Evaluation of the N-latex serum free light chain assay on the Siemens BNII analyzer and agreement with The Binding Site FreeLite assay on the SPAPlus

Publication date: Available online 13 May 2017
Source:Clinical Biochemistry
Author(s): Nicole M.A. White-Al Habeeb, Tammy Earle, Megan Spencer, Ivan M. Blasutig
ObjectivesTo evaluate the Siemens N-latex kappa free light chain (κFLC) and lambda FLC (λFLC) assays on the BNII nephelometer and assess agreement with The Binding Site Freelite FLC assays on the SPAPlus.Design and methodsOver 180 patient serum samples from routine analysis of κFLC and λFLC measured by the Freelite assay were collected for the study and measured with the N-latex κFLC and λFLC assays to assess precision, linearity, method comparison and dilutional effects.ResultsComplex precision showed coefficients of variation of 4.8–7.2% for the κFLC assay and 3.6–6.0% for the λFLC assay. Linearity assessment showed both assays were linear (κFLC, y=1.00x−0.09 and λFLC, y=1.050x−1.252). Qualitative method comparison showed 87.9% (116/132) agreement and Cohen's kappa of 80.4% between the κFLC assays and 72.6% (98/135) agreement and Cohen's kappa of 55.4% for the λFLC assays. Quantitative method comparison for κFLC<150mg/L was y=0.92x+2.21, R=0.661 and for λFLC<150mg/L was y=7.90x−137.96, R=0.526. Dilutional effects including antigen excess and non-linearity were also examined.ConclusionsThe N-latex assay showed good precision and linearity with reasonable agreement to the Freelite assay. However, the assays should not be used interchangeably to monitor patients.



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Batten disease

Batten disease: a rare, fatal genetic condition that typically begins in childhood. It is a form of a group of neurologic disorders called the neuronal ceroid lipofuscinoses, or NCLs. The term Batten disease is sometimes used to refer to all the NCL disorders. Early signs can be vision changes, seizures, clumsiness, or behavior changes. With time, neurologic deficits worsen, and the individual loses sight and motor skills. Cognitive abilities decline and dementia develops with time. The disease is often fatal by the teens or twenties. It is also known as Spielmeyer-Vogt-Sjögren-Batten disease. Batten disease is inherited in an autosomal recessive manner.

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Editorial Board

Publication date: July 2017
Source:Cellular Signalling, Volume 35





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Bone Loss After Denosumab: Only Partial Protection with Zoledronate

Abstract

A case series of six women with postmenopausal osteoporosis who had received continuous denosumab for 7 years and were then given a single infusion of zoledronate (5 mg) is reported. During denosumab treatment, bone mineral density (BMD) in the spine increased 18.5% (P = 0.006), and total hip BMD by 6.9% (P = 0.03). Post-zoledronate BMDs were measured 18–23 months after treatment, and there were significant declines at each site (P _spine = 0.043, P _hip = 0.005). Spine BMD remained significantly above the pre-denosumab baseline (+9.3%, P = 0.003), but hip BMD was not significantly different from baseline (−2.9%). At the time of post-zoledronate BMD measurements, serum PINP levels were between 39 and 60 μg/L (mean 52 μg/L), suggesting that the zoledronate treatment had not adequately inhibited bone turnover. It is concluded that this regimen of zoledronate administration is not adequate to preserve the BMD gains that result from long-term denosumab treatment.

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Coordinated regulation of IFITM1, 2 and 3 genes by an IFN-responsive enhancer through long-range chromatin interactions

Publication date: Available online 13 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Ping Li, Ming-Lei Shi, Wen-Long Shen, Zhang Zhang, De-Jian Xie, Xiang-Yuan Zhang, Chao He, Yan Zhang, Zhi-Hu Zhao
Interferon-induced transmembrane protein (IFITM) 1, 2 and 3 are a family of interferon (IFN)-induced transmembrane proteins that block entry of a broad spectrum of pathogens. However, the transcriptional regulation of these genes, especially whether there exists any enhancers and their roles during the IFN induction process remain elusive. Here, combining episomal luciferase reporter assay and in vivo genome editing, we identified an IFNβ-responsive enhancer located 35kb upstream of IFITM3 gene promoter upregulating the IFNβ-induced expression of IFITM1, 2 and 3 genes, thus contributing to IFNβ-mediated resistance to influenza A virus (IAV) infection. The enhancer was first identified and verified by data mining and luciferase reporter assay. Then we showed that signal transducers and activators of transcription (STAT) 1 bound to the enhancer after the treatment of IFNβ and was indispensable for the enhancer activity. Next, CRISPR-Cas9 mediated in vivo truncation of the enhancer considerably decreased both IFNβ and IAV-induced expression of IFTIM1, 2 and 3 in HEK293 cells. Furthermore, chromosome conformation capture revealed that the IFITM1, 2 and 3 genes physically clustered together and constitutively looped to the distal enhancer through long-range interactions in both HEK293 and A549 cells, providing structural basis for coordinated regulation of IFITM1, 2 and 3 by IFNβ. Finally, we showed that in vivo truncation of the enhancer impaired IFNβ-induced resistance to IAV infection. These findings expand our understanding of the mechanisms underlying the transcriptional regulation of IFITM1, 2 and 3 expression and its ability to mediate IFN-β signaling.



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Cell-surface G-protein-coupled receptors for tumor-associated metabolites: A direct link to mitochondrial dysfunction in cancer

Publication date: Available online 13 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Bojana Ristic, Yangzom D. Bhutia, Vadivel Ganapathy
Mitochondria are the sites of pyruvate oxidation, citric acid cycle, oxidative phosphorylation, ketogenesis, and fatty acid oxidation. Attenuation of mitochondrial function is one of the most significant changes that occurs in tumor cells, directly linked to oncogenesis, angiogenesis, Warburg effect, and epigenetics. In particular, three mitochondrial enzymes are inactivated in cancer: pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and 3-hydroxy-3-methylglutaryl CoA synthase-2 (HMGCS2). These enzymes are subject to regulation via acetylation/deacetylation. SIRT3, the predominant mitochondrial deacetylase, directly targets these enzymes for deacetylation and maintains their optimal catalytic activity. SIRT3 is a tumor suppressor, and deacetylation of these enzymes contributes to its biological function. PDH catalyzes the oxidative decarboxylation of pyruvate into acetyl CoA, SDH oxidizes succinate into fumarate, and HMGCS2 controls the synthesis of the ketone body β-hydroxybutyrate. As the activities of these enzymes are decreased in cancer, tumor cells accumulate lactate and succinate but produce less amounts of β-hydroxybutyrate. Apart from their role in cellular energetics, these metabolites function as signaling molecules via specific cell-surface G-protein-coupled receptors. Lactate signals via GPR81, succinate via GPR91, and β-hydroxybutyrate via GPR109A. In addition, lactate activates hypoxia-inducible factor HIF1α and succinate promotes DNA methylation. GPR81 and GPR91 are tumor promoters, and increased production of lactate and succinate as their agonists drives tumorigenesis by enhancing signaling via these two receptors. In contrast, GPR109A is a tumor suppressor, and decreased synthesis of β-hydroxybutyrate as its agonist suppresses signaling via this receptor, thus attenuating the tumor-suppressing function of GPR109A. In parallel with the opposing changes in lactate/succinate and β-hydroxybutyrate levels, tumor cells upregulate GPR81 and GPR91 but downregulate GPR109A. As such, these three metabolite receptors play a critical role in cancer and represent a new class of drug targets with selective antagonists of GPR81 and GPR91 for cancer treatment and agonists of GPR109A for cancer prevention.



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Image denoising via correlation-based sparse representation

Abstract

Error-based Orthogonal Matching Pursuit employed in many image denoising algorithms (e.g., K-means singular value decomposition (K-SVD) algorithm) tries to reconstruct the clean image patch by projecting the observed noisy patch onto a dictionary and picking the atom with maximum orthogonal projection. This approach does indeed minimize the power in the residual. However, minimizing the power in the residual does not guarantee that selected atoms will match the clean image patch. This leaves behind a residual that contains structures from the clean image patch. This problem becomes more pronounced at high noise levels. We propose a simple correlation-based sparse coding algorithm that is better able to pick the atom that matches the clean patch. This is achieved by picking atoms that force the residual patch to have autocorrelation similar to the autocorrelation of contaminating noise. Autocorrelation-based sparse coding and dictionary update stages are iterated, and dictionaries are learned from noisy image patches. The proposed algorithm is compared with the K-SVD denoising algorithm, BM3D and EPLL algorithms. Our results indicate that the proposed algorithm is significantly better than K-SVD and EPLL denoising. At the noise power 100, the improvement over K-SVD denoising algorithm for Barbara and fingerprint images is 1.14 and 2.64 dB, respectively. The proposed algorithm gives results that are visually comparable or better than BM3D algorithm.

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Dupilumab Improves General Health-Related Quality-of-Life in Patients with Moderate-to-Severe Atopic Dermatitis: Pooled Results from Two Randomized, Controlled Phase 3 Clinical Trials

Abstract

Introduction

Patients with moderate-to-severe atopic dermatitis (AD) report a multidimensional disease burden that includes impaired health-related quality-of-life (HRQoL). Changes in overall health status and specific dimensions that contribute to HRQoL were evaluated in adults with moderate-to-severe AD who participated in phase 3 clinical trials of dupilumab, which is a fully human monoclonal antibody that inhibits signaling of cytokines IL-4 and IL-13.

Methods

Two dupilumab phase 3 clinical trials of identical design included the 5-dimension 3-level EuroQol (EQ-5D) as a measure of HRQoL. EQ-5D data from the two trials were pooled in an analysis that, using analysis of covariance, compared subcutaneous dupilumab 300 mg once weekly (qw) or every 2 weeks (q2w) versus placebo for EQ-5D utility score change from baseline overall and for clinical responders. The proportions of patients who reported different levels of problems on the individual dimension of the EQ-5D were also compared by treatment group.

Results

Patients (n = 1379) were 57.9% male with a mean (SD) age of 38.3 (14.3) years; baseline EQ-5D utility scores ranged from 0.611 to 0.629 across treatment groups. EQ-5D least squares mean change from baseline at week 16 was 0.031 with placebo, and was significantly greater with dupilumab qw (0.207) and q2w (0.210) (both P < 0.0001), which exceeded the minimal clinically important difference and resulted in scores that approached population norms. Changes from baseline among patients who achieved AD clinical response were greater than changes among the total population. Improvements were driven by the individual EQ-5D dimensions with the greatest burden at baseline (i.e., pain/discomfort, anxiety/depression and usual activities).

