developed and standardized. However, when large collections of samples are needed for certain projects, or when samples from a rare population of patients should be collected for future experimental use, HUVEC samples should be transferred to a biobank to be saved in liquid nitrogen for a long period of time until the required collection is completed. This scenario is not always convenient since it requires a lot of effort, a large quantity of expensive culture reagents with limited expiration periods, and sometimes special facilities and well-trained cell biologists among the biobank staff. In this project, we evaluated a method of HUVEC cryopreservation, where the stage of cell culturing and expansion before the transfer of samples to the biobank is eliminated. A total of 55 samples of umbilical cord (UC) were obtained from women immediately after delivery. A primary endothelium pellet derived from 17 UC samples was isolated, frozen, and placed in long-term storage in a liquid nitrogen freezer. Other samples were used to obtain HUVEC cultures. We have demonstrated that cryopreservation of primary endothelium pellets from UC veins without culturing and expansion steps does not affect the physiological features of HUVECs. This new approach would improve the efficiency of biobanking logistics, especially in the case of banking of large collections of endothelial samples.

PMID: 29363992 [PubMed - as supplied by publisher]

Socioeconomic status and diagnosis, treatment, and mortality in men with prostate cancer. Nationwide population-based study.

Thu, 01/25/2018 - 16:56
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Socioeconomic status and diagnosis, treatment, and mortality in men with prostate cancer. Nationwide population-based study.

Int J Cancer. 2018 Jan 24;:

Authors: Tomic K, Ventimiglia E, Robinson D, Häggström C, Lambe M, Stattin P

Abstract
Patients with high socioeconomic status (SES) have better cancer outcomes than patients with low SES. This has also been shown in Sweden, a country with tax-financed health care aiming to provide care on equal terms to all residents. The association between income and educational level and diagnostics and treatment as outlined in national guidelines as well as prostate cancer (Pca) and all-cause mortality was assessed in 74,643 men by use of data in the National Prostate Cancer Register of Sweden and a number of other health care registers and demographic databases. In multivariable logistic regression analysis, men with high income had higher probability of Pca detected in a health-check-up, top vs. bottom income quartile, odds ratio (OR) 1.60 (95% CI 1.45-1.77) and lower probability of waiting more than 3 months for prostatectomy, OR 0.77 (0.69-0.86). Men with the highest incomes also had higher probability of curative treatment for intermediate and high-risk cancer, OR 1.77 (1.61-1.95) and lower risk of positive margins, (incomplete resection) at prostatectomy, OR 0.80 (0.71-0.90). Similar, but weaker associations were observed for educational level. At six years of follow-up, Pca mortality was modestly lower for men with high income, which was statistically significant for localized high-risk and metastatic Pca in men with no comorbidities. All-cause mortality was less than half in top vs. bottom quartile of income (12% vs. 30%, p<0.001) among men above age 65. Our findings underscore the importance of adherence to guidelines to ensure optimal and equal care for all patients diagnosed with cancer. This article is protected by copyright. All rights reserved.

PMID: 29363113 [PubMed - as supplied by publisher]

Quality-Assured Biobanking: The Leiden University Medical Center Model.

Thu, 01/25/2018 - 16:56
Related Articles

Quality-Assured Biobanking: The Leiden University Medical Center Model.

Methods Mol Biol. 2018;1730:361-370

Authors: Haumann R, Verspaget HW

Abstract
Prospective or "de novo" biobanking is becoming increasingly popular. Biobanks are installed to provide large collections of biological materials for future medical research. Quality assurance of biobank samples is an important aspect of biobanking. Therefore, it is vital that all samples are collected and processed in a similar manner according to standardized procedures to ensure high-quality samples and reduce variability in the analytical process. We describe the processes of the centralized biobanking facility at the Leiden University Medical Center (LUMC).

PMID: 29363088 [PubMed - in process]

Detection of PD-L1 in circulating tumor cells and white blood cells from patients with advanced non-small-cell lung cancer.

Wed, 01/24/2018 - 12:21

Detection of PD-L1 in circulating tumor cells and white blood cells from patients with advanced non-small-cell lung cancer.

