Ιατρικά Άρθρα: 10/13/17

Παρασκευή 13 Οκτωβρίου 2017

Dynamics of Plasma Cytokines in a Patient with Deficiency of Interleukin-36 Receptor Antagonist Successfully Treated with Anakinra

Generalized pustular psoriasis (GPP) is an autoinflammatory disease characterized by abrupt-onset episodes of erythematous skin plaques with countless pustules, fever, marked neutrophilia and increased acute phase reactants (APR).¹ Loss-of-function mutations in the IL36RN gene, encoding for interleukin (IL)-36 receptor antagonist (IL-36Ra), have been described in a significant proportion of GPP patients.^2,3 Previous studies have shown in vitro and ex vivo enhanced production of pro-inflammatory cytokines (IL-1, IL-6 and IL-8) and successful outcomes with anti-IL-1 drugs in patients carrying IL36RN mutations.^1,2 However, little is known about the correlation of plasma cytokines, inflammatory markers and clinical follow-up, before and after treatment with anti-IL-1 drugs.

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Comment on: A Visual Literacy Course for Dermatology Trainees

We would like to congratulate Griffin and colleagues on their report of an innovative training programme in visual literacy for dermatology registrars (residents).¹ Our experience of visual literacy training for registrars in South London resonates with that of the Manchester group, and we would like to add to this by describing our observation of some additional qualitative benefits which may be derived from such training. Training similar to that described by the Griffin et al was delivered to 10 dermatology registrars at the Dulwich Picture Gallery in London, England from September 2016 – January 2017 in 5 one hour sessions. Baseline and post-course assessments, scored on the unique accurate observations method described by Huang et al,² were carried out and demonstrated an increase in the number of unique accurate observations per image following the course compared to pre-course assessment.

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A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures

Publication date: Available online 14 October 2017
Source:Brain and Development
Author(s): Priyanka Madaan, Prashant Jauhari, Aparajita Gupta, Biswaroop Chakrabarty, Sheffali Gulati
Epilepsy of infancy with migrating focal seizures {a.k.a malignant migrating partial seizures of infancy (MMPSI)} is an uncommon epileptic encephalopathy with a poor prognosis. Migrating focal seizures with autonomic features, developmental stagnation and refractoriness to treatment are its key features. It is caused by genetic defects in various ion channels, most common being sodium activated potassium channel (KCNT1), found in up to 50% of cases. With advent of genetic diagnosis and precision medicine, many targeted therapies have been identified. Antagonist of KCNT1 coded ion channel like Quinidine has shown promising results in MMPSI. Here we report first mutation proven case of MMPSI from India. This child had a novel heterozygous missense mutation in exon10 of the KCNT1 gene (chr9:138650308; c.808C > C/G (p.Q270E)) which was pathogenic. Neither quinidine nor ketogenic diet could control his seizures. Ultimately, the child succumbed to his illness at nine months of age.

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Circulating microRNA-339-5p and -21 in plasma as an early detection predictors of lung adenocarcinoma

Publication date: Available online 13 October 2017
Source:Pathology - Research and Practice
Author(s): Yongpan Sun, Hong Mei, Chuan Xu, Hongjun Tang, Wei Wei
BackgroundMany studies have shown that differentially expressed miRs in body fluids can serve as biomarkers in non-invasive detection of the cancers. However, the clinical significance of plasma miRs in the diagnosis of lung adenocarcinoma (LA) is still not clear. Therefore, we examined the LA-specific miRs in plasma, which could be utilized to diagnosis and monitor LA in routine clinical practice.MethodsTwenty-eight LA cases and twenty-eight healthy controls were recruited to our study. MiRs differential expression in plasma was measured by miRNA Microarray assay and revalidated by using qRT-PCR based absolute quantification methods The diagnostic power of circulating miRs in LA was evaluated using the receiver operating characteristics (ROC) curves and the area under the ROC curves (AUC).ResultsTumor tissues and plasma levels of miR-339-5p were significantly down-regulated in LA patients compared with those in the control group, whereas the levels of miR-21 in LA patients were significantly higher than control group. ROC analysis showed that miR-339-5p and miR-21 could distinguish LA patients from healthy controls with high AUC (0.900 and 0.880, respectively), sensitivity (0.821 and 0.821, respectively) and specificity (0.929 and 0.964, respectively). Importantly, the combination of miR-339-5p and miR-21 markedly improved AUC (0.963), sensitivity (0.929) and specificity (0.929).ConclusionPlasma miR-339-5p or miR-21 could serve as a potential biomarker for diagnosis of LA, however, the combination of miR-339-5p and miR-21 was more efficient for LA detection.

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Applicability of an innovative steroid-profiling method to determine synthetic growth promoter abuse in cattle

Publication date: Available online 13 October 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): M.H. Blokland, E.F. van Tricht, L.A. van Ginkel, S.S. Sterk
A robust LC-MS/MS method was developed to quantify a large number of phase I and phase II steroids in urine. The decision limit is for most compounds lower than 1ngml⁻¹ with a measurement uncertainty smaller than 30%. The method is fully validated and was applied to assess the influence of administered synthetic steroids and beta-agonists on the steroidogenesis. From three animal experiments, clenbuterol, diethylstilbestrol and stanozolol, the steroid profiles in urine of bovine animals were compared before and after treatment. It was demonstrated that the steroid profiles were altered due to these treatments. A predictive multivariate model was built to identify deviations from normal population steroid profiles. The abuse of synthetic steroids can be detected in urine samples from bovine animals using this model. The samples from the animal experiments were randomly analysed using this method and predictive model. It was shown that these samples were predicted correctly in the exogenous steroids group.

Graphical abstract

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Sources of 137Cs to an Arctic fjord (Hornsund, Svalbard)

Publication date: December 2017
Source:Journal of Environmental Radioactivity, Volume 180
Author(s): Agata Zaborska
Although primary sources of anthropogenic ¹³⁷Cs have decreased nowadays, the Arctic is exposed to a variety of secondary sources. These include riverine run-off, oceanic currents, drifting sea ice, melting glaciers and permafrost. Recent reports underline the role of glaciers, specifically cryoconite holes, in radionuclide accumulation. Therefore, this study investigates the hypothesis that melting glaciers are an important means of delivering ¹³⁷Cs for Arctic fjord (Hornsund, Svalbard). As marine sediments are the final sink for most contaminants, seven 30–40 cm long sediment cores collected in 2016 were investigated for ¹³⁷Cs activity concentration. Five were collected in a transect from the central to the outer part of the fjord while two were collected within one km of the different melting tidewater glaciers. Sediment layers were dated using ²¹⁰Pb to reveal the history of ¹³⁷Cs accumulation. The measured ¹³⁷Cs activity concentrations ranged from <0.1 to 7.7 Bq kg⁻¹. The activity concentrations ranging from 0.3 to 3.1 Bq kg⁻¹ were measured in surface (0–2 cm) sediments. The total ¹³⁷Cs inventories were calculated for five station and ranged from 322 to 908 Bq m⁻², of which 29–34 Bq m⁻² were deposited within the last decade. At two stations characterized by largest sediment accumulation rates only the last decade inventories were calculated and they ranged from 13 to 444 Bq·m⁻². The mean of ¹³⁷Cs fluxes calculated for last decade ranged from 2.7 to 44.1 Bq m⁻²yr⁻¹. The history of ¹³⁷Cs environmental inputs was well revealed in the sediments as the ¹³⁷Cs penetration depth agreed with the time of its introduction to the Arctic and the most pronounced ¹³⁷Cs activity concentration peak was found in sediments dated for circa 1963. Although ¹³⁷Cs fluxes and inventories were largest in the glacial bay (Brepollen), the ¹³⁷Cs was diluted in a large amount of sedimenting material. Based on the results in this study, the glaciers do not appear to act as important sources of ¹³⁷Cs to the marine environment in the Hornsund fjord.

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Radionuclides in mushrooms and soil-to-mushroom transfer factors in certain areas of China

Publication date: December 2017
Source:Journal of Environmental Radioactivity, Volume 180
Author(s): Fei Tuo, Jing Zhang, Wenhong Li, Shuaimo Yao, Qiang Zhou, Zeshu Li
Activity concentrations of ²³⁸U, ²²⁶Ra, ²²⁸Ra, ¹³⁷Cs and ⁴⁰K in 64 mushroom samples collected in China from Yunnan, Fujian and Heilongjiang Provinces, were measured. Gamma-ray emissions were determined by using high-purity germanium (HPGe) γ spectrometry. The range of concentrations (Bq kg⁻¹ dry weight) for ²³⁸U, ²²⁶Ra, ²²⁸Ra, ¹³⁷Cs and ⁴⁰K in all investigated mushroom samples were from 0.12 to 12, 0.05 to 7.5, 0.14 to 14, MDC(<0.01) to 339, and 396 to 1880, respectively. Activity concentrations of ¹³⁷Cs in mushrooms showed some variation between species sampled at the same site. To calculate soil to mushroom transfer factors, levels of radionuclide in 15 paired soil samples and mushrooms were also investigated. The median transfer factors for ²³⁸U, ²²⁶Ra, ²²⁸Ra, ¹³⁷Cs and ⁴⁰K were 8.32 × 10⁻², 3.03 × 10⁻², 6.69 × 10⁻², 0.40 and 1.19, respectively. The results were compared with values of other areas.

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Marine ecological risk assessment methods for radiation accidents

Publication date: December 2017
Source:Journal of Environmental Radioactivity, Volume 180
Author(s): Sufen Ye, Luoping Zhang, Huan Feng
Ecological risk assessment (ERA) is a powerful technical tool that can be used to analyze potential and extreme adverse environmental impacts. With the rapid development of nuclear power plants in coastal areas around the world, the establishment of approaches and methodologies for marine ERA with a focus on radiation accidents is an urgent requirement for marine environmental management. In this study, the approaches and methodologies for ERA pertaining to marine radiation accidents (MRA) are discussed and summarized with applications in case studies, such as the nuclear accident in Fukushima, Japan, and a hypothetical accident in Daya Bay, China. The concepts of ERA and Risk Degree of ERA on MRA are defined for the first time to optimize the ERA system. The results of case studies show that the ERA approach and methodology for MRA are scientifically sound and effective in both the early and late stage of MRAs along with classic ERA Approach and the ERICA Integrated Approach. The results can be useful in the decision-making processes and the risk management at the beginning of accident as well as the ecological restoration after the accident.