Conclusion

In adults with moderate-to-severe AD, dupilumab resulted in improvements in HRQoL that were statistically significant relative to placebo and were clinically meaningful.

Funding

Sanofi and Regeneron Pharmaceuticals, Inc.

Trial registration

ClinicalTrials.gov identifiers, NCT02277743 and NCT02277769, EudraCT Numbers 2014-001198-15 and 2014-002619-40.

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Native Valve Endocarditis due to Veillonella Species: A Case Report and Review of the Literature

Veillonella species are fastidious bacteria that have been isolated from skin, dental, and respiratory tract infections and rarely have been implicated in serious infections like meningitis, endocarditis, and osteomyelitis. A 76-year-old woman presented to our hospital with fever, vomiting, and generalized weakness for 3 days. A transthoracic echocardiogram showed a mobile structure on anterior mitral valve leaflet measuring 0.9 cm suggestive of vegetation. Empiric therapy with vancomycin and piperacillin-tazobactam was started with clinical resolution of her symptoms. On day 6, the blood culture drawn at admission grew Veillonella species. A transesophageal echocardiogram confirmed a 1.2 0.4 cm echo dense structure attached to the left ventricular side of the anterior mitral leaflet. The patient was discharged home after 10 days of inpatient antibiotic therapy and completed 4 weeks of IV ceftriaxone at home without any adverse events. She was reevaluated in the clinic after completion of treatment and repeat blood cultures remained negative. We report the first case of successful treatment of endocarditis due to Veillonella species with once daily ceftriaxone.

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Dexamethasone Modulates Nonvisual Opsins, Glucocorticoid Receptor, and Clock Genes in Danio rerio ZEM-2S Cells

Here we report, for the first time, the differential cellular distribution of two melanopsins (Opn4m1 and Opn4m2) and the effects of GR agonist, dexamethasone, on the expression of these opsins and clock genes, in the photosensitive D. rerio ZEM-2S embryonic cells. Immunopositive labeling for Opn4m1 was detected in the cell membrane whereas Opn4m2 labeling shows nuclear localization, which did not change in response to light. opn4m1, opn4m2, gr, per1b, and cry1b presented an oscillatory profile of expression in LD condition. In both DD and LD condition, dexamethasone (DEX) treatment shifted the peak expression of per1b and cry1b transcripts to ZT16, which corresponds to the highest opn4m1 expression. Interestingly, DEX promoted an increase of per1b expression when applied in LD condition but a decrease when the cells were kept under DD condition. Although DEX effects are divergent with different light conditions, the response resulted in clock synchronization in all cases. Taken together, these data demonstrate that D. rerio ZEM-2S cells possess a photosensitive system due to melanopsin expression which results in an oscillatory profile of clock genes in response to LD cycle. Moreover, we provide evidence that glucocorticoid acts as a circadian regulator of D. rerio peripheral clocks.

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The Association of Chemokine Gene Polymorphisms with VKH and Behcet’s Disease in a Chinese Han Population

To investigate the association of chemokine gene polymorphisms and Behcet’s disease (BD) and Vogt Koyanagi Harada (VKH) disease in a Chinese Han population. A case-control study was performed. Three hundred and seventy-one BD patients, 371 VKH disease patients, and 605 healthy controls were recruited to determine genetic variants of 26 SNPs in 12 chemokine genes with iPLEX Gold genotyping assay and Sequenom MassARRAY or TaqMan SNP assays. In this study, values showed a weak association of five SNPs of five genes in BD and three SNPs of three genes in VKH disease. However, after Bonferroni correction, the 26 investigated SNPs showed no significant differences in genetic variants, including genotype and allele frequencies, between BD or VKH disease patients and healthy individuals. Haplotype analysis for the chemokine genes showed a significant association with the TC haplotype of CXCL12 in VKH. Stratified gender analysis and genotype-phenotype analysis were conducted to analyze the association of the 26 SNPs of 12 chemokine genes with BD and VKH disease. However, no significant association was observed after Bonferroni correction. This study showed no association of 26 SNPs in 12 chemokine genes with both BD and VKH disease in a Chinese Han population.

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Surrounding Rock Deformation Mechanism and Control Technology for Gob-Side Entry Retaining with Fully Mechanized Gangue Backfilling Mining: A Case Study

To counter the technical difficulties faced by gob-side entry retaining (GER) under multiple complex mining geological conditions in China, this paper introduces a GER method with fully mechanized gangue backfilling mining. A similar materials simulation experiment was conducted to simulate the gob-backfilled GER process by using the similar model test system containing an independently developed horizontal pushing load device. The experimental results show that the compaction speed of the backfilling area (BFA) can be improved, and the main roof subsidence can be reduced by increasing the horizontal pushing load and reducing the attenuation rate of the stress in BFA. The designed roadside backfill body (RBB) containing a flexible cushion is adaptive to the given deformation of the main roof, thus reducing the stress concentration of the RBB. The field test results show that when a 2 MPa horizontal pushing load is exerted in the BFA, arranging a 200 mm high-water-material flexible cushion can cause the BFA to swiftly change to the compaction stage. After stabilized deformation, the roadway section satisfies the design and application requirements. The feasibility and rationality of the GER with the fully mechanized gangue backfilling mining are proved, providing a safe, efficient, and environmentally friendly mining method without using a coal pillar.

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Asymmetric Dimethylarginine Induced Apoptosis and Dysfunction of Endothelial Progenitor Cells: Role of Endoplasmic Reticulum Stress Pathway

Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, is a novel risk factor of cardiovascular disease. Endothelial progenitor cells (EPCs) bear typical endothelial characteristics and are thought to contribute to neovascularization by providing new endothelial cells (ECs) after arterial injury. Many studies have shown that ADMA can induce EPC apoptosis and dysfunction, but the underlying mechanism is not well understood. EPCs from umbilical cord blood were cultured in EGM-2 medium with particular growth factors and supplemented with 10% fetal bovine serum. The cells were treated with different concentrations of ADMA (5, 10, and 50 μmol/L). Endoplasmic reticulum (ER) stress marker levels were examined by western blot analysis. After 24-hour incubation, ADMA induced apoptosis of EPCs and significantly decreased the proliferation, migration, and vasculogenesis capacity of EPCs. We also found that ADMA treatment activated phosphorylated protein kinase RNA-activated-like ER kinase (PERK), a stress sensor protein in the endoplasmic reticulum (ER). The activated PERK induced 78 kDa glucose-regulated protein (GRP-78) and C/EBP homologous protein (CHOP) expression. Additionally, the inhibition of the ER stress pathway by Salubrinal (a specific ER stress inhibitor) can attenuate ADMA-induced apoptosis of EPCs. Overall, these observations indicate that ADMA may induce the apoptosis and dysfunction of EPCs through the ER stress pathway.

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The Portfolio Balanced Risk Index Model and Analysis of Examples of Large-Scale Infrastructure Project

This paper focuses on a three-dimensional portfolio balanced risk index model for large-scale infrastructure project risk evaluation as a hot topic of current research. Taking subjectivity utility and complex evaluation motivation into consideration, a method of combinational equilibrium evaluation is built using the index form to reflect whole loss changes of risk. For risk index evaluation and measurement issues, this paper first constructs a risk evaluation index system and three risk coefficients of single factor by questionnaire survey and fuzzy evaluation. Then we calculate the risk index of single factor, which arrives at the classification and combination risk index through AHP method. Finally, we verify the index validity by analysis of examples. With this research we expand the evaluation dimension and provide a new analytical tool for risk monitoring and warning.

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A Reinforcement Learning Approach to Access Management in Wireless Cellular Networks

In smart city applications, huge numbers of devices need to be connected in an autonomous manner. 3rd Generation Partnership Project (3GPP) specifies that Machine Type Communication (MTC) should be used to handle data transmission among a large number of devices. However, the data transmission rates are highly variable, and this brings about a congestion problem. To tackle this problem, the use of Access Class Barring (ACB) is recommended to restrict the number of access attempts allowed in data transmission by utilizing strategic parameters. In this paper, we model the problem of determining the strategic parameters with a reinforcement learning algorithm. In our model, the system evolves to minimize both the collision rate and the access delay. The experimental results show that our scheme improves system performance in terms of the access success rate, the failure rate, the collision rate, and the access delay.

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Ventilator Management of Bronchopleural Fistula Secondary to Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia in a Pregnant Patient with Systemic Lupus Erythematosus

Managing mechanical ventilation in patient with bronchopleural fistula with coexisting acute respiratory distress syndrome is a challenging situation for the intensivist. We are reporting a case of a pregnant patient with systemic lupus erythematosus on immunosuppressive medications who developed methicillin-resistant Staphylococcus aureus necrotizing pneumonia complicated by bronchopleural fistula and acute respiratory distress syndrome.

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Inhibition of α-Amylases by Condensed and Hydrolysable Tannins: Focus on Kinetics and Hypoglycemic Actions

The aim of the present study was to compare the in vitro inhibitory effects on the salivary and pancreatic α-amylases and the in vivo hypoglycemic actions of the hydrolysable tannin from Chinese natural gall and the condensed tannin from Acacia mearnsii. The human salivary α-amylase was more strongly inhibited by the hydrolysable than by the condensed tannin, with the concentrations for 50% inhibition (IC50) being 47.0 and 285.4 μM, respectively. The inhibitory capacities of both tannins on the pancreatic α-amylase were also different, with IC50 values being 141.1 μM for the hydrolysable tannin and 248.1 μM for the condensed tannin. The kinetics of the inhibition presented complex patterns in that for both inhibitors more than one molecule can bind simultaneously to either the free enzyme of the substrate-complexed enzyme (parabolic mixed inhibition). Both tannins were able to inhibit the intestinal starch absorption. Inhibition by the hydrolysable tannin was concentration-dependent, with 53% inhibition at the dose of 58.8 μmol/kg and 88% inhibition at the dose of 294 μmol/kg. For the condensed tannin, inhibition was not substantially different for doses between 124.4 μmol/kg (49%) and 620 μmol/kg (57%). It can be concluded that both tannins, but especially the hydrolysable one, could be useful in controlling the postprandial glycemic levels in diabetes.

