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Δευτέρα 23 Απριλίου 2018

Clotrimazole is effective for the regression of endometriotic implants in a Wistar rat experimental model of endometriosis

Publication date: Available online 22 April 2018
Source:Molecular and Cellular Endocrinology
Author(s): Daniel Escorsim Machado, Jamila Alessandra Perini, Erika Menezes de Mendonça, Jessica Ristow Branco, Karina Cristina Rodrigues-Baptista, Jessica Alessandra-Perini, Jair Machado Espíndola-Neto, Thiago Alves dos Santos, Wagner Santos Coelho, Luiz Eurico Nasciutti, Mauro Sola-Penna, Patricia Zancan
The present work aimed to evaluate molecular, angiogenic and inflammatory changes induced by clotrimazole (CTZ) on endometriosis lesions. For this, thirty female Wistar rats with surgically implanted autologous endometrium were treated with CTZ or vehicle (200 mg/kg) via esophageal gavage for 15 consecutive days. CTZ treatment significantly decreased the growth and the size of the implants, and histological examination indicated regression and atrophy, with no toxicity to the animals. The levels of the angiogenic markers VEGF and VEGFR-2 were significantly decreased in CTZ group. The treatment also promotes a reduction on PGE2 and TNF-α levels. All these effects involve the amelioration of ERK1/2, Akt, AMPK and PERK signaling upon CTZ treatment. In conclusion, CTZ promoted an overall amelioration of endometriosis in a rat model due to the anti-angiogenic properties of the drug. Therefore, our results support the proposal of a clinical trial using CTZ for the treatment of endometriosis.

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Radiolabeled polyoxometalate clusters: Kidney dysfunction evaluation and tumor diagnosis by positron emission tomography imaging

Publication date: July 2018
Source:Biomaterials, Volume 171
Author(s): Dalong Ni, Dawei Jiang, Hyung-Jun Im, Hector F. Valdovinos, Bo Yu, Shreya Goel, Todd E. Barnhart, Peng Huang, Weibo Cai
Radiolabeled nanoprobes for positron emission tomography (PET) imaging has received special attention over the past decade, allowing for sensitive, non-invasive, and quantitative detection of different diseases. The rapidly renal clearable nanomaterials normally suffer from a low accumulation in the tumor through the enhanced permeability and retention (EPR) effect due to the rapidly reduced concentration in the blood circulation after renal clearance. It is highly important to design radiolabeled nanomaterials which can meet the balance between the rapid renal clearance and strong EPR effect within a suitable timescale. Herein, renal clearable polyoxometalate (POM) clusters of ultra-small size (∼1 nm in diameter) were readily radiolabeled with the oxophilic 89Zr to obtain 89Zr-POM clusters, which may allow for efficient staging of kidney dysfunction in a murine model of unilateral ureteral obstruction (UUO). Furthermore, the as-synthesized clusters can accumulate in the tumor through EPR effect and self-assemble into larger nanostructures in the acidic tumor microenvironment for enhanced tumor accumulation, offering an excellent balance between renal clearance and EPR effect.

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Non-invasive through-skull brain vascular imaging and small tumor diagnosis based on NIR-II emissive lanthanide nanoprobes beyond 1500 nm

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Publication date: July 2018
Source:Biomaterials, Volume 171
Author(s): Zhenluan Xue, Songjun Zeng, Jianhua Hao
Optical bioimaging by using the new short-wavelength infrared window (SWIR, also named as NIR-II, 1000–1700 nm) is emerged as a next generation imaging technique for disease diagnosis owing to the unprecedented improvements in imaging sensitivity and spatial resolution. However, it is challenging to search new imaging agents with highly biocompatible and bright narrow-band emission located in the 1500–1700 nm (referred as NIR-IIb) region. Here we developed high quality polyacrylic acid (PAA) modified NaYF4:Gd/Yb/Er nanorods (PAA-NRs) with remarkably enhanced NIR-IIb emission and decent bio-compatibility for in vivo cerebral vascular bioimaging and small tumor visualization. These PAA-NRs present efficient narrow-band NIR-IIb emission centered at 1520 with 182 nm of band-width. Owing to the highly efficient NIR-IIb emission, NIR-IIb imaging-guided small tumor (4 mm in diameter) detection is achieved. More importantly, non-invasive optical brain vessel bioimaging with high spatial (∼43.65 μm) and temporal resolution through scalp and skull is obtained without craniotomy. These findings open up the opportunity of designing non-invasive approach for visualization the brain vasculature and tumor in biomedical application.



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Optimized phospholipid-based nanoparticles for inner ear drug delivery and therapy

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Publication date: July 2018
Source:Biomaterials, Volume 171
Author(s): Keum-Jin Yang, Jihwan Son, So Young Jung, Gawon Yi, Jihye Yoo, Dong-Kee Kim, Heebeom Koo
To develop efficient carriers for inner ear drug delivery, we prepared four kinds of phospholipid-based nanoparticles: neutral, anionic, cationic, and cationic-PEG (polyethyleneglycol) particles. PEG was used to maintain long-term particle circulation in the perilymph, avoiding non-specific binding of particles to proteins. All four nanoparticles were about 200 nm in diameter, and their zeta potentials were −4.32, −26.0, +25.8, and −0.28, respectively, for neutral, anionic, cationic, and cationic-PEG nanoparticles. To test particle efficacy in vitro, we used an artificial mucosa 100 μm in thickness to model the round window membrane (RWM) and HEI-OC1 cells, which were treated with particles containing Nile Red dye. Based on the levels of particle penetration and cellular uptake in this model system, we selected an optimal particle for further study. We also observed the movement of particles in ex vivo organotypic cultures of the organ of Corti. In mice, we analyzed the biodistribution of dexamethasone (Dex) in the inner ear after intratympanic injection of Dex-loaded nanoparticles. Then, we tested the therapeutic utility of the Dex-loaded nanoparticles in a mouse model of ototoxicity. In the auditory brainstem response (ABR) test, particle provided improved hearing loss recovery at all tested frequencies, more so than did the Dex sodium phosphate (Dex-SP) solution in current clinical use. Furthermore, quantitative PCR showed that nanoparticles reduced the levels of pro-inflammatory cytokines, exhibiting anti-inflammatory effects superior to those of Dex-SP. Thus, the surface properties of nanoparticles play pivotal roles in particle penetration and distribution after intratympanic injection. Our in vitro screening system using an artificial mucosa will also be valuable in the development of carriers for inner ear drug delivery.



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Editorial Board

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Publication date: July 2018
Source:Biomaterials, Volume 170





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Multiple roles of the splicing complex SF3B in DNA end resection and homologous recombination

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Publication date: Available online 22 April 2018
Source:DNA Repair
Author(s): Rosario Prados-Carvajal, Ana López-Saavedra, Cristina Cepeda-García, Sonia Jimeno, Pablo Huertas
The appropriate repair of DNA double strand breaks is critical for genome maintenance. Thus, several cellular pathways collaborate to orchestrate a coordinated response. These include the repair of the breaks, which could be achieved by different mechanisms. A key protein involved in the regulation of the repair of broken chromosomes is CtIP. Here, we have found new partners of CtIP involved in the regulation of DNA break repair through affecting DNA end resection. We focus on the splicing complex SF3 B and show that its depletion impairs DNA end resection and hampers homologous recombination. Functionally, SF3 B controls CtIP function at, as least, two levels: by affecting CtIP mRNA levels and controlling CtIP recruitment to DNA breaks, in a way that requires ATM-mediated phosphorylation of SF3B2 at serine 289. Indeed, overexpression of CtIP rescues the resection defect caused by SF3 B downregulation. Strikingly, other SF3 B depletion phenotypes, such as impaired homologous recombination or cellular sensitivity to DNA damaging agents, are independent of CtIP levels, suggesting a more general role of SF3 B in controlling the response to chromosome breaks.



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Scholar : Studies in Theatre and Performance, Volume 38, Issue 2, June 2018 is now available online on Taylor & Francis Online

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Studies in Theatre and Performance, Volume 38, Issue 2, June 2018 is now available online on Taylor & Francis Online.