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Effects of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition with Bococizumab on Lipoprotein Particles in Hypercholesterolemic Subjects

Publication date: Available online 14 October 2017
Source:Clinical Therapeutics
Author(s): Hong Wan, Barry Gumbiner, Tenshang Joh, Tom Riel, Chandrasekhar Udata, Philippe Forgues, Pamela D. Garzone
PurposeMonoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) elicit significant reductions in serum LDL-C levels. However, little is known about their effects on lipoprotein particles. The purpose of this analysis was to evaluate the effect of PCSK9 inhibition with bococizumab (RN316/PF-04950615), a humanized monoclonal antibody to PCSK9, on LDL, VLDL, and HDL particle concentration and size in hypercholesterolemic subjects.MethodsData from 3 double-blind, placebo-controlled, randomized studies were analyzed. In study 1, a total of 67 hypercholesterolemic subjects received IV placebo or bococizumab 0.25, 0.5, 1, or 1.5 mg/kg weekly for 4 weeks. In studies 2 and 3, a total of 135 hypercholesterolemic subjects taking statins received IV placebo or bococizumab 0.25, 1, 3, or 6 mg/kg monthly for 12 weeks. Lipoprotein particle concentration and size were measured by using nuclear magnetic resonance spectroscopy.FindingsOverall, the majority of subjects were men (51.9%) aged >50 years of age and of white ethnic origin. In total, 189 subjects with both baseline and 2-week posttreatment data were included in the analysis. After PCSK9 inhibition with bococizumab 0.5, 1, 1.5, 3, and 6 mg/kg, concentrations of total LDL, total small LDL, and small VLDL particles decreased significantly versus baseline and placebo (P < 0.05), whereas concentrations of HDL particles increased (P < 0.05). The size of the LDL, VLDL, and HDL particles increased after PCSK9 inhibition. Reductions in LDL-C and total LDL particle concentrations were highly correlated.ImplicationsThe effect of inhibiting PCSK9 with bococizumab on lipoprotein particle concentration and size are consistent with the general mechanism of PCSK9 inhibitors in blocking PCSK9-mediated downregulation of LDL receptors. PCSK9 inhibition has the potential to provide a clinical benefit through the modulation of atherogenic lipoprotein particles in addition to LDL-C lowering, and this effect will likely be assessed in future analyses of data from cardiovascular outcomes trials of PCSK9 monoclonal antibodies that are currently being conducted. ClinicalTrials.gov identifiers: NCT01243151, NCT01342211, and NCT01350141.

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Longitudinal melanonychia due to voriconazole therapy during treatment of chromoblastomycosis

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A feasibility study for a triple-blind randomized controlled trial investigating the effects of oral isotretinoin on mood and quality of life in patients with acne vulgaris

Summary

Isotretinoin is used in the treatment of severe acne vulgaris (AV), but has controversially been associated with depression and suicide. Large prospective studies have failed to translate this clinically. We undertook a feasibility study to investigate the parameters of a triple-blind, randomized controlled trial (RCT) assessing the effect of oral isotretinoin on quality of life (QoL) and mood in patients with AV. Patients meeting the inclusion criteria were randomized for 2 weeks to isotretinoin or doxycycline. Participants completed verified depression and QoL screening questionnaires at baseline and week 2. In total, 194 patients with AV were screened, with 48 meeting the inclusion criteria and 13 of these being willing to participate. The follow-up rate was 92% and questionnaire response rate was 96%. To our knowledge, this is the first study to demonstrate a successful design for a triple-blind RCT investigating the effects of isotretinoin on mood in patients with AV.

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Peri-operative blood transfusion for resected colon cancer: Practice patterns and outcomes in a population-based study

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Sunil V. Patel, Kelly E. Brennan, Sulaiman Nanji, Safiya Karim, Shaila Merchant, Christopher M. Booth
Background & objectivesLiterature suggests that peri-operative blood transfusion among patients with resected colon cancer may be associated with inferior long-term survival. The study objective was to characterize this association in our population.MethodsThis is a retrospective cohort study using the population-based Ontario Cancer Registry (2002–2008). Pathology reports were obtained for a 25% random sample of all cases and constituted the study population. Log binomial regression was used to identify factors associated with transfusion. Cox proportional hazards model explored the association between transfusion and cancer specific survival (CSS) and overall survival (OS).ResultsThe study population included 7198 patients: 18% stage I, 36% stage II, 40% stage III, and 6% stage IV. Twenty-eight percent of patients were transfused. Factors independently associated with transfusion included advanced age (p<0.001), female sex (p<0.001), greater comorbidity (p<0.001), more advanced disease (p<0.001) and open surgical resection (p<0.001). Transfusion was associated with inferior CSS (HR 1.51, 95% CI 1.38–1.65) and OS (HR 1.52, 95% CI 1.41–1.63), after adjusting for important confounders.ConclusionsPeri-operative transfusion rates among patients with colon cancer have decreased over time. Transfusion is associated with inferior long-term CSS and OS.

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Acne in late adolescence is not associated with a raised risk of subsequent malignant melanoma among men

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Teresa Mota Garcia, Ayako Hiyoshi, Ruzan Udumyan, Hugo Sjöqvist, Katja Fall, Scott Montgomery
BackgroundTo evaluate the association of acne in late adolescence with the risk for subsequent malignant melanoma (MM) in men.MethodsSwedish register-based cohort study of 242,096 males born between 1952 and 1956, who took part in compulsory assessments for Swedish military conscription in late adolescence between 1969 and 1975, with subsequent diagnoses of MM (n=1,058) up to December 31, 2009. Covariates included measures of childhood circumstances and information from adolescence on presence of acne, physical fitness, cognitive function, body mass index (BMI), and a summary of diagnoses. Cox regression was used for the analysis.ResultsIn total 1,058 men were diagnosed with MM. Acne was not associated with subsequent MM, with an adjusted hazard ratio (and 95% confidence interval) of 0.95 (0.61 to 1.49). Men with parents who were agricultural workers, and men who lived in northern Sweden, had lower physical fitness, or lower cognitive function had a lower risk of MM. Overweight and obesity was associated with a raised risk, with an adjusted hazard ratio of 1.39 (1.14, 1.71).ConclusionsAcne in late adolescence is unlikely to represent a raised risk for subsequent MM in men. Overweight or obesity was identified as a raised risk for MM, possibly due to the associated increased skin surface area.

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Methodological issues of assessing the risk of a second cancer occurring in the same site as a first cancer using registry data

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Jérémie Jégu, Marie Moitry, Simona Bara, Brigitte Trétarre, Anne-Valérie Guizard, Anne-Sophie Woronoff, Laetitia Daubisse-Marliac, Véronique Bouvier, Xavier Troussard, Marc Colonna, Delphine Klein, Bénédicte Lapôtre-Ledoux, Michel Velten
ObjectiveTo present methodological issues that can arise with the assessment of the risk of a second primary cancer (SPC) occurring in the same site as a first cancer using registry data.Material and methodsData from ten French cancer registries were used, including data for patients with a first prostate cancer (in males), breast cancer (in females), and colon, lung and kidney cancer (in both sexes) diagnosed between 1989 and 2004. Standardized incidence ratios (SIRs) of SPC were computed by excluding, or not, the risk of an SPC at the same site.ResultsFor prostate cancer, the SIR dropped from 1.11 to 0.72 when the risk of SPC of the prostate was included. SIRs increased from 1.36 to 1.45, from 1.14 to 1.21, from 1.57 to 2.01, and from 1.37 to 1.51 for breast, colon, lung, and kidney respectively.ConclusionThe inclusion, or not, of an SPC at the same site can impact on SPC risk estimates.

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A systematic review of instrumental variable analyses using geographic region as an instrument

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Emily A. Vertosick, Melissa Assel, Andrew J. Vickers
BackgroundInstrumental variables analysis is a methodology to mitigate the effects of measured and unmeasured confounding in observational studies of treatment effects. Geographic area is increasingly used as an instrument.MethodsWe conducted a literature review to determine the properties of geographic area in studies of cancer treatments. We identified cancer studies performed in the United States which incorporated instrumental variable analysis with area-wide treatment rate within a geographic region as the instrument. We assessed the degree of treatment variability between geographic regions, assessed balance of measured confounders afforded by geographic area and compared the results of instrumental variable analysis to those of multivariable methods.ResultsGeographic region as an instrument was relatively common, with 22 eligible studies identified, many of which were published in high-impact journals. Treatment rates did not vary greatly by geographic region. Covariates were not balanced by the instrument in the majority of studies. Eight out of eleven studies found statistically significant effects of treatment on multivariable analysis but not for instrumental variables, with the central estimates of the instrumental variables analysis generally being closer to the null.ConclusionsWe recommend caution and an investigation of IV assumptions when considering the use of geographic region as an instrument in observational studies of cancer treatments. The value of geographic region as an instrument should be critically evaluated in other areas of medicine.

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Colchicine is an active treatment for everolimus-induced oral ulcers

Publication date: Available online 13 October 2017
Source:European Journal of Cancer
Author(s): Stanislas Ropert, Romain Coriat, Benjamin Verret, Audrey Perret, Francesca Lucibello, Ali N. Chamseddine, Jean-Pierre Armand, Angelo Paci, Olivier Mir

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Effectiveness of photodynamic therapy associated with irrigants over two biofilm models

Publication date: Available online 13 October 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Ricardo Abreu da Rosa, Manuela Favarin Santini, José Antônio Poli de Figueiredo, Fernanda Visioli, Jefferson Ricardo Pereira, Rodrigo Ricci Vivan, Francisco Montagner, Marcus Vinícius Reis Só
BackgroundThis study aimed to evaluate the antibacterial effect and the biofilm disruption promoted by antimicrobial photodynamic therapy (aPDT) associated with sodium hypochlorite (NaOCl) and chlorexidine (CHX) over monospecies and multispecies biofilms.MethodsIn monospecies model, forty-six premolars were inoculated with Enterococcus faecalis for 21days and divided into three groups: saline, CHX and NaOCl. After irrigation, aPDT was performed. Samples were collected at baseline (S1) and after irrigation (S2) and aPDT (S3). Colony-forming unit (CFU) counts were performed. In multispecies model, sixty bovine dentin blocks were infected intraorally for 72 hous and divided into six groups: saline, saline/aPDT, CHX, CHX/aPDT, NaOCl and NaOCl/aPDT. The percentage and the biovolume of live cells and the total biovolume were assessed using confocal laser scanning microscopy.ResultsCHX and NaOCl showed the lowest CFU counts (P<0.05). aPDT reduced the bacterial counts in saline (S2-S3; P<0.05). The lowest amount of live cells was observed in CHX, CHX/aPDT, NaOCl and NaOCl/aPDT. aPDT did not reduce the total biovolume (P>0.05).ConclusionaPDT associated with saline reduced the bacterial load in root canals infected with E. faecalis. aPDT did not reduce the total biovolume in situ; however, the irrigant was decisive to disrupt multispecies biofilms.