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On the Interactions of Fused Pyrazole Derivative with Selected Amino Acids: DFT Calculations

Due to the increasing prevalence of neoplasms, there is a permanent need for new selective cytostatic compounds. Anticancer drugs can act in different ways, affecting protein expression and synthesis, including disruption of signaling pathways within cells. Continuing our previous research aiming at elucidating the mechanism of pyrazole’s anticancer activity, we carried out in silico studies on the interactions of fused pyrazole derivative with alanine, lysine, glutamic acid, and methionine. The objective of the study is to improve our understanding of the possible interactions of pyrazole derivatives with the above-mentioned amino acids. For this purpose, we apply the DFT formalism (optimization using the B3LYP, CAM-B3LYP, PBE0, and M06L functionals) and interaction energy calculations (counterpoise corrected method based on the basis set superposition error, BSSE) together with QTAIM approach and estimation of the 1H NMR chemical shifts of analyzed pyrazole derivative using different basis sets and DFT functionals in CPCM solvation model (and water used as a solvent).

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Modeling Road Network Vulnerability for Evacuees and First Responders in No-Notice Evacuation

The concept of vulnerability has been employed to develop transport systems that sustain devastating disasters and ensure the efficient evacuation of neighborhoods. Existing studies of road network vulnerability overlook two important aspects of analysis: the no-notice evacuation and the different objectives of evacuees and first responders. First, a no-notice evacuation leaves limited time for proactive emergency planning; therefore, rescue strategies in this scenario rely heavily on real-time traffic information. Second, the goal of first responders in an evacuation is to move into an affected area immediately after a hazardous event unfolds, and the risk they face differs from that of evacuees. To this end, this paper develops a network-based model to evaluate vulnerability during a no-notice evacuation and applies it to a case study in Dublin, OH, USA. The model is suited to assessing network vulnerability in response to events with uncertainty and coordinating traffic control strategies in a no-notice evacuation. This study can become a valuable complement to the methodological conceptualization of vulnerability and can provide insights into developing comprehensive emergency management plans.

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From method to hermeneutics: which epistemological framework for narrative medicine?

Abstract

The past 10 years have seen considerable developments in the use of narrative in medicine, primarily through the emergence of the so-called narrative medicine. In this article, I question narrative medicine's self-understanding and contend that one of the most prominent issues is its lack of a clear epistemological framework. Drawing from Gadamer's work on hermeneutics, I first show that narrative medicine is deeply linked with the hermeneutical field of knowledge. Then I try to identify which claims can be legitimately expected from narrative medicine, and which ones cannot be. I scrutinize in particular whether narrative medicine can legitimately grasp the patient's lived experience of his or her illness. In the last section of this article, I begin to explore the potential usefulness of this epistemological clarification. This analysis allows for a further understanding of what is really at stake with narrative medicine, and thus to identify when it may be convenient, and when it may not. Furthermore, this clarification opens up promising new possibilities of dialogue with critics of the field. I conclude that narrative medicine finds its proper place as a possible tool available to mediate dialogue, which is at the heart of the clinical encounter in medical practice.

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Electrolyte and Acid–Base Disturbances in End-Stage Liver Disease: A Physiopathological Approach

Abstract

Electrolyte and acid–base disturbances are frequent in patients with end-stage liver disease; the underlying physiopathological mechanisms are often complex and represent a diagnostic and therapeutic challenge to the physician. Usually, these disorders do not develop in compensated cirrhotic patients, but with the onset of the classic complications of cirrhosis such as ascites, renal failure, spontaneous bacterial peritonitis and variceal bleeding, multiple electrolyte, and acid–base disturbances emerge. Hyponatremia parallels ascites formation and is a well-known trigger of hepatic encephalopathy; its management in this particular population poses a risky challenge due to the high susceptibility of cirrhotic patients to osmotic demyelination. Hypokalemia is common in the setting of cirrhosis: multiple potassium wasting mechanisms both inherent to the disease and resulting from its management make these patients particularly susceptible to potassium depletion even in the setting of normokalemia. Acid–base disturbances range from classical respiratory alkalosis to high anion gap metabolic acidosis, almost comprising the full acid–base spectrum. Because most electrolyte and acid–base disturbances are managed in terms of their underlying trigger factors, a systematic physiopathological approach to their diagnosis and treatment is required.

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Chronic Pancreatitis: Current Status and Challenges for Prevention and Treatment

Abstract

This paper reviews the current status of our understanding of the epidemiology, diagnosis, and management of the continuum of pancreatic diseases from acute and recurrent acute pancreatitis to chronic pancreatitis and the diseases that are often linked with pancreatitis including diabetes mellitus and pancreatic cancer. In addition to reviewing the current state of the field, we identify gaps in knowledge that are necessary to address to improve patient outcomes in these conditions.

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Cancer Center Volume and Type Impact Stage-Specific Utilization of Neoadjuvant Therapy in Rectal Cancer

Abstract

Background

Neoadjuvant chemoradiation reduces local recurrence in locally advanced rectal cancer, and adherence to national and societal recommendations remains unknown.

Objective

To determine variability in guideline adherence in rectal cancer treatment and investigate whether hospital volume correlated with variability seen.

Design

We performed a retrospective analysis using the National Cancer Database rectal cancer participant user files from 2005 to 2010. Stage-specific predictors of neoadjuvant chemotherapy and radiation use were determined, and variation in use across hospitals analyzed. Hospitals were ranked based on likelihood of preoperative therapy use by stage, and observed-to-expected ratios for neoadjuvant therapy use calculated. Hospital outliers were identified, and their center characteristics compared.

Results

A total of 23,488 patients were identified at 1183 hospitals. There was substantial variability in the use of neoadjuvant chemoradiation across hospitals. Patients managed outside clinical guidelines for both stage 1 and stage 3 disease tended to receive treatment at lower-volume, community cancer centers.

Conclusions

There is substantial variability in adherence to national guidelines in the use of neoadjuvant chemoradiation for rectal cancer across all stages. Both hospital volume and center type are associated with over-treatment of early-stage tumors and under-treatment of more invasive tumors. These findings identify a clear need for national quality improvement efforts in the treatment of rectal cancer.

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Is there a “July effect” in pediatric neurosurgery?

Abstract

Purpose

The belief that July, when resident physicians' training year begins, may be associated with increased risk of patient morbidity and mortality is known as the "July effect." This study aimed to compare complication rates after pediatric neurosurgical procedures in the first versus last academic quarters in two national datasets.

Methods

Data were extracted from the National Surgical Quality Improvement Program-Pediatrics (NSQIP-P) database for year 2012 for 30-day complication events and the Kids' Inpatient Database (KID) for year 2012 for in-hospital complication events after pediatric neurosurgical procedures. Descriptive and analytic statistical methods were used to characterize the impact of seasonal variation between the first and last quarters on complications.

Results

Three thousand six hundred twenty-four procedures in the NSQIP-P dataset and 14,855 hospitalizations in KID were included in the study cohort. No significant difference was observed between the first and fourth quarters for these complication events: wound disruption/dehiscence, wound infection, nerve injury, bleeding requiring transfusion, central line-associated BSI, deep venous thrombosis/pulmonary embolism, urinary tract infection, renal failure, re-intubation/pulmonary failure, cardiac arrest, stroke, coma, and death. There was no difference in the average length of stay or average length of surgical time. In the NSQIP-P, the first quarter was associated with a significantly increased incidence of pneumonia and unplanned re-operation; there was a trend towards increased incidence of unplanned re-admission and sepsis. In KID, there was no difference in the rate of pneumonia or sepsis.

Conclusion

For the majority of morbidity and mortality events, no significant difference was found in occurrence rates between the first and last quarters.

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Autonomic nervous system in newborns: a review based on heart rate variability

Abstract

Purpose

Heart rate variability (HRV) has been a relevant tool in the assessment of the autonomic nervous system (ANS). How autonomic control normally develops in newborns and how it is affected by gestational age (GA) is not fully understood. We aimed to review the current evidence on HRV in preterm (PT) and term neonates (TN) and investigate the relation between GA and the maturation of ANS.

Methods

Electronic databases (Pubmed, World of Science, and Scopus) were searched for studies from 1997 to 2017 examining HRV (time and frequency domain) in PT and TN who followed to the Task Force (1996) guidelines. Ten studies met our inclusion criteria and were analyzed.

Results

An increasing postnatal age was related to a significant rise of HRV parameters. Several significant differences were established between PT and TN (lower values on PTN), also found when PTN are evaluated at their theoretical term age. In general, there were no relevant results on LF/HF (low frequency/high frequency) ratio, as being an adequate marker of sympathovagal balance, but this was not a universal finding of this review. Frequency parameters that were more often used to evaluate newborns and HF showed the most relevant increase with GA.

Conclusions

HRV is an important tool to assess the maturation of ANS in newborns and there is a progressive increasing on cardiac parasympathetic activity, according to GA. HF appears as a relevant parameter in measurements of vagal maturation. HRV is higher in TN when compared with PTN and is more studied in newborns in terms of frequency domain. Standard recommendations in newborns remain to be fully defined.

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Neutrophil Extracellular Traps are associated with disease severity and microbiota diversity in Chronic Obstructive Pulmonary Disease

Neutrophil extracellular traps are associated with disease severity and loss of microbiota diversity in COPD, suggesting a role in disease pathogenesis and progression.

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CAN CADAVEROUS POLLUTION FROM ENVIRONMENTAL LEAD MISGUIDE TO FALSE POSITIVE RESULTS IN THE HISTOCHEMICAL DETERMINATION OF GUNSHOT RESIDUES? STUDY ON CADAVERIC SKIN SAMPLES

The histochemical Sodium Rhodizonate Test (Na-R) and 5% HCl Sodium Rhodizonate Test (Na-R-HCl), are techniques used in Italy and considered very useful in the study of gunshot wounds, in the determination of the shot distance [1,2] and in the differential diagnosis between the entry and exit hole [3]. These techniques are considered fundamental since energy-dispersive X-ray spectroscopy (SEM/EDX) has high costs and is not available in all laboratories. The features of gunshot wounds are macroscopically appreciable when the body is well preserved, but if the bad cadaveric conditions do not allow to understand the nature of the lesions [4], it is necessary to address such bodies (if a gunshot wound is suspected) to the histological detection of gunshot residues in a region protected from environmental pollution, such as the way of the projectile inside the body.