Real Animals on the Stage

This new issue contains the following articles:

Articles

Introduction: real animals on the stage
Teresa Grant, Ignacio Ramos Gay & Claudia Alonso Recarte
Pages: 103-112 | DOI: 10.1080/14682761.2018.1451941


'A pleasant tragicomedy, the cat being scap't'?: William Sampson's The Vow Breaker (1636) and the instability of genre
Teresa Grant
Pages: 113-129 | DOI: 10.1080/14682761.2018.1451947


'Des singes, c'était le narcisse': class, imitation and performing monkeys in late-eighteenth century Paris
Ignacio Ramos-Gay
Pages: 130-148 | DOI: 10.1080/14682761.2018.1451946


Replacing injured horses, cross-dressing and dust: modernist circus technologies in Asia
Peta Tait
Pages: 149-164 | DOI: 10.1080/14682761.2018.1451945


There is a whale in the room: Pina Bausch's animals on stage
Jennifer Parker-Starbuck
Pages: 165-175 | DOI: 10.1080/14682761.2018.1451944


Animals in socially engaged performance practice: becomings on the edges of extinction
Lourdes Orozco
Pages: 176-189 | DOI: 10.1080/14682761.2018.1451948


'When the animal cannot keep up a good appearance it had better go out of the room': vivisection and theatricality in the nineteenth and early twentieth centuries
Claudia Alonso Recarte
Pages: 190-205 | DOI: 10.1080/14682761.2018.1451943


Book Reviews

The theatre of Marie Jones: telling stories from the ground up
Patrick Lonergan
Pages: 206-207 | DOI: 10.1080/14682761.2016.1254414


African theatre 14: contemporary women
Katie Beswick
Pages: 207-208 | DOI: 10.1080/14682761.2016.1256111


Listening for theatrical form in early modern England
Simon Smith
Pages: 209-210 | DOI: 10.1080/14682761.2016.1256112


On repetition: writing, performance & art
Nathan Hedman
Pages: 210-212 | DOI: 10.1080/14682761.2016.1257686


Music direction for the stage: a view from the podium
Matthew Lockitt
Pages: 212-213 | DOI: 10.1080/14682761.2016.1259822


The Senecan aesthetic: a performance history
Joseph Andrew Smith
Pages: 214-215 | DOI: 10.1080/14682761.2016.1262601


Tennessee Williams
Verna A. Foster
Pages: 215-217 | DOI: 10.1080/14682761.2016.1265831


Vaclav Havel
Dennis Barnett
Pages: 217-218 | DOI: 10.1080/14682761.2017.1278909


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Scholar : These new articles for Aphasiology are available online

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New for Aphasiology and online now on Taylor & Francis Online:

Original Articles

An investigation of hospitality industry students' awareness and knowledge of aphasia
Nicole Guinan & Clare Carroll
Pages: 1-15 | DOI: 10.1080/02687038.2018.1466105


2018 Future Directions Forum
JOIN US at the 2018 Future Directions Forum for Journal of Clinical Child & Adolescent Psychology - June 15-16, 2018

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Elevation of isoprostanes in polycystic ovary syndrome and its relationship with cardiovascular risk factors

Abstract

Purpose

To evaluate the plasma level of 8-isoprostanes in women with polycystic ovary syndrome. To also investigate whether there is a relationship between 8-isoprostanes and several cardiovascular risk factors.

Methods

A total of 125 women with polycystic ovary syndrome and 169 healthy women were enrolled in this case–control study. 8-Isoprostanes and different parameters were measured in all subjects. Patients were evaluated for the presence of polycystic ovary syndrome according to the Rotterdam Consensus Conference criteria.

Results

8-Isoprostanes levels were significantly higher in patients with polycystic ovary syndrome (138.4 ± 104.1 pg/mL) compared with control group (68.6 ± 34.3 pg/mL) (p < 0.001). The mean of triglycerides, lipid accumulation product, C-reactive protein, homocysteine, insulin, and homeostatic model assessment for insulin resistance were significantly higher in polycystic ovary syndrome patients with high 8-isoprostanes than those with normal 8-isoprostanes (p < 0.05). The Pearson correlation analyses showed that 8-isoprostanes levels in polycystic ovary syndrome group had a positive correlation with waist circumference, triglycerides, low-density lipoprotein cholesterol, apolipoprotein B, homocysteine, insulin, homeostatic model assessment for insulin resistance.

Conclusions

Patients with polycystic ovary syndrome have higher 8-isoprostanes levels and it is associated with several cardiovascular risk factors.



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Periodontal Host Response in Subjects with Obesity

Abstract

Purpose of Review

This review focuses on recent advances in understanding the periodontal host response in obese subjects.

Recent Findings

Increased pro-inflammatory adipokines such as leptin, progranulin, resistin, and visfatin and decreased anti-inflammatory adipokines such as adiponectin, exacerbated inflammatory response, alveolar bone resorption, and inhibition of tissue regeneration have been observed in the periodontal tissue in obese subjects. Elevated oxidative stress also affects progression of periodontitis. Obesity may affect the expression of microRNAs related to inflammatory and metabolic mRNA targets in periodontal tissue.

Summary

Although obesity may promote the progression of periodontitis in multiple manners, additional studies are needed to clarify the periodontal host response in obesity.



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Scholar : New articles have been published for Journal of Natural History, Volume 52, Issue 19-20

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The following articles have been newly published in the issue Journal of Natural History, Volume 52, Issue 19-20 on Taylor & Francis Online:

Original Articles
A new genus and species in the ostracod family Candonidae (Crustacea: Ostracoda) from Texas, USA
Okan Külköylüoğlu
Pages: 1295-1310 | DOI: 10.1080/00222933.2018.1456574

The issue is in progress. To view all articles already published in this issue, please visit:
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Identification and validation nucleolin as a target of curcumol in nasopharyngeal carcinoma cells

Publication date: Available online 22 April 2018
Source:Journal of Proteomics
Author(s): Juan Wang, Jiacai Wu, Xumei Li, Haowei Liu, Jianli Qin, Zhun Bai, Bixia Chi, Chen Xu
Identification of the specific protein target(s) of a drug is a critical step in unraveling its mechanisms of action (MOA) in many natural products. Curcumol, isolated from well known Chinese medicinal plant Curcuma zedoary, has been shown to possess multiple biological activities. It can inhibit nasopharyngeal carcinoma (NPC) proliferation and induce apoptosis, but its target protein(s) in NPC cells remains unclear. In this study, we employed a mass spectrometry-based chemical proteomics approach reveal the possible protein targets of curcumol in NPC cells. Cellular thermal shift assay (CETSA), molecular docking and cell-based assay was used to validate the binding interactions. Chemical proteomics capturing uncovered that NCL is a target of curcumol in NPC cells, Molecular docking showed that curcumol bound to NCL with an −7.8 kcal/mol binding free energy. Cell function analysis found that curcumol's treatment leads to a degradation of NCL in NPC cells, and it showed slight effects on NP69 cells. In conclusion, our results providing evidences that NCL is a target protein of curcumol. We revealed that the anti-cancer effects of curcumol in NPC cells are mediated, at least in part, by NCL inhibition.SignificanceMany natural products showed high bioactivity, while their mechanisms of action (MOA) are very poor or completely missed. Understanding the MOA of natural drugs can thoroughly exploit their therapeutic potential and minimize their adverse side effects. Identification of the specific protein target(s) of a drug is a critical step in unraveling its MOA. Compound-centric chemical proteomics is a classic chemical proteomics approach which integrates chemical synthesis with cell biology and mass spectrometry (MS) to identify protein targets of natural products determine the drug mechanism of action, describe its toxicity, and figure out the possible cause of off-target. It is an affinity-based chemical proteomics method to identify small molecule-protein interactions through affinity chromatography approach coupled with mass spectrometry, has been conventionally used to identify target proteins and has yielded good results. Curcumol, has shown effective inhibition on Nasopharyngeal Carcinoma (NPC) Cells, interacted with NCL and then initiated the anti-tumor biological effect. This research demonstrated the effectiveness of chemical proteomics approaches in natural drugs molecular target identification, revealing and understanding of the novel mechanism of actions of curcumol is crucial for cancer prevention and treatment in nasopharynx cancer.