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Unraveling the mechanistic effects of electric field stimulation towards directing stem cell fate and function: A tissue engineering perspective

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Greeshma Thrivikraman, Sunil Kumar Boda, Bikramjit Basu
Electric field (EF) stimulation can play a vital role in eliciting appropriate stem cell response. Such an approach is recently being established to guide stem cell differentiation through osteogenesis/neurogenesis/cardiomyogenesis. Despite significant recent efforts, the biophysical mechanisms by which stem cells sense, interpret and transform electrical cues into biochemical and biological signals still remain unclear. The present review critically analyses the variety of EF stimulation approaches that can be employed to evoke appropriate stem cell response and also makes an attempt to summarize the underlying concepts of this notion, placing special emphasis on stem cell based tissue engineering and regenerative medicine. This review also discusses the major signaling pathways and cellular responses that are elicited by electric stimulation, including the participation of reactive oxygen species and heat shock proteins, modulation of intracellular calcium ion concentration, ATP production and numerous other events involving the clustering or reassembling of cell surface receptors, cytoskeletal remodeling and so on. The specific advantages of using external electric stimulation in different modalities to regulate stem cell fate processes are highlighted with explicit examples, in vitro and in vivo.

Graphical abstract

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Mechanotransduction of human pluripotent stem cells cultivated on tunable cell-derived extracellular matrix

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): In Gul Kim, Chang-Hyun Gil, Joseph Seo, Soon-Jung Park, Ramesh Subbiah, Taek-Hee Jung, Jong Soo Kim, Young-Hoon Jeong, Hyung-Min Chung, Jong Ho Lee, Man Ryul Lee, Sung-Hwan Moon, Kwideok Park
Cell-derived matrices (CDM) are becoming an attractive alternative to conventional biological scaffolding platforms due to its unique ability to closely recapitulate a native extracellular matrix (ECM) de novo. Although cell-substrate interactions are recognized to be principal in regulating stem cell behavior, very few studies have documented the acclimation of human pluripotent stem cells (hPSCs) on pristine and altered cell-derived matrices. Here, we investigate crosslink-induced mechanotransduction of hPSCs cultivated on decellularized fibroblast-derived matrices (FDM) to explore cell adhesion, growth, migration, and pluripotency in various biological landscapes. The results showed either substrate-mediated induction or inhibition of the Epithelial-Mesenchymal-Transition (EMT) program, strongly suggesting that FDM stiffness can be a dominant factor in mediating hPSC plasticity. We further propose an optimal FDM substratum intended for long-term hPSC cultivation in a feeder-free niche-like microenvironment. This study carries significant implications for hPSC cultivation and encourages more in-depth studies towards the fundamentals of hPSC-CDM interactions.

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Biofabricating atherosclerotic plaques: In vitro engineering of a three-dimensional human fibroatheroma model

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Anna Mallone, Chantal Stenger, Arnold Von Eckardstein, Simon P. Hoerstrup, Benedikt Weber
Atherosclerotic plaques are cholesterol-induced inflammatory niches accumulating in the vascular sub-endothelial space. Cellular and extracellular composition of human plaques is maneuvered by local inflammation that leads to alterations in the original vascular microenvironment and to the recruitment of an invading fibrous layer (fibroatharoma). In the present study we introduce a bioengineered three-dimensional model of human fibroatheroma (ps-plaque) assembled with a tailored hanging-drop protocol. Using vi-SNE based multidimensional flow cytometry data analysis we compared the myeloid cell-populations in ps-plaques to those in plaques isolated from human carotid arteries. We observed that plasmacytoid and activated dendritic cells are the main myeloid components of human carotid plaques and that both cell types are present in the biofabricated model. We found that low-density lipoproteins affect cell viability and contribute to population polarization in ps-plaques. The current work describes the first human bioengineered in vitro model of late atherosclerotic lesion for the investigation of atherosclerosis aetiopathogenesis.

Graphical abstract

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Rethinking liquid biopsy: Microfluidic assays for mobile tumor cells in human body fluids

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Kuang Hong Neoh, Ayon Ahmed Hassan, Anqi Chen, Yukun Sun, Peng Liu, Kai-Feng Xu, Alice S.T. Wong, Ray P.S. Han
Traditionally, liquid biopsy is a blood test involving the harvesting of tumor materials from peripheral blood. Tumor cells from non-blood body fluids have always been clinically available in cytological examinations but limited for use in differential diagnosis due to the low sensitivity of conventional cytopathology. With the recent significant progress in microfluidic and downstream molecular technologies, liquid biopsies have now evolved to include harvesting tumor cells and DNA fragments in all kinds of non-blood body fluids. This expansion into general body fluids presages the notion that liquid biopsy could soon be used in competition, as well as, in complementarity with tissue biopsy. Preliminary research of fluid-harvested tumor materials to spot early-stage tumors, monitor disease progression for metastasis and recurrence, and detect chemoresistance have been reported. To reflect the propagation of tumor cells in non-blood body fluids, we introduced the term Mobile Tumor Cells (MTCs), in lieu of the widely accepted term of circulating tumor cells (CTCs) resident in the bloodstream. Our review starts with a discussion on the clinical significance of MTCs, followed by a presentation of microfluidic techniques for MTC capture and various strategies for their identification. Hopefully, the phenotypic and genomic data acquired from harvested MTCs can be used to guide and improve cancer treatment decisions.

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ZIF-67 derived porous Co3O4 hollow nanopolyhedron functionalized solution-gated graphene transistors for simultaneous detection of glucose and uric acid in tears

Publication date: 15 March 2018
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Can Xiong, Tengfei Zhang, Weiyu Kong, Zhixiang Zhang, Hao Qu, Wei Chen, Yanbo Wang, Linbao Luo, Lei Zheng
Biomarkers in tears have attracted much attention in daily healthcare sensing and monitoring. Here, highly sensitive sensors for simultaneous detection of glucose and uric acid are successfully constructed based on solution-gated graphene transistors (SGGTs) with two separate Au gate electrodes, modified with GOx-CHIT and BSA-CHIT respectively. The sensitivity of the SGGT is dramatically improved by co-modifying the Au gate with ZIF-67 derived porous Co3O4 hollow nanopolyhedrons. The sensing mechanism for glucose sensor is attributed to the reaction of H2O2 generated by the oxidation of glucose near the gate, while the sensing mechanism for uric acid is due to the direct electro-oxidation of uric acid molecules on the gate. The optimized glucose and uric acid sensors show the detection limits both down to 100nM, far beyond the sensitivity required for non-invasive detection of glucose and uric acid in tears. The glucose and uric acid in real tear samples was quantitatively detected at 323.2 ± 16.1μM and 98.5 ± 16.3μM by using the functionalized SGGT device. Due to the low-cost, high-biocompatibility and easy-fabrication features of the ZIF-67 derived porous Co3O4 hollow nanopolyhedron, they provide excellent electrocatalytic nanomaterials for enhancing sensitivity of SGGTs for a broad range of disease-related biomarkers.

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Direct colorimetric detection of unamplified pathogen DNA by dextrin-capped gold nanoparticles

Publication date: 15 March 2018
Source:Biosensors and Bioelectronics, Volume 101
Author(s): Amy M. Baetsen-Young, Matthew Vasher, Leann L. Matta, Phil Colgan, Evangelyn C. Alocilja, Brad Day
The interaction between gold nanoparticles (AuNPs) and nucleic acids has facilitated a variety of diagnostic applications, with further diversification of synthesis match bio-applications while reducing biotoxicity. However, DNA interactions with unique surface capping agents have not been fully defined. Using dextrin-capped AuNPs (d-AuNPs), we have developed a novel unamplified genomic DNA (gDNA) nanosensor, exploiting dispersion and aggregation characteristics of d-AuNPs, in the presence of gDNA, for sequence-specific detection. We demonstrate that d-AuNPs are stable in a five-fold greater salt concentration than citrate-capped AuNPs and the d-AuNPs were stabilized by single stranded DNA probe (ssDNAp). However, in the elevated salt concentrations of the DNA detection assay, the target reactions were surprisingly further stabilized by the formation of a ssDNAp-target gDNA complex. The results presented herein lead us to propose a mechanism whereby genomic ssDNA secondary structure formation during ssDNAp-to-target gDNA binding enables d-AuNP stabilization in elevated ionic environments. Using the assay described herein, we were successful in detecting as little as 2.94 fM of pathogen DNA, and using crude extractions of a pathogen matrix, as few as 18 spores/µL.

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Prone sleeping position in infancy: implications for cardiovascular and cerebrovascular function

Advances in neonatal care have improved the survival rates of preterm infants, however, the likelihood of brain injury and neurodevelopmental disability remains a significant problem. Whilst the etiology of preterm brain injury is complex, impairments in the cardio- and cerebro-vascular function have been implicated. During infancy, sleep is vital for brain development. However, instabilities in cardio- and cerebro-vascular function are most marked during sleep. Sleeping position is an important part of a safe sleeping environment.

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A hydrogel matrix prolongs persistence and promotes specific localization of an oncolytic adenovirus in a tumor by restricting nonspecific shedding and an antiviral immune response

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Bo-Kyeong Jung, Eonju Oh, JinWoo Hong, Yunki Lee, Ki Dong Park, Chae-Ok Yun
Currently, intratumoral injection of an oncolytic adenovirus (Ad) is the conventional administration route in clinical trials. Nonetheless, the locally administered Ad disseminates to the surrounding nontarget tissues and has short biological activity due to immunogenicity of Ad, thus necessitating multiple injections to achieve a sufficient therapeutic index. In the present study, a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-expressing oncolytic Ad (oAd-TRAIL) was encapsulated in a gelatin hydrogel (oAd-TRAIL/gel) to enhance and prolong antitumor efficacy of the virus after a single intratumoral injection. oAd-TRAIL/gel showed greater antitumor efficacy than naked oAd-TRAIL did due to enhanced and prolonged intratumoral accumulation of Ad up to a 20-day period, showing potent induction of apoptosis and inhibition of tumor cell proliferation. Furthermore, the gel system effectively prevented shedding of oncolytic Ad from the injection site to hepatic and other healthy tissues. oAd-TRAIL/gel treatment resulted in a markedly weaker antiviral immune response against Ad relative to naked oAd-TRAIL, further contributing to prolonged persistence of the oncolytic Ad in tumor tissue. Moreover, the hydrogel matrix preserved oAd-TRAIL's ability to induce an antitumor immune response, resulting in higher intratumoral infiltration by CD4⁺/CD8⁺ T cells. Taken together, these findings show that single intratumoral administration of the Ad/hydrogel modality may prolong and potentiate the therapeutic efficacy of Ad, modulate the immune reaction in favor of the virotherapy, and enhance intratumoral localization of the virus, ultimately overcoming limitations of oncolytic virotherapy revealed in recent clinical trials.

http://ift.tt/2w4DmLS

Cuprous oxide nanoparticles trigger ER stress-induced apoptosis by regulating copper trafficking and overcoming resistance to sunitinib therapy in renal cancer

Publication date: November 2017
Source:Biomaterials, Volume 146
Author(s): Qiwei Yang, Ye Wang, Qing Yang, Yi Gao, Xiaopeng Duan, Qingcheng Fu, Chuanmin Chu, Xiuwu Pan, Xingang Cui, Yinghao Sun
While the current standard first-line treatment for advanced renal cell carcinoma (RCC) is sunitinib, patients inevitably develop resistance to this drug. However, the rapid development of nanotechnology has provided emerging techniques for the treatment of advanced tumours, including RCC. In our previous research, cuprous oxide nanoparticles (CONPs) showed ideal anti-tumour effects and low systemic toxicity. While many inorganic nanomedicines, including CONPs, have similar pharmacological effects, their detailed mechanisms remain unknown. Copper chaperone proteins, which regulate the endocellular dosage and transport of copper, also play crucial roles in the progression of cancer. In this research, we discovered that CONPs can disrupt copper transportation by regulating the copper chaperone proteins ATOX1 and CCS in RCC cells and induce endoplasmic reticulum (ER) stress in vitro and in vivo by promoting the accumulation of intracellular calcium and reactive oxygen species (ROS). Furthermore, CONPs can initiate ER- and mitochondrial-dependent apoptosis by activating caspase-3, caspase-9 and caspase-12. In addition, CONPs downregulate the expression of AXL, MET, AKT, and ERK to recover sunitinib responsiveness in RCC cells with sunitinib resistance (SR) and may therefore facilitate the development of promising new pathways to treat patients with acquired SRRCC.