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A reusable multipurpose magnetic nanobiocatalyst for industrial applications

Publication date: October 2017
Source:International Journal of Biological Macromolecules, Volume 103
Author(s): Mohammad Perwez, Razi Ahmad, Meryam Sardar
A multipurpose magnetic nanobiocatalyst is developed by conjugating Pectinex 3XL (a commercial enzyme containing pectinase, xylanase and cellulase activities) on 3-aminopropyl triethoxysilane activated magnetic nanoparticles. The nanobiocatalyst retained 87% of pectinase, 69% of xylanase and 58% of cellulase activity after conjugation on modified nanoparticles as compared to their soluble counterparts. Thermal stability data at 70°C showed increase in enzyme stability after conjugation to nanoparticles and the kinetic parameters (Km and Vmax) remain unaltered after immobilization. The immobilized enzyme system can be successfully used upto 5th cycle after that slight decrease in enzyme activities was observed. The nanobiocatalyst retained high pectinase activities in organic solvents and chemical reagents as compared to free enzymes. DLS data shows that the nanoparticles size increases from 63nm to 86nm after immobilization. Atomic Force Microscopy data confirms the deposition of enzymes on the nanoparticles. The nanobiocatalyst was used for the clarification of pine apple and orange juice and was also used for the production of bioethanol. Hydrolysis of pretreated wheat straw produced 1.39g/l and 1.59g/l after treatment with free Pectinex 3xL and nanobiocatalyst respectively. The concentration of bioethanol also increases by 1.4 fold as compared to the free enzyme.

Graphical abstract

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Synthesis and characterization of Ag2S decorated chitosan nanocomposites and chitosan nanofibers for removal of lincosamides antibiotic

Publication date: October 2017
Source:International Journal of Biological Macromolecules, Volume 103
Author(s): Vinod Kumar Gupta, Ali Fakhri, Shilpi Agarwal, Mona Azad
We report the synthesis of Ag2S-Chitosan nanocomposites and Ag2S-chitosan nanohybrids as performance adsorbents for Lincosamides such as Clindamycin antibiotic removal. Isotherms and kinetic studies were determined to understand the adsorption behavior both two adsorbent. At low adsorbent dose, removals are increased in the adsorption process, and performance is better with Ag2S-chitosan nanohybrids due to the special surface area increased. The average sizes and surface area of Ag2S-Chitosan nanocomposites and Ag2S-chitosan nanohybrids were found as 50nm, 70nm and 180.18, 238.24m²g⁻¹, respectively. In particular, Ag2S-Chitosan nanocomposites and Ag2S-chitosan nanohybrids show high maximum Clindamycin adsorption capacity (qmax) of 153.21, and 181.28mgg⁻¹, respectively. More strikingly, Ag2S-Chitosan nanocomposites and Ag2S-chitosan nanohybrids are also demonstrated to nearly completely remove Clindamycin from drinking water. The excellent adsorption performance along with their cost effective, convenient synthesis makes this range of adsorbents highly promising for commercial applications in drinking water and wastewater treatment.

Graphical abstract

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A Drosophila model for developmental nicotine exposure

by Norma Andrea Velazquez-Ulloa

Despite the known health risks of tobacco smoking, many people including pregnant women continue smoking. The effects of developmental nicotine exposure are known, but the underlying mechanisms are not well understood. Drosophila melanogaster is a model organism that can be used for uncovering genetic and molecular mechanisms for drugs of abuse. Here I show that Drosophila can be a model to elucidate the mechanisms for nicotine’s effects on a developing organism. Drosophila reared on nicotine food display developmental and behavioral effects similar to those in mammals including decreased survival and weight, increased developmental time, and decreased sensitivity to acute nicotine and ethanol. The Drosophila nicotinic acetylcholine receptor subunit alpha 7 (Dα7) mediates some of these effects. A novel role for Dα7 on ethanol sedation in Drosophila is also shown. Future research taking advantage of the genetic and molecular tools for Drosophila will allow additional discovery of the mechanisms behind the effects of nicotine during development.

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Windowed persistent homology: A topological signal processing algorithm applied to clinical obesity data

by Craig Biwer, Amy Rothberg, Heidi IglayReger, Harm Derksen, Charles F. Burant, Kayvan Najarian

Overweight and obesity are highly prevalent in the population of the United States, affecting roughly 2/3 of Americans. These diseases, along with their associated conditions, are a major burden on the healthcare industry in terms of both dollars spent and effort expended. Volitional weight loss is attempted by many, but weight regain is common. The ability to predict which patients will lose weight and successfully maintain the loss versus those prone to regain weight would help ease this burden by allowing clinicians the ability to skip treatments likely to be ineffective. In this paper we introduce a new windowed approach to the persistent homology signal processing algorithm that, when paired with a modified, semimetric version of the Hausdorff distance, can differentiate the two groups where other commonly used methods fail. The novel approach is tested on accelerometer data gathered from an ongoing study at the University of Michigan. While most standard approaches to signal processing show no difference between the two groups, windowed persistent homology and the modified Hausdorff semimetric show a clear separation. This has significant implications for clinical decision making and patient care.

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Does stroke volume variation predict fluid responsiveness in children: A systematic review and meta-analysis

by Ling Yi, Zhongqiang Liu, Lina Qiao, Chaomin Wan, Dezhi Mu

Objective

Stroke volume variation (SVV) is a reliable predictor of fluid responsiveness in adult patients. However, the predictive value of SVV is uncertain in pediatric patients. We performed the first systematic meta-analysis to evaluate the diagnostic value of SVV in predicting fluid responsiveness in children.

Methods

PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials were searched up to December 2016. Original studies assessing the diagnostic accuracy of SVV in predicting fluid responsiveness in children were considered to be eligible. A random-effects model was used to calculate pooled values of sensitivity, specificity and diagnostic odds ratio with 95% CI. The summary receiver operating characteristic curve was estimated and area under the curve was calculated. Quality of the studies was assessed with the QUADAS-2 tool.

Results

Six studies with a total of 279 fluid boluses in 224 children were included. The analysis demonstrated a pooled sensitivity of 0.68 (95% CI,0.59–0.76), pooled specificity of 0.65 (95% CI, 0.57–0.73), pooled diagnostic odds ratio of 8.24 (95% CI, 2.58–26.30), and the summary area under the summary receiver operating characteristic curve of 0.81. However, significant inter-study heterogeneity was found (pI² = 61.3%), likely due to small sample size and diverse study characteristics.

Conclusions

Current evidence suggests that SVV was of diagnostic value in predicting fluid responsiveness in children under mechanical ventilation. Given the high heterogeneity of published data, further studies are needed to confirm the diagnostic accuracy of SVV in predicting fluid responsiveness in pediatric patients.

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Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis

by Nazem Atassi, Maosheng Xu, Christina Triantafyllou, Boris Keil, Robert Lawson, Paul Cernasov, Elena Ratti, Christopher J. Long, Sabrina Paganoni, Alyssa Murphy, Nouha Salibi, Ravi Seethamraju, Bruce Rosen, Eva-Maria Ratai

The main objective of this study was to utilize high field (7T) in vivo proton magnetic resonance imaging to increase the ability to detect metabolite changes in people with ALS, specifically, to quantify levels of glutamine and glutamine separately. The second objective of this study was to correlate metabolic markers with clinical outcomes of disease progression. 13 ALS participants and 12 age-matched healthy controls (HC) underwent 7 Tesla MRI and MRS. Single voxel MR spectra were acquired from the left precentral gyrus using a very short echo time (TE = 5 ms) STEAM sequence. MRS data was quantified using LCModel and correlated to clinical outcome markers. N-acetylaspartate (NAA) and total NAA (tNA, NAA + NAAG) were decreased by 17% in people with ALS compared to HC (P = 0.004 and P = 0.005, respectively) indicating neuronal injury and/or loss in the precentral gyrus. tNA correlated with disease progression as measured by forced vital capacity (FVC) (P = 0.014; R_ρ = 0.66) and tNA/tCr correlated with overall functional decline as measured by worsening of the ALS Functional Rating Scale-Revised (ALSFRS-R) (P = 0.004; R_ρ = -0.74). These findings underscore the importance of NAA as a reliable biomarker for neuronal injury and disease progression in ALS. Glutamate (Glu) was 15% decreased in people with ALS compared to HC (P = 0.02) while glutamine (Gln) concentrations were similar between the two groups. Furthermore, the decrease in Glu correlated with the decrease in FVC (P = 0.013; R_ρ = 0.66), a clinical marker of disease progression. The decrease in Glu is most likely driven by intracellular Glu loss due to neuronal loss and degeneration. Neither choline containing components (Cho), a marker for cell membrane turnover, nor myo-Inositol (mI), a suspected marker for neuroinflammation, showed significant differences between the two groups. However, mI/tNA was correlated with upper motor neuron burden (P = 0.004, R_ρ = 0.74), which may reflect a relative increase of activated microglia around motor neurons. In summary, 7T ¹H MRS is a powerful non-invasive imaging technique to study molecular changes related to neuronal injury and/or loss in people with ALS.

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Predictive models of poly(ethylene-terephthalate) film degradation under multi-factor accelerated weathering exposures

by Abdulkerim Gok, David K. Ngendahimana, Cara L. Fagerholm, Roger H. French, Jiayang Sun, Laura S. Bruckman

Accelerated weathering exposures were performed on poly(ethylene-terephthalate) (PET) films. Longitudinal multi-level predictive models as a function of PET grades and exposure types were developed for the change in yellowness index (YI) and haze (%). Exposures with similar change in YI were modeled using a linear fixed-effects modeling approach. Due to the complex nature of haze formation, measurement uncertainty, and the differences in the samples’ responses, the change in haze (%) depended on individual samples’ responses and a linear mixed-effects modeling approach was used. When compared to fixed-effects models, the addition of random effects in the haze formation models significantly increased the variance explained. For both modeling approaches, diagnostic plots confirmed independence and homogeneity with normally distributed residual errors. Predictive R² values for true prediction error and predictive power of the models demonstrated that the models were not subject to over-fitting. These models enable prediction under pre-defined exposure conditions for a given exposure time (or photo-dosage in case of UV light exposure). PET degradation under cyclic exposures combining UV light and condensing humidity is caused by photolytic and hydrolytic mechanisms causing yellowing and haze formation. Quantitative knowledge of these degradation pathways enable cross-correlation of these lab-based exposures with real-world conditions for service life prediction.