Ann Oncol. 2018 Jan 01;29(1):193-199

Authors: Ilié M, Szafer-Glusman E, Hofman V, Chamorey E, Lalvée S, Selva E, Leroy S, Marquette CH, Kowanetz M, Hedge P, Punnoose E, Hofman P

Abstract
Background: Expression of PD-L1 in tumor cells and tumor-infiltrating immune cells has been associated with improved efficacy to anti-PD-1/PD-L1 inhibitors in patients with advanced-stage non-small-cell lung cancer (NSCLC) and emerged as a potential biomarker for the selection of patients to cancer immunotherapies. We investigated the utility of circulating tumor cells (CTCs) and circulating white blood cells (WBCs) as a noninvasive method to evaluate PD-L1 status in advanced NSCLC patients.
Patients and methods: CTCs and circulating WBCs were enriched from peripheral blood samples (ISET® platform; Rarecells) from 106 NSCLC patients. PD-L1 expression on ISET filters and matched-tumor tissue was evaluated by automated immunostaining (SP142 antibody; Ventana), and quantified in tumor cells and WBCs.
Results: CTCs were detected in 80 (75%) patients, with levels ranging from 2 to 256 CTCs/4 ml, and median of 60 CTCs/4 ml. Among 71 evaluable samples with matched-tissue and CTCs, 6 patients (8%) showed ≥1 PD-L1-positive CTCs and 11 patients (15%) showed ≥1% PD-L1-positive tumor cells in tumor tissue with 93% concordance between tissue and CTCs (sensitivity = 55%; specificity = 100%). From 74 samples with matched-tissue and circulating WBCs, 40 patients (54%) showed ≥1% PD-L1-positive immune infiltrates in tumor tissue and 39 patients (53%) showed ≥1% PD-L1 positive in circulating WBCs, with 80% concordance between blood and tissue (sensitivity = 82%; specificity = 79%). We found a trend for worse survival in patients receiving first-line cisplatin-based chemotherapy treatments, whose tumors express PD-L1 in CTCs or immune cells (progression-free and overall survival), similar to the effects of PD-L1 expression in matched-patient tumors.
Conclusions: These results demonstrated that PD-L1 status in CTCs and circulating WBCs correlate with PD-L1 status in tumor tissue, revealing the potential of CTCs assessment as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with advanced-stage NSCLC.

PMID: 29361135 [PubMed - in process]

Economic Conditions May Contribute to Increased Violence toward Children: A Nationwide Population-Based Analysis of Pediatric Injuries in Taiwanese Emergency Departments.

Wed, 01/24/2018 - 12:21

Economic Conditions May Contribute to Increased Violence toward Children: A Nationwide Population-Based Analysis of Pediatric Injuries in Taiwanese Emergency Departments.

Int J Environ Res Public Health. 2018 Jan 23;15(2):

Authors: Liu YP, Hsu RJ, Wu MH, Peng CC, Chang ST, Lei WT, Yeh TL, Liu JM, Lin CY

Abstract
Childhood injuries are unfortunately common. Analysis procedures may assist professionals who work with children with developing preventive measures for protecting children's wellness. This study explores the causes of pediatric injuries presenting to an emergency department in Taiwan. This nationwide, population-based study was conducted using data from the National Health Insurance Research Database of Taiwan (NHIRD). Patients aged <18 years were identified from approximately one million individuals listed in the NHIRD. We followed up with these patients for nine years and analyzed the causes of injuries requiring presentation to an emergency department. Variables of interest were age, sex, injury mechanisms, and temporal trends. A total of 274,028 children were identified in our study. Between 2001 and 2009, the leading causes of pediatric injuries treated in emergency departments were motor vehicle injuries, falls, and homicide. The overall incidence of injuries declined over the course of the study because of reductions in motor vehicle accidents and falls. The incidence of homicide increased during the study period, particularly between 2007 and 2009. A moderately inverse correlation between homicide rate and economic growth was observed (correlation coefficient: -0.613, p = 0.041). There was a general decline in pediatric injuries between 2001 and 2009. Public policy changes, including motorcycle helmet laws and increases in alcohol taxes, may have contributed to this decline. Unfortunately, the incidence of homicide increased over the course of the study. Ongoing financial crises may have contributed to this increase. Multidisciplinary efforts are required to reduce homicide and reinforce the importance of measures that protect children against violence.

PMID: 29360765 [PubMed - in process]