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A comprehensive profile and inter-individual variations analysis of the human normal amniotic fluid proteome

Publication date: Available online 22 April 2018
Source:Journal of Proteomics
Author(s): Xiang Liu, Yijun Song, Zhengguang Guo, Wei Sun, Juntao Liu
Amniotic fluid contains large amounts of proteins produced by amnion epithelial cells, fetal tissues, fetal excretions and placental tissues; thus, it is an important potential source of biomarkers for identifying fetal pathologies. In this study, a pooled AF sample from 7 healthy volunteers was used to provide a comprehensive profile of normal human AF proteome using immunoaffinity depletion of 14 high-abundance proteins. Each individual AF sample was used to analyze inter-individual variations with iTRAQ method. As a result, a total of 2881 non-redundant proteins were identified, and 1624 proteins were quantified based on the peak intensity-based semi-quantification (iBAQ) method. Gene Ontology (GO) analysis showed that the AF proteome was enriched in extracellular region and extracellular matrix. Further function annotation showed that the top canonical pathway was axonal guidance signaling. The inter-individual variation analysis of 7 individual AF samples showed that the median inter-individual CV (Coefficient of variation) was 0.22. iBAQ quantification analysis revealed that the inter-individual variations were not correlated with protein abundance. GO analysis indicated that intracellular proteins tended to have higher CVs, and extracellular proteins tended to have lower CVs. These data will contribute to a better understanding of amniotic fluid proteomic analysis and biomarker discovery.SignificanceAmniotic fluid is an important potential source of biomarkers for identifying fetal pathologies. This study provided a large database for the normal human amniotic fluid proteome and analysis of inter-individual variations in amniotic fluid proteomes, which will offer a baseline reference for further AF proteomic analysis and pregnancy-related disease biomarker discovery.



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Targeted data-independent acquisition for mass spectrometric detection of RAS mutations in formalin-fixed, paraffin-embedded tumor biopsies

Publication date: Available online 22 April 2018
Source:Journal of Proteomics
Author(s): Yeoun Jin Kim, Andrew G. Chambers, Fabiola Cecchi, Todd Hembrough
Genomic testing for KRAS and NRAS mutations in clinical biopsies of various cancers is routinely performed to predict futility of anti-epidermal growth factor receptor (anti-EGFR) therapies. We hypothesized that RAS mutations could be detected and quantified at the protein level for diagnostic purposes using data-independent acquisition (DIA)-based mass spectrometry in formalin-fixed, paraffin-embedded (FFPE) tumor samples. We developed a targeted DIA assay that surveys the specific mass range of all possible peptides harboring activating mutations in KRAS exon 2. When the assay was applied to tumor samples with known KRAS or NRAS mutations (G12A, G12D, G12V, and G13D), RAS-mutant and wild-type peptides were successfully detected in 11 of 13 biopsy samples. Mutation statuses obtained by DIA were concordant with those obtained by DNA sequencing, and yields of mutant peptide (mutant peptide/[mutant + wild-type peptides]) exhibited linear correlation with yields of RAS-mutant mRNA. When applied to biopsy samples with failed DNA testing results, the DIA assay identified additional RAS-mutated sample.SignificanceProteomic detection of RAS mutations by DIA in tumor biopsies can provide solid evidence of mutant RAS protein regardless of the mutation types and sites in exon 2. This robust method could rescue samples that fail genomic testing due to insufficient tumor tissue or lack of sequenceable DNA. It can be used to explore the relationship between protein expression level of mutant RAS and therapeutic outcome.



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Histology-guided proteomic analysis to investigate the molecular profiles of clear cell Renal Cell Carcinoma grades

Publication date: Available online 23 April 2018
Source:Journal of Proteomics
Author(s): Martina Stella, Clizia Chinello, Anna Cazzaniga, Andrew Smith, Manuel Galli, Isabella Piga, Angelica Grasso, Marco Grasso, Marina Del Puppo, Marta Varallo, Giorgio Bovo, Fulvio Magni
Renal Cell Carcinoma (RCC) is the most frequent form of kidney cancer and approximately 80% of cases are defined as clear cell RCC (ccRCC). Among the histopathological factors, tumour grade represents one of the most important parameters to evaluate ccRCC progression. Nonetheless, the molecular processes associated with the grading classification haven't been deeply investigated thus far. Therefore, the aim of this study was to uncover protein alterations associated with different ccRCC grade lesions. Formalin-fixed paraffin-embedded samples from ccRCC patients were analysed by histology-guided MALDI-MSI and shotgun proteomics in order to study the biological processes implicated in ccRCC. MALDI-MSI data highlighted signals able to discriminate among different grades (AUC > 0.8). The ion at m/z 1428.92 was identified as Vimentin and was overexpressed in grade 4 lesions, whereas ions at m/z 944.71, m/z 1032.78 and m/z 1325,99 were identified as histones H2A, H3, and H4, respectively. nLC-ESI-MS/MS analysis provided a further list of proteins and their abundances, showing a difference in protein content among the four grades. Moreover, the obtained molecular profiles showed a correspondence with the different Cancer-Specific Survival rate at 10 years post-surgery, as reported in literature.SignificanceDespite the generally accepted role of tumour grade in ccRCC diagnosis, the proteomic processes associated with the different tumour grades has not been extensively studied and doing so may provide insights into the development of the disease. In the current study, data obtained using MALDI-MSI was integrated with that obtained using nLC-ESI-MS/MS to highlight the proteomic alterations underlying the different ccRCC grades. The combined approach identified vimentin and three histones (H2A, H3 and H4) that were able to discriminate among the four grades whilst the nLC-ESI-MS/MS analysis alone provided a further list of proteins with an altered abundance. Furthermore, there was a good correlation between the molecular profiles generated for each grade and the different Cancer-Specific Survival rate at 10 years post-surgery. Such findings could be a valuable starting point for further studies aimed at clarifying the molecular events that occur during the development of ccRCC.

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Proteomics of liquid biopsies: Depicting RCC infiltration into the renal vein by MS analysis of urine and plasma

Publication date: Available online 22 April 2018
Source:Journal of Proteomics
Author(s): Clizia Chinello, Martina Stella, Isabella Piga, Andrew James Smith, Giorgio Bovo, Marta Varallo, Mariia Ivanova, Vanna Denti, Marco Grasso, Angelica Grasso, Marina Del Puppo, Apostolos Zaravinos, Fulvio Magni
Liquid biopsies, as blood and urine, could offer an invaluable, easily accessible source of biomarkers, and evidences for elucidating the pathological processes. Only few studies integrated the proteomes driven by more than one biofluid. Furthermore, it is not clear which biofluid better mirrors the alterations triggered by disease. Venous infiltrating RCC(Renal Cell Carcinoma) could represent an advantageous model for exploring this aspect. Herein, we investigate how blood and urine "proteomically" reflect the changes occurring during RCC infiltration into renal vein(RV) by label-free nLC-ESI-MS/MS. We found 574 and 58 differentially expressed proteins(DEPs) in response to vascular involvement. To the augment of vascular involvement, the abundance of only three proteins in urine(UROM,RALA,CNDP1) and two in plasma(APOA1,K2C1) diminished while increased for twenty-six urinary proteins. 80 proteins were found both in urine and plasma, among which twenty-eight were DEPs. A huge overlap between the two biofluids was highlighted, as expected, being urine the filtrate of blood. However, this consistency decreases when RV-occlusion occurs suggesting alternative protein releases, and a loss of kidney architecture. Moreover, several proteomic and functional signatures were biofluid-specific. In conclusion, the complementarity between the specimens allowed to achieve a deeper level of molecular complexity of the RCC venous infiltration.SignificanceAlthough plasma and urine are strongly interconnected, only few proteomic studies investigated the complementarity of these fluids as bio-sources of information. Moreover, none of them was focused to their analysis and comparison in the context of vascular infiltration of renal cancer. Herein, new insights were gained regarding the impact into urinary and plasma proteome of the changes triggered by the ccRCC invasion into vascular system and renal vein. Furthermore, the integration of the information driven by the two liquid biopsies permits to unravel biological processes otherwise lost.