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Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits

by Yasuhiro Ichikawa, Alice E. Zemljic-Harpf, Zheng Zhang, M. Dan McKirnan, Ana Maria Manso, Robert S. Ross, H. Kirk Hammond, Hemal H. Patel, David M. Roth

Anthracyclines are chemotherapeutic drugs known to induce heart failure in a dose-dependent manner. Mechanisms involved in anthracycline cardiotoxicity are an area of relevant investigation. Caveolins bind, organize and regulate receptors and signaling molecules within cell membranes. Caveolin-3 (Cav-3), integrins and related membrane repair proteins can function as cardioprotective proteins. Expression of these proteins in anthracycline-induced heart failure has not been evaluated. We tested the hypothesis that daunorubicin alters cardioprotective protein expression in the heart. Rabbits were administered daunorubicin (3 mg/kg, IV) weekly, for three weeks or nine weeks. Nine weeks but not three weeks of daunorubicin resulted in progressive reduced left ventricular function. Cav-3 expression in the heart was unchanged at three weeks of daunorubicin and increased in nine week treated rabbits when compared to control hearts. Electron microscopy showed caveolae in the heart were increased and mitochondrial number and size were decreased after nine weeks of daunorubicin. Activated beta-1 (β1) integrin and the membrane repair protein MG53 were increased after nine weeks of daunorubicin vs. controls with no change at the three week time point. The results suggest a potential pathophysiological role for Cav3, integrins and membrane repair in daunorubicin-induced heart failure.

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Whitefly attraction to rosemary (Rosmarinus officinialis L.) is associated with volatile composition and quantity

by Dganit Sadeh, Nadav Nitzan, Alona Shachter, David Chaimovitsh, Nativ Dudai, Murad Ghanim

Whitefly (Bemisia tabaci) is an important insect pest, causing severe damage to agricultural crops. The pest was recorded in a commercial rosemary (Rosmarinus officinalis, Lamiaceae) field, colonizing rosemary variety (var.) '2', but not '11'. A series of field and controlled laboratory choice bioassays confirmed the observed phenomenon. Mature potted plants of the two varieties were randomly organized in a lemon verbena (Lippia citrodora) and lemon grass (Cymbopogon spp.) fields. Seven days later var. '2' was significantly more colonized by whiteflies than var. '11'. Under lab conditions, whiteflies were significantly more attracted to var. '2' plantlets than to var. '11' following choice bioassays. Furthermore, cotton plants dipped in an essential oil emulsion of var. '2' had significantly greater colonization than cotton plants dipped in the essential oil emulsion of var. '11'. Similar results were obtained in 'plant-plant', 'plant-no plant' as well as, 'essential oil—essential oil' choice bioassay designs. Analyses of the essential oils of the two varieties identified a set of common and unique volatiles in each variety. Among these volatiles were β-caryophyllene and limonene, two compounds known to be associated with plant-insect interactions. The attraction of B. tabaci to pure (>95%) β-caryophyllene and limonene using a range of concentrations was examined in vitro by choice bioassays. The compounds were attractive to the insect at moderate concentration, but not at the lowest or highest concentrations used, where the insect was not attracted or repelled, respectively. Limonene attracted the insects at rates that were 10-fold lower than β-caryophyllene. The results emphasized the role of host plant volatiles in shaping the structure of B. tabaci populations in nature and in agricultural systems, and provided insights into the factors that contribute to the development of insect populations with unique characteristics. The results could also serve for future development of bio-pesticides and in breeding programs.

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The effectiveness of modern cardiac rehabilitation: A systematic review of recent observational studies in non-attenders versus attenders

by Jennifer Sumner, Alexander Harrison, Patrick Doherty

Background

The beneficial effects of cardiac rehabilitation (CR) have been challenged in recent years and there is now a need to investigate whether current CR programmes, delivered in the context of modern cardiology, still benefit patients.

Methods

A systematic review of non-randomised controlled studies was conducted. Electronic searches of Medline, Embase, CINAHL, science citation index (web of science), CIRRIE and Open Grey were undertaken. Non-randomised studies investigating the effects of CR were included when recruitment occurred from the year 2000 onwards in accordance with significant CR guidance changes from the late 1990’s. Adult patients diagnosed with acute myocardial infarction (AMI) were included. Non-English articles were considered. Two reviewers independently screened articles according to pre-defined selection criteria as reported in the PROSPERO database (CRD42015024021).

Results

Out of 2,656 articles, 8 studies involving 9,836 AMI patients were included. Studies were conducted in 6 countries. CR was found to reduce the risk of all-cause and cardiac-related mortality and improve Health-Related Quality of Life (HRQOL) significantly in at least one domain. The benefits of CR in terms of recurrent MI were inconsistent and no significant effects were found regarding re-vascularisation or re-hospitalisation following AMI.

Conclusion

Recent observational evidence draws different conclusions to the most current reviews of trial data with respect to total mortality and re-hospitalisation, questioning the representativeness of historic data in the modern cardiological era. Future work should seek to clarify which patient and service level factors determine the likelihood of achieving improved all-cause and cardiac mortality and reduced hospital re-admissions.

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Measurement of tissue azithromycin levels in self-collected vaginal swabs post treatment using liquid chromatography and tandem mass spectrometry (LC-MS/MS)

by Lenka A. Vodstrcil, Thusitha W. T. Rupasinghe, Fabian Y. S. Kong, Dedreia Tull, Karen Worthington, Marcus Y. Chen, Wilhelmina M. Huston, Peter Timms, Malcolm J. McConville, Christopher K. Fairley, Catriona S. Bradshaw, Sepehr N. Tabrizi, Jane S. Hocking

Background

Azithromycin is recommended for the treatment of uncomplicated urogenital chlamydia infection although the standard 1gram dose sometimes fails to eradicate the infection (treatment failure). One hypothesis proposed for treatment failure has been insufficient levels of the antibiotic at the site of infection. We developed an assay using liquid chromatography and tandem mass spectrometry (LC-MS/MS) to measure azithromycin concentration in high-vaginal swabs and monitor how concentration changes over time following routine azithromycin treatment.

Methods

Azithromycin concentrations were measured in two groups of women either within the first 24h of taking a 1g dose (N = 11) or over 9 days (N = 10). Azithromycin concentrations were normalised to an internal standard (leucine enkephalin), and the bulk lipid species phosphatidylcholine [PC(34:1)], using an Agilent 6490 triple quadrupole instrument in positive ionisation mode. The abundances of azithromycin, PC(34:1), and leu-enkephalin were determined by multiple reaction monitoring and absolute levels of azithromycin estimated using standard curves prepared on vaginal specimens.

Results

Vaginal azithromycin concentrations of women were rapidly obtained after 5h post-treatment (mean concentration = 1031mcg/mg of lipid, range = 173-2693mcg/mg). In women followed for 9 days, peak concentrations were highest after day 2 (mean concentration = 2206mcg/mg, range = 721-5791mcg/mg), and remained high for at least 9 days with a mean concentration of 384mcg/mg (range = 139-1024mcg/mg) on day 9.

Conclusion

Our study confirmed that a single 1g dose of azithromycin is rapidly absorbed and remains in the vagina at relatively high levels for at least a week, suggesting that poor antibiotic absorption is unlikely to be an explanation for treatment failure.

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Soluble bone-derived osteopontin promotes migration and stem-like behavior of breast cancer cells

by Graciella M. Pio, Ying Xia, Matthew M. Piaseczny, Jenny E. Chu, Alison L. Allan

Breast cancer is a leading cause of cancer death in women, with the majority of these deaths caused by metastasis to distant organs. The most common site of breast cancer metastasis is the bone, which has been shown to provide a rich microenvironment that supports the migration and growth of breast cancer cells. Additionally, growing evidence suggests that breast cancer cells that do successfully metastasize have a stem-like phenotype including high activity of aldehyde dehydrogenase (ALDH) and/or a CD44⁺CD24^- phenotype. In the current study, we tested the hypothesis that these ALDH^hiCD44⁺CD24^- breast cancer cells interact with factors in the bone secondary organ microenvironment to facilitate metastasis. Specifically, we focused on bone-derived osteopontin and its ability to promote the migration and stem-like phenotype of breast cancer cells. Our results indicate that bone-derived osteopontin promotes the migration, tumorsphere-forming ability and colony-forming ability of whole population and ALDH^hiCD44⁺CD24^- breast cancer cells in bone marrow-conditioned media (an ex vivo representation of the bone microenvironment) (p≤0.05). We also demonstrate that CD44 and RGD-dependent cell surface integrins facilitate this functional response to bone-derived osteopontin (p≤0.05), potentially through activation of WNK-1 and PRAS40-related pathways. Our findings suggest that soluble bone-derived osteopontin enhances the ability of breast cancer cells to migrate to the bone and maintain a stem-like phenotype within the bone microenvironment, and this may contribute to the establishment and growth of bone metastases.

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Genome-wide transcriptome profiling of radish (Raphanus sativus L.) in response to vernalization

by Chen Liu, Shufen Wang, Wenling Xu, Xianxian Liu

Vernalization is a key process for premature bolting. Although many studies on vernalization have been reported, the molecular mechanism of vernalization is still largely unknown in radish. In this study, we sequenced the transcriptomes of radish seedlings at three different time points during vernalization. More than 36 million clean reads were generated for each sample and the portions mapped to the reference genome were all above 67.0%. Our results show that the differentially expressed genes (DEGs) between room temperature and the early stage of vernalization (4,845) are the most in all treatments pairs. A series of vernalization related genes, including two FLOWERING LOCUS C (FLC) genes, were screened according to the annotations. A total of 775 genes were also filtered as the vernalization related candidates based on their expression profiles. Cold stress responsive genes were also analyzed to further confirm the sequencing result. Several key genes in vernalization or cold stress response were validated by quantitative RT-PCR (RT-qPCR). This study identified a number of genes that may be involved in vernalization, which are useful for other functional genomics research in radish.