Graphical abstract

http://ift.tt/2feg13R

Heart valve scaffold fabrication: Bioinspired control of macro-scale morphology, mechanics and micro-structure

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Antonio D'Amore, Samuel K. Luketich, Giuseppe M. Raffa, Salim Olia, Giorgio Menallo, Antonino Mazzola, Flavio D'Accardi, Tamir Grunberg, Xinzhu Gu, Michele Pilato, Marina V. Kameneva, Vinay Badhwar, William R. Wagner
Valvular heart disease is currently treated with mechanical valves, which benefit from longevity, but are burdened by chronic anticoagulation therapy, or with bioprosthetic valves, which have reduced thromboembolic risk, but limited durability. Tissue engineered heart valves have been proposed to resolve these issues by implanting a scaffold that is replaced by endogenous growth, leaving autologous, functional leaflets that would putatively eliminate the need for anticoagulation and avoid calcification. Despite the diversity in fabrication strategies and encouraging results in large animal models, control over engineered valve structure-function remains at best partial. This study aimed to overcome these limitations by introducing double component deposition (DCD), an electrodeposition technique that employs multi-phase electrodes to dictate valve macro and microstructure and resultant function. Results in this report demonstrate the capacity of the DCD method to simultaneously control scaffold macro-scale morphology, mechanics and microstructure while producing fully assembled stent-less multi-leaflet valves composed of microscopic fibers. DCD engineered valve characterization included: leaflet thickness, biaxial properties, bending properties, and quantitative structural analysis of multi-photon and scanning electron micrographs. Quasi-static ex-vivo valve coaptation testing and dynamic organ level functional assessment in a pressure pulse duplicating device demonstrated appropriate acute valve functionality.

http://ift.tt/2z4qupR

Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Jooho Park, Jeong Uk Choi, Kwangmeyung Kim, Youngro Byun
The development of highly funtional and orally available nanoparticles is the ultimate goal in nanoparticle delivery. Various functional nanoparticles have been studied to that end but there has yet to be an oral nanoparticle that can be successfully applied. Here, we describe for the first time a novel bile acid conjugated nanoparticle that can be selectively absorbed by bile acid transporters in the small intestine. The bile acid conjugate nanoparticles that were first treated with enterocytes were successfully attached to the cell surface and then internalized inside the cells. We show that bile acid based interaction between a nanoparticle and its transporter induces its endocytosis and cellular uptake. This feature of cellular activity, described here for the first time, could be well utilized in the uptake of nanoparticles or macromolecules inside epithelial cells for oral delivery. In animal studies, bile acid conjugated self-assembling nanocomplexes successfully interacted with bile acid transporters in the ileum and were subsequently taken up into the epithelial cells. Considering the importance of orally deliverable nanoparticles, this nanotechnology using bile acid conjugation and transporter mediated endocytosis could be a crucial method for the successful application of various nanoparticles.

Graphical abstract

http://ift.tt/2wGSUdb

MTA promotes chemotaxis and chemokinesis of immune cells through distinct calcium-sensing receptor signaling pathways

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Fengjiao Chang, Jin Man Kim, Youngnim Choi, Kyungpyo Park
Mineral trioxide aggregate (MTA) has been introduced as a choice material for regenerative dentistry. To date, the diverse biological activities of MTA, including its anti-inflammatory effects, have been extensively discussed. However, there is limited insight into the link between MTA and immune cell migration. In this study, we report the role of MTA in enhancing both chemotactic and chemokinetic immune cell migration through distinct signaling pathways. By using versatile live imaging techniques, we demonstrated that MTA-mediated CaSR activation induced diverse downstream pathways to govern cell migratory capacity. In this context, Cdc42 generates cytoskeleton-driven cellular protrusions to steer directional cell migration (chemotaxis) whereas Ca²⁺-calmodulin dependent myosin light chain kinase induces cell contractility that plays an important role in speeding up the average migration speed (chemokinesis). Our findings illuminate an unrecognized role for MTA and the related CaSR signaling network in immune cell migration, providing evidence that can drive development of novel approaches to immunological therapy.

http://ift.tt/2i2XewL

Editorial board

Publication date: December 2017
Source:Biomaterials, Volume 147

http://ift.tt/2xOxPMF

Unraveling the mechanistic effects of electric field stimulation towards directing stem cell fate and function: A tissue engineering perspective

Graphical abstract

http://ift.tt/2ymgw6k

Molecular insights for the biological interactions between polyethylene glycol and cells

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Li Xu, Jiapei Yang, Bai Xue, Chuan Zhang, Leilei Shi, Chenwei Wu, Yue Su, Xin Jin, Yumin Liu, Xinyuan Zhu
As the gold standard polymer for drug delivery system, polyethylene glycol (PEG) has excellent biocompatibility. It's reported that the low nonspecific interactions between PEG and body contribute to its biocompatibility. However, here we discover dynamic biological interactions exist between PEG and cells on the molecular level. PEG (2 kD) can induce metabolism modulations and survival autophagy by creating an intracellular hypoxic environment, which act as cellular survival strategies in response to the hypoxia. In the cellular adaption process during hypoxia, PEG-treated cells decrease energy consumption by reducing cell growth rate, increase energy supply by amino acid catabolism in a short period, and survival autophagy over a relatively long period, to keep energy homeostasis and survival. Our research provides molecular insights for understanding the mechanism underlying the excellent biocompatibility of PEG, which will be of fundamental importance for further related studies on other polymers and development of polymeric materials with improved characteristics.

Graphical abstract

http://ift.tt/2fyVJSc

Mechanotransduction of human pluripotent stem cells cultivated on tunable cell-derived extracellular matrix

Extracellular matrix-derived extracellular vesicles promote cardiomyocyte growth and electrical activity in engineered cardiac atria

Publication date: November 2017
Source:Biomaterials, Volume 146
Author(s): Minae An, Kihwan Kwon, Junbeom Park, Dong-Ryeol Ryu, Jung-A. Shin, Jihee Lee Kang, Ji Ha Choi, Eun-Mi Park, Kyung Eun Lee, Minna Woo, Minsuk Kim
Extracellular matrix (ECM) plays a critical role in the provision of the necessary microenvironment for the proper regeneration of the cardiac tissue. However, specific mechanisms that lead to ECM-mediated cardiac regeneration are not well understood. To elucidate the potential mechanisms, we investigated ultra-structures of the cardiac ECM using electron microscopy. Intriguingly, we observed large quantities of micro-vesicles from decellularized right atria. RNA and protein analyses revealed that these contained exosomal proteins and microRNAs (miRNAs), which we referred to herein as ECM-derived extracellular vesicles (ECM-EVs). One particular miRNA from ECM-EVs, miR-199a-3p, promoted cell growth of isolated neonatal cardiomyocytes and sinus nodal cells by repressing homeodomain-only protein (HOPX) expression and increasing GATA-binding 4 (Gata4) acetylation. To determine the mechanisms, we knocked down Gata4 and showed that miR-199a-3p actions required Gata4 for cell proliferation in isolated neonatal cardiomyocytes and sinus nodal cells. To further explore the role of this miRNA, we isolated neonatal cardiac cells and recellularized into atrial ECM, referred here has engineered atria. Remarkably, miR-199a-3p mediated the enrichment of cardiomyocyte and sinus nodal cell population, and enhanced electrocardiographic signal activity of sinus nodal cells in the engineered atria. Importantly, antisense of miRNA (antagomir) against miR-199a-3p was capable of abolishing these actions of miR-199a-3p in the engineered atria. We further showed in Ang II-infused animal model of sinus nodal dysfunction that miR-199-3p-treated cardiac cells remarkably ameliorated and restored the electrical activity as shown by normalization of the ECG, in contrast to untreated cells, which did not show electrical recovery. In conclusion, these results provide clear evidence of the critical role of ECM, in not only providing a scaffold for cardiac tissue growth, but also in promoting atrial electrical function through ECM-derived miR-199a-3p.

http://ift.tt/2wQLQZT

Successful transdermal allergen delivery and allergen-specific immunotherapy using biodegradable microneedle patches

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Ji Hye Kim, Jung U. Shin, Seo Hyeong Kim, Ji Yeon Noh, Hye Ran Kim, Jungsoo Lee, Howard Chu, Kyoung Yong Jeong, Kyung Hee Park, Jung Dong Kim, Hong Kee Kim, Do Hyeon Jeong, Tai-Soon Yong, Jung-Won Park, Kwang Hoon Lee
Allergen-specific immunotherapy (SIT) is an effective treatment modality for allergic diseases such as atopic dermatitis (AD). However, frequent visits over a 3-year period as well as looming adverse events tend to discourage patient compliance. Therefore, a more convenient, effective, and safe method of SIT is needed.For several decades, use of microneedles has been promoted as an efficient and precise transdermal drug delivery method. In this study, we developed Dermatophagoides farinae (D. farinae) extract (DfE)-loaded microneedle patches, and evaluated their safety and efficacy as a novel SIT method. After 4 weeks of patch application, efficient allergen delivery and successful induction of immune response to DfE were demonstrated in mice, with no apparent adverse events. AD-induced NC/Nga mice received microneedle immunotherapy (MNIT) (10 μg), subcutaneous immunotherapy (SCIT) (10 μg), SCIT (100 μg), or placebo. Both MNIT (10 μg) and SCIT (100 μg) treatments improved clinical and histologic manifestations of AD skin lesions, altered immunoglobulin production, dampened Th2 cellular response, and boosted Treg infiltrates, without significant side effects; whereas SCIT (10 μg) or placebo subsets failed to show any effects. Based on the favorable safety and efficacy profiles demonstrated in mice by MNIT in the current study, we believe that MNIT may serve as a new SIT modality.