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The identification of discontinuous epitope in the human cystatin C – Monoclonal antibody HCC3 complex

Publication date: Available online 22 April 2018
Source:Journal of Proteomics
Author(s): M. Rafalik, M. Spodzieja, A.S. Kołodziejczyk, S. Rodziewicz-Motowidło, A. Szymańska, A. Grubb, P. Czaplewska
Human cystatin C (hCC) is a cysteine proteinase inhibitor involved in pathophysiological processes of dimerization and amyloid formation. These processes are directly associated with a number of neurodegenerative disorders such as Alzheimer disease or hereditary cystatin C amyloid angiopathy (HCCAA). One of the ideas on how to prevent amyloid formation is to use immunotherapy. HCC3 is one of a group of antibodies binding to hCC and reducing the in vitro formation of cystatin C dimers. Therefore, identification of the binding sites in the hCC-HCC3 complex may facilitate a search of effective drugs against HCCAA as well as understanding the mechanisms of neurodegenerative disorders.In this work we present epitope identification of the hCC-HCC3 complex using methods such as affinity chromatography, epitope excision and extraction MS approach, enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry (HDX MS). Comprehensive analysis of the obtained results allowed us to identify the epitope sequence with the key fragment covering hCC L1 loop and two potential epitopic fragments – α-helical part, hCC (17–28) and β4 strand in C-terminal part of hCC. The presence of the L1 loop in the epitope sequence accounts for the significant reduction of hCC dimer formation in the presence of HCC3 antibody.Significance of the studyDeciphering the mechanism of the cystatin C aggregation process and detailed analysis of the interactions between hCC, or its pathogenic variant, and monoclonal antibodies, potentially constituting aggregation inhibitors, might be of great value as there still is a complete lack of any kind of efficient therapy for young people with the pathogenic mutation of hCC.



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Brain-related proteins as potential CSF biomarkers of Alzheimer's disease: A targeted mass spectrometry approach

Publication date: Available online 22 April 2018
Source:Journal of Proteomics
Author(s): Ilijana Begcevic, Davor Brinc, Marshall Brown, Eduardo Martinez-Morillo, Oliver Goldhardt, Timo Grimmer, Viktor Magdolen, Ihor Batruch, Eleftherios P. Diamandis
Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline. The main disease hallmarks include amyloid beta aggregates and neurofibrillary tangles. Brain pathology is reflected in cerebrospinal fluid (CSF); the core biomarkers amyloid beta 1–42, total and phosphorylated tau protein levels are changed, relative to cognitively normal elderly. Still, there is a need for additional biomarkers which could identify disease more accurately and at an earlier stage, predict severity and be used in research settings. Here we evaluated 30 brain-related proteins as candidate biomarkers of AD. Proteins were quantified in CSF samples from cognitively healthy individuals (n = 23) and patients with mild cognitive impairment (MCI) due to AD (n = 20) or dementia due to AD (n = 10) using selected reaction monitoring mass spectrometry assays. APLP1 protein was increased in MCI relative to control (p < 0.001). The best discrimination between MCI vs. controls was observed with a model combining APLP1 and SPP1 proteins (area under the curve, AUC = 0.84). The strongest associations between protein abundance and disease severity were found for APLP1, CNTN2 and SPP1 proteins, which had a significant correlation with MMSE and CDR tests (p < 0.05). This study identifies new proteins with biomarker potential at various stages of AD severity.SignificanceThe current study evaluated 30 brain-related, highly specific proteins as candidate biomarkers of AD diagnosis. Protein APLP1 showed promise as early AD biomarker; protein panel APLP1 and SPP1 had the best diagnostic potential in discriminating MCI from control group, while proteins APLP1, SPP1 and CNTN2 may be indicators of disease progression, demonstrating weak to moderate correlation with cognitive tests. This study therefore identifies new proteins with biomarker potential at early AD stage. If the performance of proposed biomarkers is further confirmed, these proteins may add value in the clinic or clinical trial settings as diagnostic biomarkers (alone or in combination with the existing biomarkers) of the prodromal AD stage, and in monitoring disease progression.

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Tildrakizumab-asmn: What’s in a Name?



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High removal performance of a magnetic FPA90-Cl anion resin for bromate and coexisting precursors: kinetics, thermodynamics, and equilibrium studies

Abstract

In this study, the FPA90-Cl resin was magnetized with supported Fe3O4 particles using a chemical co-precipitation method and its removal performance of bromate and coexisting precursors was explored. The magnetized FPA90-Cl resin was structurally characterized by SEM, FT-IR, and XRD. The effects of the initial concentrations, temperature, and resin dosage on bromate and bromide ion removal in drinking water were investigated using batch experiments. The magnetized FPA90-Cl resin exhibited a high removal efficiency for bromate and bromide ions at three initial concentrations, and the residual bromate concentrations were under the maximum contaminant level (MCL) of 10 μg L−1 after 80 min. The adsorption data of bromate and bromide ion could be well described by a pseudo-first-order kinetic model (R2 ˃ 0.98). The bromate removal alone was further studied by varying the initial solution pH, temperature, and competitive anions. The results showed that the magnetized FPA90-Cl resin could be used over a wide pH range (4.0–9.0). The maximum sorption capacity of the magnetized FPA90-Cl resin for bromate reached 132.83 mg g−1 at 298 K. The Freundlich and Redlich-Peterson isotherm models fit the bromate adsorption equilibrium better (R2 ˃ 0.99) than the Langmuir isotherm model (R2 ˃ 0.98). The thermodynamic analysis showed that the bromate adsorption process was endothermic. The negative ΔG and positive ΔS indicated that the process was spontaneous and that randomness increased after adsorption, respectively. The competition of coexisting anions with bromate was in the order of SO42− > CO32− > Cl− > NO3− > HCO3− > PO43−. Additionally, the magnetized FPA90-Cl resin could maintain a high bromate and bromide ion adsorption capacity after five cycles of regeneration by a 0.1 M NaCl solution.

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Κυριακή 22 Απριλίου 2018

mRECIST criteria to assess recurrent thyroid carcinoma treatment response after radiofrequency ablation: a prospective study

Abstract

Purpose

Surgical removal is recommended for recurrent thyroid carcinomas (RTCs) unable to uptake radioiodine and/or not responsive to chemotherapy. However, repeated neck dissection is difficult for surgeons. Thus, radiofrequency ablation (RFA) was proposed for RTCs. The aim of this prospective study is to assess RTC treatment response after RFA, according to well-established criteria.

Methods

Sixteen lesions in 13 patients were treated by RFA. All patients refused/were excluded from repeated surgery or other conventional therapy. CT and US examinations were performed before RFA to evaluate lesion volume and vascularization. All RFA procedures were performed under US-guidance by an 18-gauge, electrode. Treatment response was evaluated by CT, according to RECIST 1.1 and to mRECIST guidelines; CT examinations were performed during follow-up (6–18 months); the volume of residual vital tumour tissue and the percentage of necrotic tissue were estimated by contrast enhanced CT.

Results

RFA was well tolerated by all patients; in two cases laryngeal nerve paralysis was observed. Mean pre-treatment volume was 4.18 ± 3.53 ml. Vital tumour tissue and percentage of necrosis at 6, 12 and 18 months were 0.18 ± 0.25, 0.11 ± 0.13, 0.29 ± 0.40 ml and 91.9 ± 11.1, 90.4 ± 13.3, 80.8 ± 23.1%. According to RECIST 1.1, target lesion response was classified as complete response (CR) in one case, partial response (PR) in 11/16, stable disease in 4/16 cases. According to mRECIST, 11/16 cases were classified as CR and the remaining 5 as PR.

Conclusion

RFA is a safe procedure to treat the viable tumour tissue and to reduce the RTC volume; as to the criteria to assess treatment response, mRECIST appears to be more accurate.



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Microbial fuel cells coupling with the three-dimensional electro-Fenton technique enhances the degradation of methyl orange in the wastewater

Abstract

The emission of the source effluent of azo dyes has resulted in a serial of environmental problems including of the direct damage of the natural esthetics, the inhibition of the oxygen exchange, the shortage of the photosynthesis, and the reduction of the aquatic flora and fauna. A bioelectrochemical platform (3D-EF-MFCs) combining two-chamber microbial fuel cells and three dimensional electro-Fenton technique were delicately designed and assembled to explore the decolorization, bio-genericity performance of the methyl orange, and the possible biotic-abiotic degradation mechanisms. The 3D-EF-MFCs processes showed higher decolorization efficiencies, COD removals, and better bioelectricity performance than the pure electro-Fenton-microbial fuel cell (EF-MFC) systems. The two-chamber experiments filling with the granular activated carbons were better than the single-chamber packing system on the whole. The moderate increase of Fe2+ ions dosing in the cathode chamber accelerated the formation of •OH, which further enhanced the degradation of the methyl orange (MO). The cathode-decolorization and COD removals were decreased with the increase of MO concentration. However, the degradation performance of MO was indirectly improved in the anode compartment at the same conditions. The bed electrodes played a mediator role in the anode and cathode chambers, certainly elevated the voltage output and the power density, and lowered the internal impedance of EF-MFC process.