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Modulation of the growth and metabolic response of cyanobacteria by the multifaceted activity of naringenin

by Beata Żyszka, Mirosław Anioł, Jacek Lipok

The interactions between the plant-derived bioflavonoid, naringenin, and prokaryotic microalgae representatives (cyanobacteria), were investigated with respect to its influence on the growth and metabolic response of these microorganisms. To achieve reliable results, the growth of cyanobacteria was determined based on measurements of chlorophyll content, morphological changes were assessed through microscopic observations, and the chemical response of cells was determined using liquid and gas chromatography (HPLC; GC-FID). The results show that micromolar levels of naringenin stimulated the growth of cyanobacteria. Increased growth was observed for halophilic strains at naringenin concentrations below 40 mg L^-1, and in freshwater strains at concentrations below 20 mg L^-1. The most remarkable stimulation was observed for the freshwater species Nostoc muscorum, which had a growth rate that was up to 60% higher than in the control. When naringenin was examined at concentrations above 40 mg L^-1, the growth of the tested microorganisms was inhibited. Simultaneously, an intensive excretion of exopolysaccharides was observed. Microscopic observations strongly suggest that these effects resulted from a structural disturbance of cyanobacterial cell walls that was exerted by naringenin. This phenomenon, in combination with the absorption of naringenin into cell wall structures, influenced cell permeability and thus the growth of bacteria. Fortunately, almost all the naringenin added to the culture was incorporated into to cell substructures and could be recovered through extraction, raising the possibility that this modulator could be recycled.

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Trace element and metal sequestration in vitellaria and sclerites, and reactive oxygen intermediates in a freshwater monogenean, Paradiplozoon ichthyoxanthon

by Beric M. Gilbert, Annemariè Avenant-Oldewage

Exposure to metals and other trace elements negatively affects infection dynamics of monogeneans, including diplozoids, but, physiological mechanisms linked to exposure have yet to be documented. In this study sequestration of trace elements and reactive oxygen intermediate production in the monogenean, Paradiplozoon ichthyoxanthon, was demonstrated. During dissection of host fish, Labeobarbus aeneus, the gills were excised and assessed for P. ichthyoxanthon, which were removed and frozen for fluorescence microscopy or fixed for transmission electron microscopy. Trace elements were sequestered in the vitellaria and sclerites in P. ichthyoxanthon, and the presence of reactive oxygen intermediates was observed predominantly in the tegument of the parasite. Trace elements and metals identified and ranked according to weight percentages (wt%) in the vitellaria were Cu > C > Au > O > Cr > Fe > Si while for the sclerites C > Cu > O > Au > Fe > Cr > Si were identified. For most element detected, readings were higher in the vitellaria than the sclerites, except for C and O which were higher in sclerites. Specifically for metals, all levels detected in the vitellaria were greater than in sclerites. Based on the proportion of trace elements present in the vitellaria and sclerites it appears that most trace elements including metals were sequestered in the vitellaria. The results of reactive oxygen intermediate production in the tegument of the parasite suggests either trace element accumulation takes place across the tegument or results from the action of the host’s immune response on the parasite. The results serve as the first demonstration of trace element sequestration and reactive oxygen intermediates in a freshwater monogenean parasite.

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When Bitcoin encounters information in an online forum: Using text mining to analyse user opinions and predict value fluctuation

by Young Bin Kim, Jurim Lee, Nuri Park, Jaegul Choo, Jong-Hyun Kim, Chang Hun Kim

Bitcoin is an online currency that is used worldwide to make online payments. It has consequently become an investment vehicle in itself and is traded in a way similar to other open currencies. The ability to predict the price fluctuation of Bitcoin would therefore facilitate future investment and payment decisions. In order to predict the price fluctuation of Bitcoin, we analyse the comments posted in the Bitcoin online forum. Unlike most research on Bitcoin-related online forums, which is limited to simple sentiment analysis and does not pay sufficient attention to note-worthy user comments, our approach involved extracting keywords from Bitcoin-related user comments posted on the online forum with the aim of analytically predicting the price and extent of transaction fluctuation of the currency. The effectiveness of the proposed method is validated based on Bitcoin online forum data ranging over a period of 2.8 years from December 2013 to September 2016.

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Percutaneous coronary intervention with second-generation drug-eluting stent versus bare-metal stent: Systematic review and cost–benefit analysis

by Thomas G. Poder, Jihane Erraji, Lucien P. Coulibaly, Kouamé Koffi

Background

Drug-eluting stents (DESs) were considered as ground-breaking technology promising to eradicate restenosis and the necessity to perform multiple revascularization procedures subsequent to percutaneous coronary intervention. Soon after DESs were released on the market, however, there were reports of a potential increase in mortality and of early or late thrombosis. In addition, DESs are far more expensive than bare-metal stents (BMSs), which has led to their limited use in many countries. The technology has improved over the last few years with the second generation of DESs (DES-2). Moreover, costs have come down and an improved safety profile with decreased thrombosis has been reported.

Objective

Perform a cost–benefit analysis of DES-2s versus BMSs in the context of a publicly funded university hospital in Quebec, Canada.

Methods

A systematic review of meta-analyses was conducted between 2012 and 2016 to extract data on clinical effectiveness. The clinical outcome of interest for the cost–benefit analysis was target-vessel revascularization (TVR). Cost units are those used in the Quebec health-care system. The cost–benefit analysis was based on a 2-year perspective. Deterministic and stochastic models (discrete-event simulation) were used, and various risk factors of reintervention were considered.

Results

DES-2s are much more effective than BMSs with respect to TVR rate ratio (i.e., 0.29 to 0.62 in more recent meta-analyses). DES-2s seem to cause fewer deaths and in-stent thrombosis than BMSs, but results are rarely significant, with the exception of the cobalt–chromium everolimus DES. The rate ratio of myocardial infraction is systematically in favor of DES-2s and very often significant. Despite the higher cost of DES-2s, fewer reinterventions can lead to huge savings (i.e., -$479 to -$769 per patient). Moreover, the higher a patient’s risk of reintervention, the higher the savings associated with the use of DES-2s.

Conclusion

Despite the higher purchase cost of DES-2s compared to BMSs, generalizing their use, in particular for patients at high risk of reintervention, should enable significant savings.

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Singularity: Scientific containers for mobility of compute

by Gregory M. Kurtzer, Vanessa Sochat, Michael W. Bauer

Here we present Singularity, software developed to bring containers and reproducibility to scientific computing. Using Singularity containers, developers can work in reproducible environments of their choosing and design, and these complete environments can easily be copied and executed on other platforms. Singularity is an open source initiative that harnesses the expertise of system and software engineers and researchers alike, and integrates seamlessly into common workflows for both of these groups. As its primary use case, Singularity brings mobility of computing to both users and HPC centers, providing a secure means to capture and distribute software and compute environments. This ability to create and deploy reproducible environments across these centers, a previously unmet need, makes Singularity a game changing development for computational science.

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Take me where I want to go: Institutional prestige, advisor sponsorship, and academic career placement preferences

by Diogo L. Pinheiro, Julia Melkers, Sunni Newton

Placement in prestigious research institutions for STEM (science, technology, engineering, and mathematics) PhD recipients is generally considered to be optimal. Yet some doctoral recipients are not interested in intensive research careers and instead seek alternative careers, outside but also within academe (for example teaching positions in Liberal Arts Schools). Recent attention to non-academic pathways has expanded our understanding of alternative PhD careers. However, career preferences and placements are also nuanced along the academic pathway. Existing research on academic careers (mostly research-centric) has found that certain factors have a significant impact on the prestige of both the institutional placement and the salary of PhD recipients. We understand less, however, about the functioning of career preferences and related placements outside of the top academic research institutions. Our work builds on prior studies of academic career placement to explore the impact that prestige of PhD-granting institution, advisor involvement, and cultural capital have on the extent to which STEM PhDs are placed in their preferred academic institution types. What determines whether an individual with a preference for research oriented institutions works at a Research Extensive university? Or whether an individual with a preference for teaching works at a Liberal Arts college? Using survey data from a nationally representative sample of faculty in biology, biochemistry, civil engineering and mathematics at four different Carnegie Classified institution types (Research Extensive, Research Intensive, Master’s I & II, and Liberal Arts Colleges), we examine the relative weight of different individual and institutional characteristics on institutional type placement. We find that doctoral institutional prestige plays a significant role in matching individuals with their preferred institutional type, but that advisor involvement only has an impact on those with a preference for research oriented institutions. Gender effects are also observed, particularly in the role of the advisor in affecting preferred career placement.

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Correction: Pattern of genetic differentiation of an incipient speciation process: The case of the high Andean killifish Orestias

by Claudia Jimena Guerrero-Jiménez, Fabiola Peña, Pamela Morales, Marco A. Méndez, Michel Sallaberry, Irma Vila, Elie Poulin

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Egg production patterns of two invertebrate species in rocky subtidal areas under different fishing regimes along the coast of central Chile

by Marta Blanco, Andres Ospina-Álvarez, Catherine González, Miriam Fernández

Fishing is a major source of human impact, reducing density and size of a wide range of exploited species in comparison to areas exhibiting strong regulations (no-take and partially protected areas, including Territorial Use Rights for Fisheries, TURFs). Since size and density might have important consequences on reproduction, and therefore natural re-seeding, we monitored adult size, density and potential fecundity of the keyhole limpet (Fissurella latimarginata) and the red sea urchin (Loxechinus albus) in areas under two fishing regimes (TURFs and Open Access Areas, OAAs). Analyzing the distribution of suitable habitats, we predict spatial patterns of potential egg production, to identify reproductive hotspots along the central coast of Chile. The current system of TURFs in central Chile showed higher potential egg production of F. latimarginata and of L. albus than expected under a complete OAAs scenario (67 and 52% respectively). Potential egg production showed more than a twofold reduction when the complete TURFs scenario was compared against complete OAAs condition in both species. Individual size and density explained between 60% and 100% of the variability in potential egg production, suggesting the importance of the enhancement of both biological variables in TURFs in Chile. Potential egg production for both species in the northern part of the studied domain was higher due to the combined effect of (a) suitable habitat and (b) concentration of TURFs. Our results suggest that partially protected areas, such as TURFs can significantly enhance the production of propagules that could seed exploited areas.