http://ift.tt/2zkazEZ

Enhanced antitumor efficacy of arginine modified amphiphilic nanoparticles co-delivering doxorubicin and iSur-pDNA via the multiple synergistic effect

Publication date: January 2018
Source:Biomaterials, Volume 150
Author(s): Yudong Song, Cui Tang, Chunhua Yin
Arginine and α-tocopherol succinate (α-TOS) double grafted N-trimethyl chitosan chloride (TMC) nanoparticles (TAS NPs) were designed and developed for effective co-delivery of doxorubicin (DOX) and Survivin shRNA-expressing pDNA (iSur-pDNA). With DOX loading into the hydrophobic core and iSur-pDNA combining to the hydrophilic shell, TAS/DOX/pDNA NPs demonstrated favorable structural stability and sustained release properties in vitro. With the special non-clathrin-dependent endocytosis, TAS/DOX/pDNA NPs presented higher cellular uptake and mainly distributed in ER and Golgi rather than lysosomes following internalization. The in vitro nuclear localization, gene silencing efficiency, cell apoptosis, and growth inhibition of tumor cells were significantly promoted by arginine modification. In the tumor-bearing mice model, TAS/DOX/pDNA NPs possessed the maximum antitumor efficiency as compared with single delivery of DOX or iSur-pDNA. Particularly, blank TAS NPs were selectively be toxic to tumor cells as evidenced by their capabilities to inhibit proliferation and induce apoptosis of tumor cells. The promising tumor treatment of TAS/DOX/pDNA NPs via a multiple synergistic manner arising from DOX and pDNA as well as the vectors would provide a potential strategy for a dual-delivery system to improve their therapeutic efficacies.

http://ift.tt/2xxiEJm

Biofabricating atherosclerotic plaques: In vitro engineering of a three-dimensional human fibroatheroma model

Graphical abstract

http://ift.tt/2ymXhcV

Vascular smooth muscle cells derived from inbred swine induced pluripotent stem cells for vascular tissue engineering

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Jiesi Luo, Lingfeng Qin, Mehmet H. Kural, Jonas Schwan, Xia Li, Oscar Bartulos, Xiao-qiang Cong, Yongming Ren, Liqiong Gui, Guangxin Li, Matthew W. Ellis, Peining Li, Darrell N. Kotton, Alan Dardik, Jordan S. Pober, George Tellides, Marsha Rolle, Stuart Campbell, Robert J. Hawley, David H. Sachs, Laura E. Niklason, Yibing Qyang
Development of autologous tissue-engineered vascular constructs using vascular smooth muscle cells (VSMCs) derived from human induced pluripotent stem cells (iPSCs) holds great potential in treating patients with vascular disease. However, preclinical, large animal iPSC-based cellular and tissue models are required to evaluate safety and efficacy prior to clinical application. Herein, swine iPSC (siPSC) lines were established by introducing doxycycline-inducible reprogramming factors into fetal fibroblasts from a line of inbred Massachusetts General Hospital miniature swine that accept tissue and organ transplants without immunosuppression within the line. Highly enriched, functional VSMCs were derived from siPSCs based on addition of ascorbic acid and inactivation of reprogramming factor via doxycycline withdrawal. Moreover, siPSC-VSMCs seeded onto biodegradable polyglycolic acid (PGA) scaffolds readily formed vascular tissues, which were implanted subcutaneously into immunodeficient mice and showed further maturation revealed by expression of the mature VSMC marker, smooth muscle myosin heavy chain. Finally, using a robust cellular self-assembly approach, we developed 3D scaffold-free tissue rings from siPSC-VSMCs that showed comparable mechanical properties and contractile function to those developed from swine primary VSMCs. These engineered vascular constructs, prepared from doxycycline-inducible inbred siPSCs, offer new opportunities for preclinical investigation of autologous human iPSC-based vascular tissues for patient treatment.

http://ift.tt/2hoe5WH

Rethinking liquid biopsy: Microfluidic assays for mobile tumor cells in human body fluids

Multifunctional superparamagnetic nanoparticles conjugated with fluorescein-labeled designed ankyrin repeat protein as an efficient HER2-targeted probe in breast cancer

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Dong-Li Li, Jian-Er Tan, Ying Tian, Shun Huang, Peng-Hui Sun, Meng Wang, Yan-Jiang Han, Hong-Sheng Li, Hu-Bing Wu, Xing-Mei Zhang, Yi-Kai Xu, Quan-Shi Wang
Based on the discordance of human epidermal growth factor receptor-2 (HER2) expression between primary and metastatic/recurrent breast cancer, HER2 molecular imaging, which had potential to systemically assess and dynamically monitor HER2 expression, might improve the selection of patients for anti-HER2 therapy. In this study, designed ankyrin repeat protein (DARPin) G3, a novel binding protein with picomolar affinity for HER2, was used and multifunctional superparamagnetic nanoparticles modified with fluorescein-5-maleimide-labeled DARPin G3 (SPIO-G3-5MF) were developed for HER2 imaging. Our results showed that SPIO-G3-5MF nanoparticles, which possessed uniform size of about 100 nm, favorable dispersity and low cytotoxicity, could selectively bind to HER2-positive breast cancer cells even in the presence of trastuzumab. Biodistribution assay demonstrated that abundant accumulation and long retention of SPIO-G3-5MF were observed in HER2-positive transplantation breast tumors although a portion of SPIO-G3-5MF nanoparticles were unavoidably captured by liver and spleen. Further MR imaging revealed that SPIO-G3-5MF could selectively image HER2-positive transplantation breast tumors, yielding remarkable T2 signal reduction (50.33 ± 2.90% at 6 h and 47.29 ± 9.36% at 24 h). Our study suggested that SPIO-G3-5MF might be a promising MR molecular probe for diagnosing and monitoring HER2 expression state of breast cancer in the future.

http://ift.tt/2xOxQA8

Active immunotherapy for TNF-mediated inflammation using self-assembled peptide nanofibers

Publication date: December 2017
Source:Biomaterials, Volume 149
Author(s): Carolina Mora-Solano, Yi Wen, Huifang Han, Jianjun Chen, Anita S. Chong, Michelle L. Miller, Rebecca R. Pompano, Joel H. Collier
Active immunotherapies raising antibody responses against autologous targets are receiving increasing interest as alternatives to the administration of manufactured antibodies. The challenge in such an approach is generating protective and adjustable levels of therapeutic antibodies while at the same time avoiding strong T cell responses that could lead to autoimmune reactions. Here we demonstrate the design of an active immunotherapy against TNF-mediated inflammation using short synthetic peptides that assemble into supramolecular peptide nanofibers. Immunization with these materials, without additional adjuvants, was able to break B cell tolerance and raise protective antibody responses against autologous TNF in mice. The strength of the anti-TNF antibody response could be tuned by adjusting the epitope content in the nanofibers, and the T-cell response was focused on exogenous and non-autoreactive T-cell epitopes. Immunization with unadjuvanted peptide nanofibers was therapeutic in a lethal model of acute inflammation induced by intraperitoneally delivered lipopolysaccharide, whereas formulations adjuvanted with CpG showed comparatively poorer protection that correlated with a more Th1-polarized response. Additionally, immunization with peptide nanofibers did not diminish the ability of mice to clear infections of Listeria monocytogenes. Collectively this work suggests that synthetic self-assembled peptides can be attractive platforms for active immunotherapies against autologous targets.

http://ift.tt/2g8vAdX

pH multistage responsive micellar system with charge-switch and PEG layer detachment for co-delivery of paclitaxel and curcumin to synergistically eliminate breast cancer stem cells

Publication date: December 2017
Source:Biomaterials, Volume 147
Author(s): Zhe Yang, Na Sun, Rui Cheng, Chenyang Zhao, Zerong Liu, Xian Li, Jie Liu, Zhongmin Tian
Several studies have demonstrated that cancer stem cells (CSCs) are responsible for replenishing bulk tumor cells, generating new tumors and causing metastasis and relapse. Although combination therapy with multiple chemotherapeutics is considered to be a promising approach for simultaneously eliminating non-CSCs and CSCs, it is difficult to deliver drugs into the inner region of a solid tumor where the CSCs are located due to a lack of capillaries. Here, we synthesized a pH-sensitive polymer, poly(ethylene glycol)-benzoic imine-poly(γ-benzyl-l-aspartate)-b-poly(1-vinylimidazole) block copolymer (PPBV), to develop a pH multistage responsive micellar system for co-delivering paclitaxel and curcumin and synergistically eliminating breast cancer stem cells (bCSCs) and non-bCSCs. This pH multistage responsive micellar system could intelligently switch its surface charge from neutral to positive, de-shield its PEG layer and reduce its size after long-circulation and extravasation from leaky blood vessels at tumor sites, thus facilitating their cellular uptake and deep tumor penetration. These advantages were also beneficial for the combinational therapy efficacy of PTX and CUR to reach the maximum level and achieve superior tumor inhibition activity and effective bCSCs-killing capacity in vivo. Consequently, this pH multistage responsive micellar system is a powerful platform for collaborative therapy with PTX and CUR to simultaneously eliminate bCSCs and non-CSCs.