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Conditional deletion of Id2 or Notch1 in oligodendrocyte progenitor cells does not ameliorate disease outcome in SOD1G93A mice

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Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Caroline Eykens, Annelies Nonneman, Cathy Jensen, Antonio Iavarone, Philip Van Damme, Ludo Van Den Bosch, Wim Robberecht
Oligodendrocytes are essential for structural and trophic support of motor axons. Their impairment has been implicated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder of motor neurons. Oligodendrocyte progenitor cells fail to differentiate into mature oligodendrocytes and thereby jeopardize the health of motor neurons. Here, we report that oligodendrocytic ablation of inhibitor of DNA binding 2 (Id2) or Notch receptor 1 (Notch1), 2 negative master modulators of oligodendrocyte differentiation, fails to alleviate oligodendrocyte dysfunction or alter disease outcome in a murine model of ALS. Our data suggest that these inhibitors are not suitable targets for intervention in ALS.



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The lysosome system is severely impaired in a cellular model of neurodegeneration induced by HSV-1 and oxidative stress

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Publication date: August 2018
Source:Neurobiology of Aging, Volume 68
Author(s): Henrike Kristen, Isabel Sastre, Teresa Muñoz-Galdeano, Maria Recuero, Jesus Aldudo, Maria J. Bullido
The causal agent(s) and molecular mechanisms of Alzheimer's disease (AD) remain unclear. Mounting evidence suggests that herpes simplex virus type 1 (HSV-1) infection is involved in the AD pathogenesis. Oxidative stress (OS) may also be crucial in the AD development. Our group previously reported that both HSV-1 and OS trigger the appearance of AD-type neurodegeneration markers. The main aim of the present study was to identify the mechanisms involved in this triggering. Expression studies revealed the involvement of a set of OS-regulated genes in HSV-1-infected cells and in cells harboring the Swedish mutation of the amyloid beta precursor protein gene. Functional annotation of these genes revealed the lysosome system to be impaired, suggesting that the interaction of OS with both HSV-1 and amyloid beta precursor protein mutations affects lysosomal function. Functional studies revealed HSV-1 infection and OS to increase the lysosome load, reduce the activity of lysosomal hydrolases, affect cathepsin maturation, and inhibit the endocytosis-mediated degradation of the epidermal growth factor receptor. These findings suggest alterations in the lysosome system to be involved in different forms of AD.



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Distribution, fractions, and potential release of thallium in acidic soils nearby a waste copper mining site from southern China

Abstract

Although thallium (Tl) is a highly toxic element, little information is available on the environmental risks of Tl in agricultural soils with intensive practices, particularly nearby mining sites. Therefore, we investigated the potential release of Tl in acidic soils with intensive cultivation nearby a waste copper mining site from southern China based on its level and chemical fractions as well as simulated release under artificial acid rain. Results showed that the average Tl content was 1.31 mg/kg in the studied area, which significantly exceeds the permissible thallium value of 1 mg/kg for agricultural soil in China. Some vertical increases of soil Tl from different land uses indicate the potential transport of Tl downward to groundwater. High positive correlations between surficial soil Tl and rubidium (Rb) and copper (Cu) indicated that Tl has the lithophile and chalcophile behavior. Tl in soils is mainly entrapped in residual fraction. The exchangeable fraction of Tl in agricultural soils was less than undisturbed natural soils and copper mined soils. Additionally, the percentage of Tl release from undisturbed natural soils and soils of copper ore area was more than that from agricultural soils in simulated acid rain. Furthermore, the releases of Tl from the soils increased with the acidity of artificial acid rain. Thus, more attention must be paid to land management of this similar area to avoid the risk of Tl impact on human health.



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Influence of fishing activity over the marine debris composition close to coastal jetty

Abstract

Worldwide, the marine debris emissions have been provoking impacts in ecosystems, generating massive mortality of different species with commercial interest. In South America, we have a lack of studies to verify the marine debris composition in transitional environments such as adjacent regions of coastal jetties. These are hydraulic engineering constructions used to maintain the navigation channel access between the sea-estuarine interface and are also used by teleost fishes, crustaceans, and mollusks like artificial shelters (reefs), being excellent fishing grounds. Therefore, the present study was devoted to qualitatively evaluate the composition of marine debris in an internal jetty portion of a Laguna Estuarine System (LES) located in South America (Brazil). Six hundred freediving were conducted to collect marine debris in the study region. The in situ campaigns were performed in 2016 during all spring season (sand substrata) in four distinct zones with 26,400 m2 each one covering almost all adjacent jetty extension, to evaluate possible spatial changes in the marine debris composition. All material obtained was identified, measured, weighed, and ordered in eight groups, with six groups being related to the fishing activity and two groups related to the tourism/community in the study region. So, it was possible to observe possible relations between the marine debris distribution to artisanal and recreational local fishing. After 600 freediving sampling efforts, 2142 marine debris items were obtained, totaling close to 100 kg of solid waste removed from the inner portion of the coastal jetty. Notably, 1752 units (50 kg) of fishing leads were collected being this item the main marine debris residue found in the four sampled areas, corresponding to nearly 50% of the total weight of the collected waste. Ninety-eight percent of marine debris were derived from the local fishing activities, and just 2% were derived from tourism/community. Considering the total contribution related to fishing, 83% of the marine debris were composed by lead (sinkers) adopted by recreational and artisanal fishing. Notably, the catch activity in this region has a close influence over the marine debris composition. Reductions of marine debris emissions derived from the fishing activities have been a global challenge, once this problem is occurring in practically all marine and estuarine environments under the anthropic action. The presence of marine debris changes the local landscape and can provoke serious environmental problems, such as ghost fishing that affects a wide variability of marine mammals, birds, and fishes. Most of marine debris collected came from recreational and artisanal fishing, being the fishing leads the most prominent material, especially in sector 4. This fact is possibly related to the intense mullet fishing using cast nets, usual in this sample area. In the other sectors, there was a great predominance of grapnel fishing leads, widely adopted by recreational fishermen in open water environments. The "fingernails" present in these fishing leads ensure the sinking of the line for a specific location independently of possible flow oscillations of the tidal current and/or currents generated by winds. The massive quantity of fishing leads into the sectors is a dangerous fact. Notably, lead is a heavy, non-biodegradable, and extremely toxic metal that, due to the anthropogenic activities, has been increasing around the world. Future efforts in our study region should evaluate the seasonal marine debris composition to observe possible changes along the different seasons of the year. In this way, it would be possible to infer quantitatively the emission of marine debris derived from the fishing activity, assessing its impacts and enabling the adoption of environmental management strategies. This effort adopted a qualitative analysis, serving to show the current situation of this region that we now know to be vulnerable to the presence of marine debris derived from the fishing activity.



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Balloon-borne tropospheric CO2 observations over the equatorial eastern and western Pacific

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Publication date: July 2018
Source:Atmospheric Environment, Volume 184
Author(s): Yoichi Inai, Shuji Aoki, Hideyuki Honda, Hiroshi Furutani, Yutaka Matsumi, Mai Ouchi, Satoshi Sugawara, Fumio Hasebe, Mitsuo Uematsu, Masatomo Fujiwara
Vertical profiles of carbon dioxide (CO2) mixing ratio in the equatorial eastern and western Pacific were measured by newly developed balloon-borne CO2 sondes in February 2012 (two soundings) and February–March 2015 (four soundings), respectively. The 1–10 km vertically averaged CO2 mixing ratios lie between the background surface values in the Northern Hemisphere (NH) and those in the Southern Hemisphere (SH) monitored at ground-based sites during these periods. A backward trajectory analysis, taking account of convective mixing processes using geostationary satellite cloud-image data, is applied to the measured CO2 profiles to estimate the origin of the observed air masses. Air masses originating in the SH show low CO2 mixing ratios that are similar to the background values in the SH. This relationship is confirmed by a positive correlation (∼0.6) between the CO2 mixing ratio and the latitude of air mass origin which is found from trajectory calculations. This result suggests that the CO2 distribution in the troposphere over the equatorial Pacific is controlled by monthly time-scale, large-scale CO2 distribution and weekly time-scale atmospheric transport processes. Furthermore, this study shows that the combination of CO2 sonde measurements and trajectory analysis, taking account of convective mixing, is a useful tool in investigating CO2 transport processes.