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Mechanisms of Immune Tolerance in Leukemia and Lymphoma

Publication date: Available online 13 May 2017
Source:Trends in Immunology
Author(s): Emily K. Curran, James Godfrey, Justin Kline
The mechanisms through which immune responses are generated against solid cancers are well characterized and knowledge of the immune evasion pathways exploited by these malignancies has grown considerably. However, for hematological cancers, which develop and disseminate quite differently than solid tumors, the pathways that regulate immune activation or tolerance are less clear. Growing evidence suggests that, while numerous immune escape pathways are shared between hematological and solid malignancies, several unique pathways are exploited by leukemia and lymphoma. Below we discuss immune evasion mechanisms in leukemia and lymphoma, highlighting key differences from solid tumors. A more complete characterization of the mechanisms of immune tolerance in hematological malignancies is critical to inform the development of future immunotherapeutic approaches.



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Effects of Cardiotonic Steroids on Isolated Perfused Kidney and NHE3 Activity in Renal Proximal Tubules

Publication date: Available online 12 May 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Alana N. Godinho, Graciana T. Costa, Nádia O. Oliveira, Bruno A. Cardi, Daniel Esdras A. Uchoa, Edilberto R. Silveira, Luis Eduardo M. Quintas, François G. Noël, Manassés C. Fonteles, Krishnamurti M. Carvalho, Cláudia F. Santos, Lucília M.A. Lessa, Nilberto R.F. do Nascimento
Cardiotonic steroids (CS) are known as modulators of sodium and water homeostasis. These compounds contribute to the excretion of sodium under overload conditions due to its natriuretic property related to the inhibition of renal Na⁺/K⁺-ATPase (NKA) pump α1 isoform. NHE3, the main route for Na⁺ reabsorption in the proximal tubule, depends on the Na⁺ gradient generated by NKA pump. In the present study we aimed to investigate the effects of marinobufagin (MBG) and telocinobufagin (TBG) on the renal function of isolated perfused rat kidney and on the inhibition of NKA activity. Furthermore, we investigated the mechanisms for the cardiotonic steroids-mediated natriuretic effect, by evaluating and comparing the effects of bufalin (BUF), ouabain (OUA), MBG and TBG on NHE3 activity in renal proximal tubule in vivo. TBG significantly increased GFR, UF, natriuresis and kaliuresis in isolated perfused rat kidney, and inhibits the activity of NKA at a much higher rate than MBG. By stationary microperfusion technique, the perfusion with BUF, OUA, TBG or MBG promoted an inhibitory effect on NHE3 activity, whereas BUF was the most effective agent, and demonstrated a dose-dependent response, with maximal inhibition at 50nM. Furthermore, our data showed the role of NKA - Src kinase pathway in the inhibition of NHE3 by CS. Finally, a downstream step, MEK1/2-ERK1/2 was also investigated, and, similar to Src inhibition, MEK1/2 inhibitor (UO126) suppressed BUF effect. Our findings indicate the involvement of NKA-SRc-Kinase-Ras-Raf-ERK1/2 pathway in the downregulation of NHE3 by cardiotonic steroids in renal proximal tubule, promoting a reduction of the proximal sodium reabsorption and natriuresis.



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Characterisation of the selective binding of antibiotics vancomycin and teicoplanin by the VanS receptor regulating type A vancomycin resistance in the enterococci

Publication date: Available online 13 May 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): C.S. Hughes, E. Longo, M.K. Phillips-Jones, R. Hussain
A-type resistance towards “last-line” glycopeptide antibiotic vancomycin in the leading hospital acquired infectious agent, the enterococci, is the most common in the UK. Resistance is regulated by the VanRASA two-component system, comprising the histidine sensor kinase VanSA and the partner response regulator VanRA. The nature of the activating ligand for VanSA has not been identified, therefore this work sought to identify and characterise ligand(s) for VanSA. In vitro approaches were used to screen the structural and activity effects of a range of potential ligands with purified VanSA protein. Of the screened ligands (glycopeptide antibiotics vancomycin and teicoplanin, and peptidoglycan components N-acetylmuramic acid, D-Ala-D-Ala and Ala-D-y-Glu-Lys-D-Ala-D-Ala) only glycopeptide antibiotics vancomycin and teicoplanin were found to bind VanSA with different affinities (vancomycin 70 μM; teicoplanin 30 and 170 μM), and were proposed to bind via exposed aromatic residues tryptophan and tyrosine. Furthermore, binding of the antibiotics induced quicker, longer-lived phosphorylation states for VanSA, proposing them as activators of type A vancomycin resistance in the enterococci.

Graphical abstract

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Heightened perception of breast cancer risk in young women at risk of familial breast cancer

Abstract

The objective of this study was to explore the factors that influence perceived personal risk of developing breast cancer (BC) in younger women (<35) who are considering or have undergone bilateral prophylactic mastectomy (BPM). Qualitative interviews guided by interpretative phenomenological analysis were conducted with 46 women who had a strong family history of BC and had either undergone (n = 26) or were considering (n = 20) BPM. Participants were recruited from Australia and New Zealand via hospitals, a genetics clinic, a research cohort, a registry and online. Three main themes were identified: information that increases fear of BC and death, underlying anxiety and fear and screening anxiety. A further two themes: relief following surgery and confusion about residual risk following surgery were identified. Younger women (<35) appeared to have heightened and sometimes inaccurate perceptions of their BC risk. They appeared less relieved of anxiety and fear of developing BC by BPM surgery, in comparison to previous research with older women (>40). Those who had undergone BPM seemed more anxious about their risk of developing BC than those who were still considering surgery. This research has important implications for practice, particularly improving communication of accurate risk statistics. Future research should examine why some women interpret information differently and explore the benefits of psychological consultation for very anxious women.

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Component Resolved Diagnosis in Hymenoptera Anaphylaxis

Abstract

Purpose of Review

Hymenoptera anaphylaxis is one of the leading causes of severe allergic reactions and can be fatal. Venom-specific immunotherapy (VIT) can prevent a life-threatening reaction; however, confirmation of an allergy to a Hymenoptera venom is a prerequisite before starting such a treatment. Component resolved diagnostics (CRD) have helped to better identify the responsible allergen.

Recent Findings

Many new insect venom allergens have been identified within the last few years. Commercially available recombinant allergens offer new diagnostic tools for detecting sensitivity to insect venoms. Additional added sensitivity to nearly 95% was introduced by spiking yellow jacket venom (YJV) extract with Ves v 5. The further value of CRD for sensitivity in YJV and honey bee venom (HBV) allergy is more controversially discussed. Recombinant allergens devoid of cross-reactive carbohydrate determinants often help to identify the culprit venom in patients with double sensitivity to YJV and HBV. CRD identified a group of patients with predominant Api m 10 sensitization, which may be less well protected by VIT, as some treatment extracts are lacking this allergen.

Summary

The diagnostic gap of previously undetected Hymenoptera allergy has been decreased via production of recombinant allergens. Knowledge of analogies in interspecies proteins and cross-reactive carbohydrate determinants is necessary to distinguish relevant from irrelevant sensitizations.

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The acceptability and tolerability of nasal douching in children with allergic rhinitis: A systematic review

Publication date: July 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 98
Author(s): Nelson Gutiérrez-Cardona, Paula Sands, Graham Roberts, Jane S. Lucas, Woolf Walker, Rami Salib, Andrea Burgess, Hasnaa Ismail-Koch
BackgroundAllergic rhinitis (AR) is a significant issue in children. Treatment options include allergen avoidance, pharmacotherapy and immunotherapy. The use of nasal saline douching (NSD) in children has recently gained acceptability. However, there is limited data regarding the acceptability and tolerability of NSD in children with AR.MethodsA search was conducted using Medline and Embase databases from January 1946 until June 2015 on the use of NSD in children aged 4–12 years with AR. All publications identified that assessed the beneficial effects, acceptability and tolerability were included.Results40 studies were analyzed. Data varied considerably in terms of saline solutions used, modality of application, participant numbers, study design, follow up and outcomes. Factors that appear to influence the acceptability and tolerability of NSD include parental and health professionals' preconceptions, and characteristics of the solution.ConclusionsNasal saline douching appears to be effective, being accepted and tolerated in the majority of children (78–100%). NSD has a significant positive impact on the quality of life in children with allergic rhinitis. When used as an adjunctive treatment having mainly a cleansing property, NSD potentiates the effects and may reduce the dose required of AR medications. Among the principal factors that influence the acceptability and tolerability of NSD are the child's age, delivery system and method, and tonicity. Nasal saline douching provides an accessible, low cost, low morbidity, easy to use treatment in children with allergic rhinitis.



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Zoledronic acid renders human M1 and M2 macrophages susceptible to Vδ2 + γδ T cell cytotoxicity in a perforin-dependent manner

Abstract

Vδ2⁺ T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2⁺ T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2⁺ T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C–C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2⁺ T cell cytotoxicity. Vδ2⁺ T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive—at least in part—to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2⁺ T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy.

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Paracrine release of IL-2 and anti-CTLA-4 enhances the ability of artificial polymer antigen-presenting cells to expand antigen-specific T cells and inhibit tumor growth in a mouse model

Abstract

Accumulating evidence indicates that bead-based artificial antigen-presenting cells (aAPCs) are a powerful tool to induce antigen-specific T cell responses in vitro and in vivo. To date, most conventional aAPCs have been generated by coupling an antigen signal (signal 1) and one or two costimulatory signals, such as anti-CD28 with anti-LFA1 or anti-4-1BB (signal 2), onto the surfaces of cell-sized or nanoscale magnetic beads or polyester latex beads. The development of a biodegradable scaffold and the combined use of multiple costimulatory signals as well as third signals for putative clinical applications is the next step in the development of this technology. Here, a novel biodegradable aAPC platform for active immunotherapy was developed by co-encapsulating IL-2 and anti-CTLA-4 inside cell-sized polylactic-co-glycolic acid microparticles (PLGA-MPs) while co-coupling an H-2K^b/TRP2-Ig dimer and anti-CD28 onto the surface. Cytokines (activating signal) and antibodies (anti-inhibition signal) were efficiently co-encapsulated in PLGA-MP-based aAPCs and co-released without interfering with each other. The targeted, sustained co-release of IL-2 and anti-CTLA-4 achieved markedly enhanced, synergistic effects in activating and expanding tumor antigen-specific T cells both in vitro and in vivo, as well as in inhibiting tumor growth in a mouse melanoma model, as compared with conventional two-signal aAPCs and IL-2 or anti-CTLA-4 single-released aAPCs. These data revealed the feasibility and importance of the paracrine release of multiple costimulatory molecules and cytokines from biodegradable aAPCs and thus provide a proof of principle for the future use of polymeric aAPCs for active immunotherapy of tumors and infectious diseases.