Graphical abstract

http://ift.tt/2f7bdwT

Single-walled carbon nanotube: One specific inhibitor of cancer stem cells in osteosarcoma upon downregulation of the TGFβ1 signaling

Publication date: December 2017
Source:Biomaterials, Volume 149
Author(s): Yanyan Miao, Haixia Zhang, Yubin Pan, Jian Ren, Miaoman Ye, Fangfang Xia, Rui Huang, Zhuoheng Lin, Shuai Jiang, Ya Zhang, Zhou Songyang, Yan Zhang
Cancer stem cells (CSCs) are believed to have a critical role in tumorigenesis, metastasis, therapeutic resistance or recurrence. Therefore, strategies designed to specifically target and eliminate CSCs have become one of the most promising and desirable ways for tumor treatment. Osteosarcoma stem cells (OSCs), the CSCs in osteosarcoma (OS), are critically associated with OS progression. Here, we show that single-walled carbon nanotubes (SWCNTs), including unmodified SWCNT (SWCNT-Raw) and SWCNT-COOH, have the ability to specifically inhibit the process of TGFβ1-induced OS cells dedifferentiation, prevent the stem cell phenotypes acquisition in OS cells and reduce the OSC viability under conditions which mimic the OS microenvironment. Concurrently, SWCNT treatment significantly down-regulates the expression of OSC markers in OS, and markedly reduces the tumor microvessel density and tumor growth. Furthermore, we found that SWCNT could suppress the TGFβ1-induced activation of TGFβ type I receptor and downstream signaling, which are key for the OSC formation and maintenance. Our results reveal an unexpected function of SWCNT in negative modulation of OSCs, and provide significant implications for the potential CSCs-targeted therapeutic applications of SWCNT.

http://ift.tt/2wCwLZd

Modular flow chamber for engineering bone marrow architecture and function

Publication date: November 2017
Source:Biomaterials, Volume 146
Author(s): Christian A. Di Buduo, Paolo M. Soprano, Lorenzo Tozzi, Stefania Marconi, Ferdinando Auricchio, David L. Kaplan, Alessandra Balduini
The bone marrow is a soft, spongy, gelatinous tissue found in the hollow cavities of flat and long bones that support hematopoiesis in order to maintain the physiologic turnover of all blood cells. Silk fibroin, derived from Bombyx mori silkworm cocoons, is a promising biomaterial for bone marrow engineering, because of its tunable architecture and mechanical properties, the capacity of incorporating labile compounds without loss of bioactivity and demonstrated ability to support blood cell formation. In this study, we developed a bone marrow scaffold consisting of a modular flow chamber made of polydimethylsiloxane, holding a silk sponge, prepared with salt leaching methods and functionalized with extracellular matrix components. The silk sponge was able to support efficient platelet formation when megakaryocytes were seeded in the system. Perfusion of the chamber allowed the recovery of functional platelets based on multiple activation tests. Further, inhibition of AKT signaling molecule, which has been shown to be crucial in regulating physiologic platelet formation, significantly reduced the number of collected platelets, suggesting the applicability of this tissue model for evaluation of the effects of bone marrow exposure to compounds that may affect platelet formation. In conclusion, we have bioengineered a novel modular system that, along with multi-porous silk sponges, can provide a useful technology for reproducing a simplified bone marrow scaffold for blood cell production ex vivo.

http://ift.tt/2wTxgBo

The Sunshine ACT And Oncology: Lessons Learned From Urology

Publication date: Available online 13 October 2017
Source:Seminars in Oncology
Author(s): Mahir Maruf, Piyush K. Agarwal, Abhinav Sidana

http://ift.tt/2wUNN50

Emerging roles for long noncoding RNAs in B-cell development and malignancy

Publication date: Available online 13 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): M. Winkle, J.L. Kluiver, Diepstra Arjan, A. van den Berg
Long noncoding (lnc)RNAs have emerged as essential mediators of cellular biology, differentiation and malignant transformation. LncRNAs have a broad range of possible functions at the transcriptional, posttranscriptional and protein level and their aberrant expression significantly contributes to the hallmarks of cancer cell biology. In addition, their high tissue- and cell-type specificity makes lncRNAs especially interesting as biomarkers, prognostic factors or specific therapeutic targets. Here, we review current knowledge on lncRNA expression changes during normal B-cell development, indicating essential functions in the differentiation process. In addition we address lncRNA deregulation in B-cell malignancies, the putative prognostic value of this as well as the molecular functions of multiple deregulated lncRNAs. Altogether, the discussed work indicates major roles for lncRNAs in normal and malignant B cells affecting oncogenic pathways as well as the response to common therapeutics.

http://ift.tt/2yg9kZT

Prognostic Outcomes in Advanced Breast Cancer: The Metastasis-free Interval is Important

Publication date: Available online 13 October 2017
Source:Human Pathology
Author(s): Tiansheng Shen, Cheng Gao, Kui Zhang, Gene P. Siegal, Shi Wei
Metastatic breast cancer is a heterogeneous disease with a diverse clinical course. There have been limited studies regarding prognostic outcomes in patients with de novo metastatic breast cancer versus those with metastatic recurrence, with controversial observations. In this study, we sought to examine the difference in survival outcomes among patients with advanced breast cancer stratified based on metastasis-free interval (MFI), and to further explore the role of systemic therapy in these patient groups. Of 569 consecutive patients with stage IV breast cancer between 1998 and 2013, 201 had de novo metastatic disease (metastasis at diagnosis) and 368 developed metastatic recurrence, including 168 with a MFI≤24months and 200 with a MFI>24months. In the 492 patients who received systemic therapy, de novo metastasis was an independent favorable prognostic factor for overall survival after metastasis when compared to metastatic recurrence irrespective of MFI. Compared to the patients with metastatic recurrence with a MFI≤24months, those with a MFI>24months had a significantly superior survival outcome, although it did not reach statistical significance by multivariate analysis. In contrast, de novo metastatic breast cancer was associated with a worse prognosis when compared to recurring metastasis in the patients who did not receive systemic treatment. These findings provide more insight into the natural history of advanced breast cancer thus necessitating further investigation into the molecular mechanism of drug resistance.

http://ift.tt/2iantkQ

Ketogenic Diet and Anorexia Nervosa

Publication date: Available online 13 October 2017
Source:Medical Hypotheses
Author(s): Barbara Scolnick
This hypothesis suggest that starvation-induced ketosis, which leads to a fundamental biochemical change in the metabolic fuel supply of the brain, is uniquely anxiolytic and rewarding to patients prone to AN. Ketosis can easily be replicated by a unique diet marked by high fat, moderate protein, and very low carbohydrate. This diet, known as a ketogenic diet (KGD) mimics starvation, thus allowing the patient to experience the anxiolytic state of ketosis, and yet avoid the morbidity of starvation.

http://ift.tt/2giN0aR

The VEGF Paradox : Does diabetic retinopathy protect from age related macular degeneration?

Publication date: Available online 13 October 2017
Source:Medical Hypotheses
Author(s): Mario Saravia, Luis Zeman, Mariana Ingolotti, Ariel Schlaen
Age-related macular disease (AMD) and diabetic retinopathy (DR) are prevalent diseases. Vascular endothelial growth factor (VEGF) related retinal neovascularization is a common feature in both. Consequently, both pathologies are treated with anti-VEGF therapy. We have previously reported a lower incidence of AMD in patients with DR compared to controls. The present study hypothesizes that DR in stages in which the concentration of intravitreal VEGF is increased, might have a protective role for both the onset and development of AMD.

http://ift.tt/2ynBvpw

Effect of the ultraviolet light treatment and storage methods on the biological activity of a titanium implant surface

Publication date: Available online 13 October 2017
Source:Dental Materials
Author(s): Sung-Hwan Choi, Won-Seok Jeong, Jung-Yul Cha, Jae-Hoon Lee, Kee-Joon Lee, Hyung-Seog Yu, Eun-Ha Choi, Kwang-Mahn Kim, Chung-Ju Hwang
ObjectiveWe evaluated whether the biological activity of the surface of titanium, when stored in an aqueous solution, in low vacuum, and under ambient conditions after ultraviolet light (UV) treatment is comparable to that of the surface immediately after UV treatment for 15min and that after dielectric barrier discharge (DBD) plasma treatment for 15min.MethodsGrade IV titanium discs with machined surfaces were irradiated with UV and their surface properties were evaluated immediately and after storage for 28days in distilled H2O (dH2O), a vacuum desiccator (31.325kPa), and a sealed container under air. Their surface characteristics were evaluated by atomic force microscopy, X-ray diffraction, contact angle analysis, and X-ray photoelectron spectroscopy. Biological activities were determined by analyzing the albumin adsorption, MC3T3-E1 cell adhesion, and cytoskeleton development.ResultsHydrophilicity of titanium surfaces stored in dH2O was comparable to that immediately after UV treatment and higher than that immediately after DBD plasma treatment (P<0.001). Storage in dH2O and in low vacuum immediately after UV treatment prevented hydrocarbon contamination and maintained elevated amounts of titanium and oxygen. After 28 days, protein adsorption, cellular adhesion, and cytoskeletal development of MC3T3-E1 cells on the titanium surfaces stored in dH2O were significantly enhanced compared to those stored in low vacuum and under ambient conditions while being comparable to those immediately after UV and DBD plasma treatments.SignificanceUV treatment of the titanium implants followed by wet storage is useful for maintaining enhanced biological activity and overcoming biological aging during shelf storage.

http://ift.tt/2i8DzeP

Disrupted Physiological Reactivity Among Children with a History of Suicidal Ideation: Moderation by Parental Expressed Emotion-Criticism

Publication date: Available online 13 October 2017
Source:Biological Psychology
Author(s): Kiera M. James, Mary L. Woody, Cope Feurer, Anastacia Y. Kudinova, Brandon E. Gibb
ObjectiveThe goal of this study was to examine physiological reactivity during parent-child interactions in children with and without a history of suicidal ideation (SI), a group known to be at increased risk for suicidal thoughts and behaviors in the future. We also examined the potential moderating role of parental expressed emotion-criticism (EE-Crit) to determine whether the presence of parental criticism may help to identify a subgroup of children with a history of SI most at risk for physiological dysregulation.MethodParticipants were 396 children (age 7-11; 54% male, 71.7% Caucasian) and their biological parent. Children's levels of high frequency heart rate variability (HF-HRV) were assessed during a resting baseline period followed by a positive and negative discussion with their parent. Additionally, parents completed the Five-Minute Speech Sample to determine levels of EE-Crit toward their child, and children completed an interview assessing their history of SI.ResultsConsistent with our hypothesis, we found that exposure to parental criticism moderated the relation between a child's history of SI and their HF-HRV reactivity to the discussions. Specifically, while most children exhibited the typical pattern of HF-HRV suppression from baseline to both interactions, the highest risk children (i.e., children with a history of SI who also had highly critical parents) did not display any change in HF-HRV across the tasks, suggesting a failure to engage a typical psychophysiological response during emotional contexts.ConclusionsThese results suggest a specific physiological mechanism that may place these children at risk for suicidal thoughts and behaviors in the future.

http://ift.tt/2xEmxMn

Global proteome and phosphoproteome dynamics indicate novel mechanisms of vitamin C induced dormancy in Mycobacterium smegmatis

Publication date: Available online 13 October 2017
Source:Journal of Proteomics
Author(s): Claudia Albeldas, Naadir Ganief, Bridget Calder, Kehilwe C. Nakedi, Shaun Garnett, Andrew J.M. Nel, Jonathan M. Blackburn, Nelson C. Soares
Vitamin C has been found to affect mycobacteria in multiple ways, including increasing susceptibility to antimicrobial drugs, inducing dormancy, and having a bactericidal effect. However, the regulatory events mediating vitamin C related adaptations remain largely elusive. Ser/Thr/Tyr protein phosphorylation plays an important regulatory role in mycobacteria, contributing to environmental adaptation, including dormancy and drug resistance. This study utilised the model organism, Mycobacterium smegmatis, and TiO2 phosphopeptide enrichment combined with mass spectrometry-based proteomics methods to elucidate the mycobacterial signalling and regulatory response to sub-lethal concentrations of vitamin C. After initial validation of peptide spectra, 224 non-redundant phosphosites in 154 proteins were retained with high confidence. Data analysis revealed that 30 peptides were differentially phosphorylated with Vitamin C treatment, including novel phosphosites found on both PknG and GarA. Of these significant proteins, we validated 11 by parallel reaction monitoring of high-confidence phosphopeptides. Interestingly, 17/30 phosphopeptides were annotated as part of transmembrane proteins, suggesting that it is likely vitamin C triggers typical signal transduction events in which the protein periplasmic domain perceives environmental signals and the cytoplasmic domain is then phosphorylated. Finally, the diverse nature of phosphorylated proteins involved in signalling, transport, and carbohydrate biosynthesis indicates the extent of such regulatory phosphorylation events.Biological significanceOur findings provide new mechanistic insight into a coordinated network of signalling and regulatory responses to sub-lethal vitamin C in Mycobacterium smegmatis and provide evidence that vitamin C is able to act as a novel extracellular signalling molecule. Vitamin C treatment caused changes in both the proteome and phosphoproteome associated with response to oxidative stress, a shift in metabolic regulation and progression toward dormancy, as well as phospho-dependent activation of specific secretory pathways and activation of specific two component and Ser/Thr/Tyr protein kinase activities. This study confirms the potential of vitamin C as convenient means to study aspects of mycobacterial dormancy, including those regulated at post-translational level.