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Meta-modeling of ADMS-Urban by dimension reduction and emulation

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Publication date: July 2018
Source:Atmospheric Environment, Volume 184
Author(s): Vivien Mallet, Anne Tilloy, David Poulet, Sylvain Girard, Fabien Brocheton
ADMS-Urban is a non-linear, static, urban air quality model, with high-dimensional outputs. A simulation of NO2 and PM10 concentrations every hour during a full year and over an entire city can take dozens of days of computations, which greatly limits the range of methods that can be applied to the model, especially for uncertainty quantification. This work presents a method to replace the complete model, ADMS-Urban, with a meta-model or surrogate model, i.e., a reasonably close approximation of ADMS-Urban whose computational cost is negligible. When the emissions are formulated as a function of the day and the hour, the complete-model inputs essentially contain a few scalar values, to describe the meteorological conditions, the background pollution and the target date. The complete-model outputs are first projected onto a reduced subspace. The relations between the projection coefficients and the low-dimensional inputs are then emulated by a fast statistical emulator, based on Kriging or radial basis functions (RBF). The mean error between the meta-model and ADMS-Urban is 22% with Kriging and 27% with RBF for NO2, and 14% with Kriging and 20% with RBF for PM10. The meta-model performs as well as ADMS-Urban when compared to the observations. Its computational cost is almost negligible to compute the concentrations at a given hour and date for an entire city: 50 ms with RBF and 150 ms with Kriging to simulate 1 h on one core, while the complete model requires 8 min on 16 cores.



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The effect of heat recovery on near-source plume dispersion of a simple cycle gas turbine

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Publication date: July 2018
Source:Atmospheric Environment, Volume 184
Author(s): Bo Yang, Jiajun Gu, K. Max Zhang
The waste heat recovery (HR) systems are employed to increase the overall thermal efficiency of electric generation units (EGUs). Although the emission factors (in terms of gram of pollutants per unit of thermal energy consumed or electric energy generated) generally decreases after installing HR systems, the emission rates in terms of grams of pollutants per unit of time remain unchanged. However, HR systems reduce stack exit temperature, resulting in lower effective emission heights, which lead to higher near-source ground level concentrations (GLCs) of air pollutants. In order to comprehensively evaluate the near-source air quality impact from deploying HR systems, we proposed a new modeling framework by integrating a computationally efficient Gaussian-based dispersion model (AERMOD) and a (relatively) more accurate computational fluid dynamics (CFD) model. As a demonstration of the proposed framework, we investigated the HR impact on NOx concentrations near a simple cycle gas turbine located in Brentwood, NY. Specifically, we applied the AERMOD modeling system to screen the hourly GLCs over five years, and highest values (and the corresponding hours) were shown to cluster into two main meteorological conditions: the stable atmospheric boundary layer with relatively high wind speed (Stable, HW) and the unstable atmospheric boundary layer with relatively low wind speed (Unstable, LW). These two conditions were further simulated using a CFD model that have been extensively evaluated previously for detailed analysis. By setting different stack exit temperatures, the near-source air quality impact of different waste heat conversion rates was evaluated. We introduced a concept called the heat recovery amplified factor (HRAF), defined as the ratio between the maximum GLC with HR system and that without HR system, as an indicator of HR impact. HRAF was shown to be much more sensitive to temperature in the Unstable, LW condition than in the Stable, HW condition. Although the results were limited to a specific simple cycle gas turbine, the proposed modeling framework and HRAF can be used for evaluating the HR systems impact for other emission sources.



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Evaluating EDGARv4.tox2 speciated mercury emissions ex-post scenarios and their impacts on modelled global and regional wet deposition patterns

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Publication date: July 2018
Source:Atmospheric Environment, Volume 184
Author(s): Marilena Muntean, Greet Janssens-Maenhout, Shaojie Song, Amanda Giang, Noelle E. Selin, Hui Zhong, Yu Zhao, Jos G.J. Olivier, Diego Guizzardi, Monica Crippa, Edwin Schaaf, Frank Dentener
Speciated mercury gridded emissions inventories together with chemical transport models and concentration measurements are essential when investigating both the effectiveness of mitigation measures and the mercury cycle in the environment. Since different mercury species have contrasting behaviour in the atmosphere, their proportion in anthropogenic emissions could determine the spatial impacts. In this study, the time series from 1970 to 2012 of the EDGARv4.tox2 global mercury emissions inventory are described; the total global mercury emission in 2010 is 1772 tonnes. Global grid-maps with geospatial distribution of mercury emissions at a 0.1° × 0.1° resolution are provided for each year. Compared to the previous tox1 version, tox2 provides updates for more recent years and improved emissions in particular for agricultural waste burning, power generation and artisanal and small-scale gold mining (ASGM) sectors. We have also developed three retrospective emissions scenarios based on different hypotheses related to the proportion of mercury species in the total mercury emissions for each activity sector; improvements in emissions speciation are seen when using information primarily from field measurements. We evaluated them using the GEOS-Chem 3-D mercury model in order to explore the influence of speciation shifts, to reactive mercury forms in particular, on regional wet deposition patterns. The reference scenario S1 (EDGARv4.tox2_S1) uses speciation factors from the Arctic Monitoring and Assessment Programme (AMAP); scenario S2 ("EPA_power") uses factors from EPA's Information Collection Request (ICR); and scenario S3 ("Asia_filedM") factors from recent scientific publications. In the reference scenario, the sum of reactive mercury emissions (Hg-P and Hg2+) accounted for 25.3% of the total global emissions; the regions/countries that have shares of reactive mercury emissions higher than 6% in total global reactive mercury are China+ (30.9%), India+ (12.5%) and the United States (9.9%). In 2010, the variations of reactive mercury emissions amongst the different scenarios are in the range of −19.3 t/yr (China+) to 4.4 t/yr (OECD_Europe). However, at the sector level, the variation could be different, e.g., for the iron and steel industry in China reaches 15.4 t/yr. Model evaluation at the global level shows a variation of approximately ±10% in wet deposition for the three emissions scenarios. An evaluation of the impact of mercury speciation within nested grid sensitivity simulations is performed for the United States and modelled wet deposition fluxes are compared with measurements. These studies show that using the S2 and S3 emissions of reactive mercury, can improve wet deposition estimates near sources.



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On the use of superparamagnetic hydroxyapatite nanoparticles as an agent for magnetic and nuclear in vivo imaging

Publication date: Available online 22 April 2018
Source:Acta Biomaterialia
Author(s): Alessio Adamiano, Michele Iafisco, Monica Sandri, Martina Basini, Paolo Arosio, Tamara Canu, Giovanni Sitia, Antonio Esposito, Vincenzo Iannotti, Giovanni Ausanio, Eirini Fragogeorgi, Maritina Rouchota, George Loudos, Alessandro Lascialfari, Anna Tampieri
The identification of alternative biocompatible magnetic NPs for advanced clinical application is becoming an important need due to raising concerns about iron accumulation in soft issues associated to the administration of superparamagnetic iron oxide nanoparticles (NPs). Here, we report on the performance of previously synthetized iron-doped hydroxyapatite (FeHA) NPs as contrast agent for magnetic resonance imaging (MRI). The MRI contrast abilities of FeHA and Endorem® (dextran coated iron oxide NPs) were assessed by 1H nuclear magnetic resonance relaxometry and their performance in healthy mice was monitored by a 7 Tesla scanner. FeHA applied a higher contrast enhancement, and had a longer endurance in the liver with respect to Endorem® at iron equality. Additionally, a proof of concept of FeHA use as scintigraphy imaging agent for positron emission tomography (PET) and single photon emission computed tomography (SPECT) was given labeling FeHA with 99mTc-MDP by a straightforward surface functionalization process. Scintigraphy/x-ray fused imaging and ex vivo studies confirmed its dominant accumulation in the liver, and secondarily in other mononuclear phagocyte system organs. FeHA efficiency as MRI-T2 and PET-SPECT imaging agent combined to its already reported intrinsic biocompatibility qualify this material as promising for innovative nanomedical applications.Statement of SignificanceThe ability of iron-doped hydroxyapatite nanoaprticles (FeHA) to work in vivo as imaging agents for magnetic resonance (MR) and nuclear imaging is demonstrated. FeHA applied an higher MR contrast in the liver, spleen and kidneys of mice with respect to Endorem®. The successful radiolabeling of FeHA allowed for scintigraphy/X-ray and ex vivo biodistribution studies, confirming MR results and envisioning FeHA application for dual-imaging