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Dianthin-30 or gelonin versus monomethyl auristatin E, each configured with an anti-calcitonin receptor antibody, are differentially potent in vitro in high-grade glioma cell lines derived from glioblastoma

Abstract

We have reported that calcitonin receptor (CTR) is widely expressed in biopsies from the lethal brain tumour glioblastoma by malignant glioma and brain tumour-initiating cells (glioma stem cells) using anti-human CTR antibodies. A monoclonal antibody against an epitope within the extracellular domain of CTR was raised (mAb2C4) and chemically conjugated to either plant ribosome-inactivating proteins (RIPs) dianthin-30 or gelonin, or the drug monomethyl auristatin E (MMAE), and purified. In the high-grade glioma cell line (HGG, representing glioma stem cells) SB2b, in the presence of the triterpene glycoside SO1861, the EC₅₀ for mAb2C4:dianthin was 10.0 pM and for mAb2C4:MMAE [antibody drug conjugate (ADC)] 2.5 nM, 250-fold less potent. With the cell line U87MG, in the presence of SO1861, the EC₅₀ for mAb2C4:dianthin was 20 pM, mAb2C4:gelonin, 20 pM, compared to the ADC (6.3 nM), which is >300 less potent. Several other HGG cell lines that express CTR were tested and the efficacies of mAb2C4:RIP (dianthin or gelonin) were similar. Co-administration of the enhancer SO1861 purified from plants enhances lysosomal escape. Enhancement with SO1861 increased potency of the immunotoxin (>3 log values) compared to the ADC (1 log). The uptake of antibody was demonstrated with the fluorescent conjugate mAb2C4:Alexa Fluor 568, and the release of dianthin-30:Alexa Fluor488 into the cytosol following addition of SO1861 supports our model. These data demonstrate that the immunotoxins are highly potent and that CTR is an effective target expressed by a large proportion of HGG cell lines representative of glioma stem cells and isolated from individual patients.

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Expression of PD-L1 in keratoacanthoma and different stages of progression in cutaneous squamous cell carcinoma

Abstract

Background

Programmed cell death 1 (PD-1) and its ligands (PD-L1) play a major role in the immune responses of a variety of cancers.

Objectives

To investigate the expression of PD-L1 in different progression forms of cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma (KA).

Methods

We performed immunohistochemical staining of 21 KA, 26 actinic keratoses (AK), 20 Bowen´s diseases (BD), and 26 high-risk cSCC. The staining patterns were assessed using the tumour proportion score and staining intensity evaluation. Immunohistology scores were statistically analysed.

Results

PD-L1 expression of tumour cells as well as tumour-infiltrating cells (TILs) was significantly higher in KA and cSCC when compared to AK and BD (P = 0.00028 and P = 0.00033, respectively). We observed a very strong positive correlation between the PD-L1 protein expression of tumour cells of KA and the PD-L1 protein expression of TILs (r = 0.97; P < 0.0001). A similar correlation was also found for cSCC (r = 0.86; P < 0.0001). The percentage of PD-L1 + tumours was 33.3% for KA and 26.9% for cSCC. Similarly, the percentage of PD-L1 + TILs in KA and cSCC was 33.3 and 34.6%, respectively.

Conclusions

PD-L1 is differently expressed in cSCC and closely related non-melanoma skin cancer. cSCC exhibit PD-L1 expression in a fourth of cases, indicating that PD1/PD-L1 inhibitors might be beneficial in a proportion of patients with an inoperable or metastatic cSCC. Unlike AK and BD, TILs and tumour cells of KA and cSCC present very similar PD-L1 expression profiles indicating a common immune escape mechanism.

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Common extracellular matrix regulation of myeloid cell activity in the bone marrow and tumor microenvironments

Abstract

The complex interaction between cells undergoing transformation and the various stromal and immunological cell components of the tumor microenvironment (TME) crucially influences cancer progression and diversification, as well as endowing clinical and prognostic significance. The immunosuppression characterizing the TME depends on the recruitment and activation of different cell types including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Less considered is the non-cellular component of the TME. Here, we focus on the extracellular matrix (ECM) regulatory activities that, within the TME, actively contribute to many aspects of tumor progression, acting on both tumor and immune cells. Particularly, ECM-mediated regulation of tumor-associated immunosuppression occurs through the modulation of myeloid cell expansion, localization, and functional activities. Such regulation is not limited to the TME but occurs also within the bone marrow, wherein matricellular proteins contribute to the maintenance of specialized hematopoietic stem cell niches thereby regulating their homeostasis as well as the generation and expansion of myeloid cells under both physiological and pathological conditions. Highlighting the commonalities among ECM-myeloid cell interactions in bone marrow and TME, in this review we present a picture in which myeloid cells might sense and respond to ECM modifications, providing different ECM-myeloid cell interfaces that may be useful to define prognostic groups and to tailor therapeutic interventions.

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MicroRNAs in injury and repair

Abstract

Organ damage and resulting pathologies often involve multiple deregulated pathways. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate a multitude of genes at the post-transcriptional level. Since their discovery over two decades ago, miRNAs have been established as key players in the molecular mechanisms of mammalian biology including the maintenance of normal homeostasis and the regulation of disease pathogenesis. In recent years, there has been substantial progress in innovative techniques to measure miRNAs along with advances in targeted delivery of agents modulating their expression. This has expanded the scope of miRNAs from being important mediators of cell signaling to becoming viable quantitative biomarkers and therapeutic targets. Currently, miRNA therapeutics are in clinical trials for multiple disease areas and vast numbers of patents have been filed for miRNAs involved in various pathological states. In this review, we summarize miRNAs involved in organ injury and repair, specifically with regard to organs that are the most susceptible to injury: the liver, heart and kidney. In addition, we review the current state of knowledge on miRNA biology, miRNA biomarkers and nucleotide-based therapeutics designed to target miRNAs to prevent organ injury and promote repair.

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A primer on systematic reviews in toxicology

Abstract

Systematic reviews, pioneered in the clinical field, provide a transparent, methodologically rigorous and reproducible means of summarizing the available evidence on a precisely framed research question. Having matured to a well-established approach in many research fields, systematic reviews are receiving increasing attention as a potential tool for answering toxicological questions. In the larger framework of evidence-based toxicology, the advantages and obstacles of, as well as the approaches for, adapting and adopting systematic reviews to toxicology are still being explored. To provide the toxicology community with a starting point for conducting or understanding systematic reviews, we herein summarized available guidance documents from various fields of application. We have elaborated on the systematic review process by breaking it down into ten steps, starting with planning the project, framing the question, and writing and publishing the protocol, and concluding with interpretation and reporting. In addition, we have identified the specific methodological challenges of toxicological questions and have summarized how these can be addressed. Ultimately, this primer is intended to stimulate scientific discussions of the identified issues to fuel the development of toxicology-specific methodology and to encourage the application of systematic review methodology to toxicological issues.

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Multigene phylogeny reveals a new species and novel records and hosts in the genus Ramularia from Iran

Abstract

Ramularia is a species-rich genus in the order Capnodiales (Dothideomycetes, Ascomycota) that includes numerous phytopathogenic taxa, several of which are economically important plant pathogens. In this study, six isolates of Ramularia were recovered from leaf spot symptoms on six herbaceous and woody plants from Guilan, East and West Azarbaijan provinces in the north and northwest of Iran. The isolates were studied by a polyphasic approach involving morphological and cultural data, and multi-gene phylogeny (ITS, TEF1-α, ACT, HIS, RPB2 and GAPDH). The isolates were grouped in three species clades of the R. eucalypti species complex. Of these, R. mali is recorded for the first time in Asia and R. glennii represents a new record for the mycobiota of Iran. Ramularia taleshina on Alnus subcordata is described as a new species. Ramularia taleshina is phylogenetically related to R. mali, but they can be differentiated by morphological and cultural characters as well as molecular data. Acalypha australis, Ficus carica and Platanus sp. are reported as new hosts of R. glennii, and Prunus cerasus and Vitis vinifera as new hosts of R. mali.

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Perceptions of Painful Diabetic Peripheral Neuropathy in South-East Asia: Results from Patient and Physician Surveys

Abstract

There are no data on physician–patient communication in painful diabetic peripheral neuropathy (pDPN) in the Asia–Pacific region. The objective of this study was to examine patient and physician perceptions of pDPN and clinical practice behaviors in five countries in South-East Asia. Primary care physicians and practitioners, endocrinologists, diabetologists, and patients with pDPN completed separate surveys on pDPN diagnosis, impact, management, and physician–patient interactions in Hong Kong, Malaysia, the Philippines, Taiwan, and Thailand. Data were obtained from 100 physicians and 100 patients in each country. The majority of physicians (range across countries, 30–85%) were primary care physicians and practitioners. Patients were mostly aged 18–55 years and had been diagnosed with diabetes for >5 years. Physicians believed pDPN had a greater impact on quality of life than did patients (ranges 83–92% and 39–72%, respectively), but patients believed pDPN had a greater impact on items such as sleep, anxiety, depression, and work than physicians. Physicians considered the diagnosis and treatment of pDPN a low priority, which may be reflected in the generally low incidence of screening (range 12–65%) and a lack of awareness of pDPN. Barriers to treatment included patients’ lack of awareness of pDPN. Both physicians and patients agreed that pain scales and local language descriptions were the most useful tools in helping to describe patients’ pain. Most patients were monitored upon diagnosis of pDPN (range 55–97%), but patients reported a shorter duration of monitoring compared with physicians. Both physicians and patients agreed that it was patients who initiated conversations on pDPN. Physicians most commonly referred to guidelines from the American Diabetes Association or local guidelines for the management of pDPN. This study highlights important differences between physician and patient perceptions of pDPN, which may impact on its diagnosis and treatment. For a chronic and debilitating complication like pDPN, the physician–patient dialogue is central to maximizing patient outcomes. Strategies, including education of both groups, need to be developed to improve communication.

Funding

Pfizer.

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