Graphical abstract

http://ift.tt/2g88svx

Nodal areas of potential geographic error in adjuvant radiotherapy for biliary tract cancer

Publication date: Available online 13 October 2017
Source:Radiotherapy and Oncology
Author(s): Joanna Socha, Maciej Michalak, Grzegorz Wołąkiewicz, Lucyna Kepka
PurposeTo determine the areas of potential geographic error in adjuvant radiotherapy (RT) for biliary-tract cancer (BTC) by comparing pathological-surgical data on the pattern of nodal spread with the extent of elective nodal CTV used in published RT studies in this setting.Material/methodsA literature search was performed to select articles on: 1/adjuvant RT for BTC, that provided information on the lymph node stations (LNS) included in the CTV; 2/the pathological-surgical data on the patterns of nodal involvement/recurrence in BTC. Risk of nodal involvement/recurrence and frequency of inclusion in the CTV in RT studies for each of the LNS were compared to determine the areas of potential geographic misses and unnecessary irradiation, separately for intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC) and gallbladder-cancer (GBC).ResultsAreas of potential geographic misses include: for right IHC: paraaortic and superior mesenteric artery (SMA) LNS; for left or hilar IHC: left gastric, lesser gastric curvature, paraaortic, and SMA LNS; for proximal EHC: paraaortic LNS; for middle EHC: paraaortic and SMA LNS; for distal EHC: paraaortic, SMA, and anterior pancreatico-duodenal LNS; for GBC: paraaortic, SMA, and posterior pancreatico-duodenal LNS. Celiac-LNS is unnecessarily irradiated for middle/distal EHC.ConclusionsIn view of discrepancies between pathological-surgical data and the CTVs used in common practice, there is an obvious need for international consensus guidelines.

http://ift.tt/2kND5M2

ZnO/ZrO2 nanocomposite: Sonosynthesis, characterization and its application for wastewater treatment

Publication date: March 2018
Source:Ultrasonics Sonochemistry, Volume 41
Author(s): Shokufeh Aghabeygi, Mostafa Khademi-Shamami
ZnO/ZrO2 nanocomposites with different ZnO: ZrO2 molar ratios (2:1, 1:1, and 1:2)were prepared by sol gel approach under ultrasonic irradiation. For preparation of the nano-composites, the ZnO gel was directly incorporated into the ZrO2 gel at different molar ratios. The reaction mixture was stirred continuously for two days and then it was ultrasonoicated for 30min. The filtrated composite gel was washed, and then calcinated at 300°C in furnace for 3h. X-ray powder diffraction patterns exhibited well-formed crystal structures and pure crystalline phases in the synthesized nanoparticles (NPs). The FT-IR analyses indicated that the positions of peaks related to Zn-O and Zr-O absorption bands did not change in nano-composites. In addition, FESEM images indicated uniform spherical morphology of the NPs. The highest photo-degradation performance of Congo red (as a model water pollutant) was obtained by 1:2molar ratio of ZrO2: ZnO in the nano-composite. The particle size and band gap were considered as important factors on nano-catalysts performance. Furthermore, the effects of ultrasonic irradiation, pH, and the concentration of pollutant in solution were investigated on photocatalytic performance of optimum nanocomposite.

http://ift.tt/2gjRgqF

Biochemical and pharmacological characterization of three opioid-nociceptin hybrid peptide ligands reveals substantially differing modes of their actions

Publication date: Available online 13 October 2017
Source:Peptides
Author(s): Anna I. Erdei, Adina Borbély, Anna Magyar, Nóra Taricska, András Perczel, Ottó Zsíros, Győző Garab, Edina Szűcs, Ferenc Ötvös, Ferenc Zádor, Mihály Balogh, Mahmoud Al-Khrasani, Sándor Benyhe
In an attempt to design opioid-nociceptin hybrid peptides, three novel bivalent ligands, H-YGGFGGGRYYRIK-NH2, H-YGGFRYYRIK-NH2 and Ac-RYYRIKGGGYGGFL-OH were synthesized and studied by biochemical, pharmacological, biophysical and molecular modelling tools. These chimeric molecules consist of YGGF sequence, a crucial motif in the N-terminus of natural opioid peptides, and Ac-RYYRIK-NH2, which was isolated from a combinatorial peptide library as an antagonist or partial agonist that inhibits the biological activity of the endogenously occurring heptadecapeptide nociceptin. Solution structures for the peptides were studied by analysing their circular dichroism spectra. Receptor binding affinities were measured by equilibrium competition experiments using four highly selective radioligands. G-protein activating properties of the multitarget peptides were estimated in [³⁵S]GTPγS binding tests. The three compounds were also measured in electrically stimulated mouse vas deferens (MVD) bioassay. H-YGGFGGGRYYRIK-NH2 (BA55), carrying N-terminal opioid and C-terminal nociceptin-like sequences interconnected with GGG tripeptide spacer displayed a tendency of having either unordered or β-sheet structures, was moderately potent in MVD and possessed a NOP/KOP receptor preference. A similar peptide without spacer H-YGGFRYYRIK-NH2 (BA62) exhibited the weakest effect in MVD, more α-helical periodicity was present in its structure and it exhibited the most efficacious agonist actions in the G-protein stimulation assays. The third hybrid peptide Ac-RYYRIKGGGYGGFL-OH (BA61) unexpectedly displayed opioid receptor affinities, because the opioid message motif is hidden within the C-terminus. The designed chimeric peptide ligands presented in this study accommodate well into a group of multitarget opioid compounds that include opioid-non-opioid peptide dimer analogues, dual non-peptide dimers and mixed peptide- non-peptide bifunctional ligands.

http://ift.tt/2ympErx

Peptide welding technology – A simple strategy for generating innovative ligands for G protein coupled receptors

Publication date: Available online 13 October 2017
Source:Peptides
Author(s): Girolamo Calo, Anna Rizzi, Chiara Ruzza, Federica Ferrari, Salvatore Pacifico, Elaine C. Gavioli, Severo Salvadori, Remo Guerrini
Based on their high selectivity of action and low toxicity, naturally occurring peptides have great potential in terms of drug development. However, the pharmacokinetic properties of peptides, in particular their half life, are poor. Among different strategies developed for reducing susceptibility to peptidases, and thus increasing the duration of action of peptides, the generation of branched peptides has been described. However, the synthesis and purification of branched peptides is extremely complicated thus limiting their druggability. Here we present a novel and facile synthesis of tetrabranched peptides acting as GPCR ligands and their in vitro and vivo pharmacological characterization. Tetrabranched derivatives of nociceptin/orphanin FQ (N/OFQ), N/OFQ related peptides, opioid peptides, tachykinins, and neuropeptide S were generated with the strategy named peptide welding technology (PWT) and characterized by high yield and purity of the desired final product. In general, PWT derivatives displayed a pharmacological profile similar to that of the natural sequence in terms of affinity, pharmacological activity, potency, and selectivity of action in vitro. More importantly, in vivo studies demonstrated that PWT peptides are characterized by increased potency associated with long lasting duration of action. In conclusion, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects.

http://ift.tt/2ginC5n

A Bombyx homolog of ovo is a segmentation gene that acts downstream of Bm-wnt1(Bombyx wnt1 homolog)

Publication date: January 2018
Source:Gene Expression Patterns, Volume 27
Author(s): Hajime Nakao
Insect embryogenesis is divided into long and short/intermediate germ types. The long germ type may exhibit Drosophila-like hierarchical segmentation mechanisms, whereas the short/intermediate type assumes some repeating mechanisms that are considered to be ancestral. Embryogenesis in Bombyx mori possesses both characteristics. Here, Bombyx ovo homolog (Bm-ovo) was identified as a gene involved in segmentation. Ovo is a Drosophila gene that encodes a zinc finger transcription factor and studies on its homolog functions in other systems have suggested that it acts as a switch to enable the initiation of differentiation from a progenitor cell state. This is the first description for ovo homologs being involved in insect segmentation. Bm-ovo is expressed dynamically during embryogenesis in a pattern that resembles that of gap and pair-rule genes. In Bm-ovo RNAi knockdown embryos, posterior segmentation does not proceed. In addition, defects in anterior segments are observed. In Bm-wnt1 knockdown embryos, the Bm-ovo expression pattern was changed, suggesting that Bm-wnt1 is an upstream regulator of Bm-ovo. The involvement of Bm-ovo may represent a novel ancestral step under the control of wnt genes in insect segmentation: this step may resemble those operating in cell differentiation processes.

http://ift.tt/2z6Ej7v

Intensity Inhomogeneity Correction of SD-OCT Data Using Macular Flatspace

Publication date: Available online 12 October 2017
Source:Medical Image Analysis
Author(s): Andrew Lang, Aaron Carass, Bruno M. Jedynak, Sharon D. Solomon, Peter A. Calabresi, Jerry L. Prince
Images of the retina acquired using optical coherence tomography (OCT) often suffer from intensity inhomogeneity problems that degrade both the quality of the images and the performance of automated algorithms utilized to measure structural changes. This intensity variation has many causes, including off-axis acquisition, signal attenuation, multi-frame averaging, and vignetting, making it difficult to correct the data in a fundamental way. This paper presents a method for inhomogeneity correction by acting to reduce the variability of intensities within each layer. In particular, the N3 algorithm, which is popular in neuroimage analysis, is adapted to work for OCT data. N3 works by sharpening the intensity histogram, which reduces the variation of intensities within different classes. To apply it here, the data are first converted to a standardized space called macular flat space (MFS). MFS allows the intensities within each layer to be more easily normalized by removing the natural curvature of the retina. N3 is then run on the MFS data using a modified smoothing model, which improves the efficiency of the original algorithm. We show that our method more accurately corrects gain fields on synthetic OCT data when compared to running N3 on non-flattened data. It also reduces the overall variability of the intensities within each layer, without sacrificing contrast between layers, and improves the performance of registration between OCT images.