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Bioadhesives for Internal Medical Applications: A Review

Publication date: Available online 22 April 2018
Source:Acta Biomaterialia
Author(s): Wenzhen Zhu, Yon Jin Chuah, Dong-An Wang
Bioadhesives such as tissue adhesives, hemostatic agents, and tissue sealants have gained increasing popularity in different areas of clinical operations during the last three decades. Bioadhesives can be categorized into internal and external ones according to their application conditions. External bioadhesives are generally applied in topical medications such as wound closure and epidermal grafting. Internal bioadhesives are mainly used in intracorporal conditions with direct contact to internal environment including tissues, organs and body fluids, such as chronic organ leak repair and bleeding complication reduction. This review focuses on internal bioadhesives that, in contrast with external bioadhesives, emphasize much more on biocompatibility and adhesive ability to wet surfaces rather than on gluing time and intensity. The crosslinking mechanisms of present internal bioadhesives can be generally classified as follows: 1) chemical conjugation between reactive groups; 2) free radical polymerization by light or redox initiation; 3) biological or biochemical coupling with specificity; and 4) biomimetic adhesion inspired from natural phenomena. In this review, bioadhesive products of each class are summarized and discussed by comparing their designs, features, and applications as well as their prospects for future development.Statement of SignificanceDespite the emergence of numerous novel bioadhesive formulations in recent years, thus far, the classification of internal and external bioadhesives has not been well defined and universally acknowledged. Many of the formulations have been proposed for treatment of several diseases even though they are not applicable for such conditions. This is because of the lack of a systematic standard or evaluation protocol during the development of a new adhesive product. In this review, the definition of internal and external bioadhesives is given for the first time, and with a focus on internal bioadhesives, the criteria of an ideal internal bioadhesive are adequately discussed; this is followed by the review of recently developed internal bioadhesives based on different gluing mechanisms.

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A polypeptide based podophyllotoxin conjugate for the treatment of multi drug resistant breast cancer with enhanced efficiency and minimal toxicity

Publication date: Available online 22 April 2018
Source:Acta Biomaterialia
Author(s): Huicong Zhou, Shixian Lv, Dawei Zhang, Mingxiao Deng, Xuefei Zhang, Zhaohui Tang, Xuesi Chen
Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown significant activity against P-glycoprotein (P-gp) mediated multi drug resistant cancer cells. However, because of the poor aqueous solubility and high toxicity, PPT cannot be used in clinical cancer therapy. In order to enhance the efficiency and reduce side effect of PPT, a polypeptide based PPT conjugate PLG-g-mPEG-PPT was developed and used for the treatment of multi drug resistant breast cancer. The PLG-g-mPEG-PPT was prepared by conjugating PPT to poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG) via ester bonds. The PPT conjugates self-assembled into nanoparticles with average sizes about 100 nm in aqueous solution. Western blotting assay showed that the PLG-g-mPEG-PPT could effectively inhibit the expression of P-gp in the multiple drug resistant MCF-7/ADR cells. In vitro cytotoxicity assay indicated that the resistance index (RI) values of PLG-g-mPEG-PPT on different drug-resistant cancer cell lines exhibited 57-270 folds reduction than of traditional microtubule inhibitor chemotherapeutic drug PTX or DTX. Hemolysis assay demonstrated that the conjugation greatly decreased the hemolytic activity of free PPT. Maximum tolerated dose (MTD) of PLG-g-mPEG-PPT increased greatly (13.3 folds) as compared to that of free PPT. In vivo study showed that the PLG-g-mPEG-PPT conjugate remarkably enhanced the antitumor efficacy against MCF-7/ADR xenograft tumors with an tumor suppression rate (TSR) of 82.5%, displayed significantly improved anticancer efficacy as compared to free PPT (TSR=37.1%) with minimal toxicity when both of the two formulations were used in MTD.Statement of SignificanceThe development of multiple drug resistance (MDR) of cancer cells is the main cause of chemotherapy failure. The over-expression of P-glycoprotein (P-gp) has been recognized to be the most important cause of MDR in cancer. Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown strong activity against P-gp mediated multidrug resistant cancer cells by simultaneously inhibiting the over-expression of P-gp and the growth of cancer cells. However, PPT can not be used in clinical cancer treatment due to its poor aqueous solubility and high toxicity. Herein, we developed a polypeptide based PPT conjugate PLG-g-mPEG-PPT by conjugating PPT to poly(L-glutamic acid)-g-methoxy poly(ethylene glycol). The PLG-g-mPEG-PPT shows significantly decreased hemolytic activity, greatly improved maximum tolerated dose and remarkably enhanced antitumor efficacy against MCF-7/ADR xenograft tumors as compared to free PPT.

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Graphene oxide reinforced core–shell structured Ag@Cu2O with tunable hierarchical morphologies and their morphology–dependent electrocatalytic properties for bio-sensing applications

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Publication date: 30 July 2018
Source:Biosensors and Bioelectronics, Volume 112
Author(s): Tian Gan, Zhikai Wang, Zhaoxia Shi, Dongyun Zheng, Junyong Sun, Yanming Liu
In this study, a facile solution approach was developed for the synthesis of a series of core–shell structured Ag@Cu2O nanocrystals of various shapes including triangles, spheres, and cubes with well–defined stable heterojunctions. The electrooxidation of dopamine (DA), uric acid (UA), guanine (G), and adenine (A) using these hybrids revealed morphology–dependent sensing properties, with activities and accumulation ability following the order, triangular Ag@Cu2O > spherical Ag@Cu2O > cubic Ag@Cu2O. Further, we constructed a novel graphene oxide (GO) nanosheet–reinforced triangular Ag@Cu2O ternary hetero–nanostructure. Such a hybrid with a three–dimensional interconnected hierarchical architecture is suitable for catalysis, since it not only leads to improved interfacial electron transfer, but also readily exposes the highly catalytic Ag@Cu2O to the reactants. Therefore, more enhanced electrochemical activities were observed for the oxidation of DA, UA, G, and A. This study provides an efficient way to synthesize morphology–controlled Ag@Cu2O heterogeneous catalysts for the fabrication of potential biosensors, and also opens up attractive avenues in the design of multifunctional ternary noble metal–semiconductor–carbon hybrids.



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A robust electrochemical immunosensor based on hydroxyl pillar[5]arene@AuNPs@g-C3N4 hybrid nanomaterial for ultrasensitive detection of prostate specific antigen

Publication date: 30 July 2018
Source:Biosensors and Bioelectronics, Volume 112
Author(s): Xu Zhou, Long Yang, Xiaoping Tan, Genfu Zhao, Xiaoguang Xie, Guanben Du
Prostate specific antigen (PSA) is the most significant biomarker for the screening of prostate cancer in human serum. However, most methods for the detection of PSA often require major laboratories, precisely analytical instruments and complicated operations. Currently, the design and development of satisfying electrochemical biosensors based on biomimetic materials (e.g. synthetic receptors) and nanotechnology is highly desired. Thus, we focused on the combination of molecular recognition and versatile nanomaterials in electrochemical devices for advancing their analytical performance and robustness. Herein, by using the present prepared multifunctional hydroxyl pillar[5]arene@gold nanoparticles@graphitic carbon nitride (HP5@AuNPs@g–C3N4) hybrid nanomaterial as robust biomimetic element, a high-performance electrochemical immunosensor for detection of PSA was constructed. The as-prepared immunosensor, with typically competitive advantages of low cost, simple preparation and fast detection, exhibited remarkable robustness, ultra-sensitivity, excellent selectivity and reproducibility. The limit of detection (LOD) and linear range were 0.12 pg mL–1 (S/N = 3) and 0.0005–10.00 ng mL–1, respectively. The satisfying results provide a promising approach for clinical detection of PSA in human serum.