http://ift.tt/2gE5qQB

Dataset of the livability performance of the City of Birmingham, UK, as measured by its citizen wellbeing, resource security, resource efficiency and carbon emissions

Publication date: Available online 13 October 2017
Source:Data in Brief
Author(s): Joanne M. Leach, Susan E. Lee, Christopher T. Boyko, Claire J. Coulton, Rachel Cooper, Nicholas Smith, Hélène Joffe, Milena Büchs, James D. Hale, Jonathan P. Sadler, Peter A. Braithwaite, Luke S. Blunden, Valeria De Laurentiis, Dexter V.L. Hunt, AbuBakr S. Bahaj, Katie Barnes, Christopher J. Bouch, Leonidas Bourikas, Marianna Cavada, Andrew Chilvers, Stephen J. Clune, Brian Collins, Ellie Cosgrave, Nick Dunn, Jane Falkingham, Patrick James, Corina Kwami, Martin Locret-Collet, Francesca Medda, Adriana Ortegon, Serena Pollastri, Cosmin Popan, Katerina Psarikidou, Nick Tyler, John Urry, Yue Wu, Victoria Zeeb, Chris D.F. Rogers
This data article presents the UK City LIFE1 data set for the city of Birmingham, UK. UK City LIFE1 is a new, comprehensive and holistic method for measuring the livable sustainability performance of UK cities. The Birmingham data set comprises 346 indicators structured simultaneously (1) within a four-tier, outcome-based framework in order to aid in their interpretation (e.g., promote healthy living and healthy long lives, minimize energy use, uncouple economic vitality from CO2 emissions) and (2) thematically in order to complement government and disciplinary siloes (e.g., health, energy, economy, climate change). Birmingham data for the indicators are presented within an Excel spreadsheet with their type, units, geographic area, year, source, link to secondary data files, data collection method, data availability and any relevant calculations and notes. This paper provides a detailed description of UK city LIFE1 in order to enable comparable data sets to be produced for other UK cities. The Birmingham data set is made publically available at http://ift.tt/2z6UoK6 to facilitate this and to enable further analyses. The UK City LIFE1 Birmingham data set has been used to understand what is known and what is not known about the livable sustainability performance of the city and to inform how Birmingham City Council can take action now to improve its understanding and its performance into the future (see "Improving city-scale measures of livable sustainability: A study of urban measurement and assessment through application to the city of Birmingham, UK" [2]).

http://ift.tt/2zllAWE

Gain-of-Function Mutations in G-protein Coupled Receptor Genes Associated with Human Endocrine Disorders

Summary

The human genome encodes more than 700 G-protein coupled receptors (GPCRs), many of which are involved in hormone secretion. To date, more than 100 gain-of-function (activating) mutations in at least ten genes for GPCRs, in addition to several loss-of-function mutations, have been implicated in human endocrine disorders. Previously reported gain-of-function GPCR mutations comprise various missense substitutions, frameshift mutations, intragenic inframe deletions, and copy-number gains. Such mutations appear in both germline and somatic tumour cells, and lead to various hormonal abnormalities reflecting excessive receptor activity. Phenotypic consequences of these mutations include distinctive endocrine syndromes, as well as relatively common hormonal abnormalities. Such mutations encode hyperfunctioning receptors with increased constitutive activity, broadened ligand specificity, increased ligand sensitivity, and/or delayed receptor desensitization. Furthermore, recent studies proposed a paradoxical gain-of-function mechanism caused by inactive GPCR mutants. Molecular diagnosis of GPCR activating mutations serves to improve the clinical management of mutation-positive patients. This review aims to introduce new aspects regarding gain-of-function mutations in GPCR genes associated with endocrine disorders.

http://ift.tt/2xFhdbO

Comparison of Early Outcomes and Restenosis Rate Between Carotid Endarterectomy and Carotid Artery Stenting Using Propensity Score Matching Analysis

Publication date: Available online 12 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Seon-Hee Heo, Kyoung-Won Yoon, Shin-Young Woo, Yang-Jin Park, Young-Wook Kim, Keon-Ha Kim, Chin-Sang Chung, Oh-Young Bang, Dong-Ik Kim
Objective/BackgroundDespite randomised evidence, the debate continues about the preferred treatment strategy for carotid stenosis in routine clinical practice. The aim of this study was to compare early outcomes and restenosis rates after carotid endarterectomy (CEA) and carotid stenting (CAS) in unselected patients using propensity score matching (PSM).MethodsThe 30 day incidence of major adverse clinical events (MACE; defined as stroke, transient ischaemic attack, myocardial infarction, or death) and procedure related complications, as well as restenosis rates during follow-up were compared between unselected patients undergoing CEA or CAS between January 2002 and December 2015 at a single institution. PSM was used to balance the following factors between the CEA and CAS cohorts: age, sex, hypertension, diabetes, dyslipidaemia, smoking, atrial fibrillation, previous percutaneous coronary intervention or coronary artery bypass grafting, valvular heart disease, contralateral carotid occlusion, degree of carotid stenosis, and symptomatic status. Statistical comparisons of outcomes were based on logistic regression analysis and log rank test.ResultsOf 1184 patients (654 CEA and 530 CAS), 452 PSM pairs of CEA and CAS patients were created. The CAS group showed a relatively higher 30 day incidence of MACE (7.5% vs. 2.4%; odds ratio [OR] 3.261, 95% confidence interval [CI] 1.634–6.509; p = .001) but a lower incidence of procedure related complications (1.5% vs. 5.3%; OR 0.199, 95% CI 0.075–0.528; p = .001). During a mean follow-up of 49.1 months (range 1–180 months), restenosis rates were higher after CAS than after CEA (1.5% vs. 1.0% at 12 months and 5.4% vs. 1.2% at 24 months, respectively; p = .008).ConclusionThis PSM based observation reconfirmed previous trial results in both asymptomatic and symptomatic patients with carotid artery stenosis in routine clinical practice: CEA showed lower 30 day MACE and mid-term restenosis rates than CAS.

http://ift.tt/2kO8u0U

Clinical Validation of ThyroidPrint: A Gene Expression Signature for Diagnosis of Indeterminate Thyroid Nodules

Condition: Indeterminate Thyroid Cytology
Intervention: Diagnostic Test: In vitro Diagnostic
Sponsors: Pontificia Universidad Catolica de Chile; Geneprodx
Recruiting

http://ift.tt/2i8SHZw

Trichodysplasia spinulosa associated with HIV infection: clinical response to acitretin and valganciclovir

http://ift.tt/2kQb0Uz

Stevens–Johnson syndrome induced by modafinil

http://ift.tt/2kQaW7h

Pure Mucinous (Colloid) Adenocarcinoma of the Conjunctiva

Mucinous carcinomas of the periorbital area are very rare malignant tumors and can be primary or secondary to metastasis. Primary mucinous carcinomas of the eyelid include, most commonly, primary cutaneous mucinous carcinoma with endocrine mucin-producing sweat gland carcinoma being a remote second.[1,2,3,4] To our knowledge, primary mucinous carcinomas of conjunctiva or lacrimal gland elements have not been described in the literature.[5,6] Metastatic carcinoma from visceral sites should also be considered in the differential diagnosis.

http://ift.tt/2zl9f4M

Lupus-like cutaneous reaction following pembrolizumab: an immune-related adverse event associated with anti-PD-1 therapy

PD-1 (programmed cell death-1) inhibitors, used to treat metastatic melanoma and other malignancies, are associated with development of immune-related adverse events in the skin. Such reactions include morbilliform eruptions, vitiligo, alopecia areata, and bullous pemphigoid. In this report, we describe a patient who developed a lupus-like cutaneous reaction in the setting of pembrolizumab therapy for metastatic melanoma, adding to the spectrum of reactions which may be observed in association with PD-1 inhibitor therapy.

http://ift.tt/2xF2D44

Leukocytoclastic vasculitis presenting in association with Coxiella burnetii (Q fever); a case report

Q fever caused by Coxiella burnetii usually presents asymptomatically or as an undifferentiated febrile disease and rarely as rash or other cutaneous manifestations of the disease. Here we present a 41 year old male complaining of body aches, fevers, nausea, malaise, bilateral knee pain, and vomiting. Clinical examination revealed a notable erythematous blanching rash all over his body. Workup revealed positive serologic testing for C burnetii and skin biopsy of the rash revealed leukocytoclastic vasculitis.

http://ift.tt/2zm6mk7

Anti-TNF-α antibody alleviates insulin resistance in rats with sepsis-induced stress hyperglycemia

Abstract

Purpose

To explore the effects and mechanisms of anti-tumor necrosis factor-α (TNF-α) antibody on insulin resistance (IR) in rats with sepsis-induced stress hyperglycemia.

Methods

The sepsis-induced stress hyperglycemic rat model was constructed by cecal ligation and puncture combined with the intraperitoneal injection of lipopolysaccharide. The rats were randomly divided into six groups: normal control (NC) group, surgical rats (Cntl) group, high-dose anti-TNF-α antibody therapy (TNF, 6 mg/kg) group, low-dose anti-TNF-α antibody therapy (Tnf, 3 mg/kg) group, insulin therapy (INS) group, and INS + Tnf group. The blood glucose and serum insulin concentrations were detected, followed by analysis of intraperitoneal glucose tolerance test (IPGTT) and hyperinsulinemic–euglycemic clamp. Finally, the expression levels of phospho-Akt (p-Akt), Akt, p-mTOR, mTOR, nuclear factor-κB (NFκB), I kappa beta kinase (IKKβ), and suppressor of cytokine signaling (SOCS-3) were detected by western blotting.

Results

There was no significant difference in blood glucose concentrations among these groups, while the serum insulin concentration in TNF and Tnf groups was lower than that in the Cntl group at postoperative 6 h (P < 0.05). IPGTT analysis revealed that blood glucose level was lower in the TNF group than that in the Cntl group (P < 0.05). The glucose infusion rate in the Cntl group was lower than that in the Tnf and TNF groups (P < 0.05). The p-Akt/Akt, p-mTOR/mTOR ratio, and expression levels of NFκB, IKKβ and SOCS-3 were lower in the drug intervention than that in the Cntl group (P < 0.05).

Conclusions

Anti-TNF-α antibody could reduce IR by inhibiting AKt/mTOR signaling pathway and the expression levels of NFκB, IKKβ, and SOCS-3 in rats with sepsis-induced stress hyperglycemia.

http://ift.tt/2hEgVXC

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Παρασκευή 13 Οκτωβρίου 2017

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