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Electrochemiluminescence quenching of luminol by CuS in situ grown on reduced graphene oxide for detection of N-terminal pro-brain natriuretic peptide

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Publication date: 30 July 2018
Source:Biosensors and Bioelectronics, Volume 112
Author(s): Xiaojian Li, Peng Lu, Bin Wu, Yaoguang Wang, Huan Wang, Bin Du, Xuehui Pang, Qin Wei
A novel electrochemiluminescence (ECL) signal-off strategy based on CuS in situ grown on reduced graphene oxide (CuS-rGO) quenching luminol/H2O2 system was firstly proposed. Luminol was grafted on the surface of Au@Fe3O4-Cu3(PO4)2 nanoflowers (Luminol-Au@Fe3O4-Cu3(PO4)2) which exhibited excellent catalytic effect towards the reduction of H2O2 to enhance the ECL intensity of luminol. Cu3(PO4)2 nanoflowers showed large surface area which can immobilize more Fe3O4 and Au nanoparticles. The quenching mechanism of CuS-rGO was due to ECL resonance energy transfer (RET). The spectral overlap between fluorescence spectrum of Luminol-Au@Fe3O4-Cu3(PO4)2 and UV–vis absorption spectrum of CuS-rGO revealed that resonance energy transfer was possible. Au nanoparticles were immobilized on the surface of CuS-rGO to capture secondary antibodies. After a sandwich-type immunoreaction, a remarkable decrease of ECL signal was observed. Under the optimal conditions, the immunosensor showed excellent performance for N-terminal pro-brain natriuretic peptide (NT-proBNP) detection with a wide detection range from 0.5 pg mL−1 to 20 ng mL−1 and a low detection limit of 0.12 pg mL−1 (S/N = 3). The prepared NT-proBNP immunosensor displayed high sensitivity, excellent stability and good specificity.



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Alpha-lactose reverses liver injury via blockade of Tim-3-mediated CD8 apoptosis in sepsis

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Publication date: Available online 22 April 2018
Source:Clinical Immunology
Author(s): Zhengping Wei, Pingfei Li, Yao Yao, Hai Deng, Shengwu Yi, Cong Zhang, Han Wu, Xiuxiu Xie, Minghui Xia, Ran He, Xiang-Ping Yang, Zhao-Hui Tang
In sepsis, the liver plays a crucial role in regulating immune responses and is also a target organ for immune-related injury. Despite the critical function of CD8+ T cells against opportunistic viral infections, the CD8 immune response in the liver during sepsis remains elusive. Here we found that Tim-3 is highly up-regulated in liver CD8+ T cells in a mouse cecal ligation and puncture model and in peripheral blood CD8+ T cells of human patients with sepsis. The expression of Tim-3 in liver CD8+ T cells displayed a bi-phasic pattern and deletion of Tim-3 led to reduction of CD8+ T cell apoptosis. Administration of α-lactose, a molecule with a similar structure to galactin-9, reduced Tim-3 expression and liver injury in sepsis. Our results demonstrate that targeting Tim-3 to boost CD8+ T cell immune response may offer an improved outcome in patients with sepsis.



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Absolute cosine-based SVM-RFE feature selection method for prostate histopathological grading

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Publication date: Available online 19 April 2018
Source:Artificial Intelligence in Medicine
Author(s): Shahnorbanun Sahran, Dheeb Albashish, Azizi Abdullah, Nordashima Abd Shukor, Suria Hayati Md Pauzi
ObjectiveFeature selection (FS) methods are widely used in grading and diagnosing prostate histopathological images. In this context, FS is based on the texture features obtained from the lumen, nuclei, cytoplasm and stroma, all of which are important tissue components. However, it is difficult to represent the high-dimensional textures of these tissue components. To solve this problem, we propose a new FS method that enables the selection of features with minimal redundancy in the tissue components.MethodologyWe categorise tissue images based on the texture of individual tissue components via the construction of a single classifier and also construct an ensemble learning model by merging the values obtained by each classifier. Another issue that arises is overfitting due to the high-dimensional texture of individual tissue components. We propose a new FS method, SVM-RFE(AC), that integrates a Support Vector Machine-Recursive Feature Elimination (SVM-RFE) embedded procedure with an absolute cosine (AC) filter method to prevent redundancy in the selected features of the SV-RFE and an unoptimised classifier in the AC.ResultsWe conducted experiments on H&E histopathological prostate and colon cancer images with respect to three prostate classifications, namely benign vs. grade 3, benign vs. grade 4 and grade 3 vs. grade 4. The colon benchmark dataset requires a distinction between grades 1 and 2, which are the most difficult cases to distinguish in the colon domain. The results obtained by both the single and ensemble classification models (which uses the product rule as its merging method) confirm that the proposed SVM-RFE(AC) is superior to the other SVM and SVM-RFE-based methods.ConclusionWe developed an FS method based on SVM-RFE and AC and successfully showed that its use enabled the identification of the most crucial texture feature of each tissue component. Thus, it makes possible the distinction between multiple Gleason grades (e.g. grade 3 vs. grade 4) and its performance is far superior to other reported FS methods.



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Segmentation of corneal endothelium images using a U-Net-based convolutional neural network

Publication date: Available online 19 April 2018
Source:Artificial Intelligence in Medicine
Author(s): Anna Fabijańska
Diagnostic information regarding the health status of the corneal endothelium may be obtained by analyzing the size and the shape of the endothelial cells in specular microscopy images. Prior to the analysis, the endothelial cells need to be extracted from the image. Up to today, this has been performed manually or semi-automatically. Several approaches to automatic segmentation of endothelial cells exist; however, none of them is perfect. Therefore this paper proposes to perform cell segmentation using a U-Net-based convolutional neural network. Particularly, the network is trained to discriminate pixels located at the borders between cells. The edge probability map outputted by the network is next binarized and skeletonized in order to obtain one-pixel wide edges. The proposed solution was tested on a dataset consisting of 30 corneal endothelial images presenting cells of different sizes, achieving an AUROC level of 0.92. The resulting DICE is on average equal to 0.86, which is a good result, regarding the thickness of the compared edges. The corresponding mean absolute percentage error of cell number is at the level of 4.5% which confirms the high accuracy of the proposed approach. The resulting cell edges are well aligned to the ground truths and require a limited number of manual corrections. This also results in accurate values of the cell morphometric parameters. The corresponding errors range from 5.2% for endothelial cell density, through 6.2% for cell hexagonality to 11.93% for the coefficient of variation of the cell size.

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Handwritten dynamics assessment through convolutional neural networks: An application to Parkinson's disease identification

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Publication date: Available online 16 April 2018
Source:Artificial Intelligence in Medicine
Author(s): Clayton R. Pereira, Danilo R. Pereira, Gustavo H. Rosa, Victor H.C. Albuquerque, Silke A.T. Weber, Christian Hook, João P. Papa
Background and objectiveParkinson's disease (PD) is considered a degenerative disorder that affects the motor system, which may cause tremors, micrography, and the freezing of gait. Although PD is related to the lack of dopamine, the triggering process of its development is not fully understood yet.MethodsIn this work, we introduce convolutional neural networks to learn features from images produced by handwritten dynamics, which capture different information during the individual's assessment. Additionally, we make available a dataset composed of images and signal-based data to foster the research related to computer-aided PD diagnosis.ResultsThe proposed approach was compared against raw data and texture-based descriptors, showing suitable results, mainly in the context of early stage detection, with results nearly to 95%.ConclusionsThe analysis of handwritten dynamics using deep learning techniques showed to be useful for automatic Parkinson's disease identification, as well as it can outperform handcrafted features.



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How do we talk about doctors and drugs? Sentiment analysis in forums expressing opinions for medical domain

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Publication date: Available online 22 April 2018
Source:Artificial Intelligence in Medicine
Author(s): Salud María Jiménez-Zafra, M. Teresa Martín-Valdivia, M. Dolores Molina-González, L. Alfonso Ureña-López
ObjectiveThe main goal of this study is to examine how people express their opinion in medical forums. We analyze the language used in order to determine the best way to tackle sentiment analysis in this domain.MethodsWe have applied supervised learning and lexicon-based sentiment analysis approaches over two different corpora extracted from social web. Specifically, we have focused on two aspects: drugs and doctors. We have selected two forums and we have collected corpora for each one: (i) DOS, a Spanish corpus of drug reviews and (ii) COPOS, a Spanish corpus of patients' opinions about physicians.ResultsThe classification results show that drug reviews are more difficult to classify than those about physicians. In order to understand the difference in the results, we have studied the linguistic features of both corpora.ConclusionsAlthough opinions about physicians and drugs are written in most cases by non-professional users, reviews about physicians are characterized by the use of an informal language while reviews about drugs are characterized by a combination of informal language with specific terminology (e.g. adverse effects, drug names) with greater lexical diversity, making the task of sentiment analysis difficult.



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Transabdominal Breast Augmentation: A Review of 114 Cases Performed over 14 Years

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