Characterization of O-antigen delivered by Generalized Modules for Membrane Antigens (GMMA) vaccine candidates against nontyphoidal Salmonella

Publication date: Available online 18 December 2016
Source:Vaccine
Author(s): G. De Benedetto, R. Alfini, P. Cescutti, M. Caboni, L. Lanzilao, F. Necchi, A. Saul, C.A. MacLennan, S. Rondini, F. Micoli
Invasive nontyphoidal Salmonella disease (iNTS) is a leading cause of death and morbidity in Africa. The most common pathogens are Salmonella enterica serovars Typhimurium and Enteritidis. The O-antigen portion of their lipopolysaccharide is a target of protective immunity and vaccines targeting O-antigen are currently in development. Here we investigate the use of Generalized Modules for Membrane Antigens (GMMA) as delivery system for S. Typhimurium and S. Enteritidis O-antigen. Gram-negative bacteria naturally shed outer membrane in a blebbing process. By deletion of the tolR gene, the level of shedding was greatly enhanced. Further genetic modifications were introduced into the GMMA-producing strains in order to reduce reactogenicity, by detoxifying the lipid A moiety of lipopolysaccharide. We found that genetic mutations can impact on expression of O-antigen chains. All S. Enteritidis GMMA characterized had an O-antigen to protein w/w ratio higher than 0.6, while the ratio was 0.7 for S. Typhimurium ΔtolR GMMA, but decreased to less than 0.1 when further mutations for lipid A detoxification were introduced. Changes were also observed in O-antigen chain length and level and/or position of O-acetylation. When tested in mice, the GMMA induced high levels of anti-O-antigen-specific IgG functional antibodies, despite variation in density and O-antigen structural modifications.In conclusion, simplicity of manufacturing process and low costs of production, coupled with encouraging immunogenicity data, make GMMA an attractive strategy to further investigate for the development of a vaccine against iNTS.



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Epidemiology of hepatitis B infection in Finland: Implications for immunisation policy

Publication date: Available online 18 December 2016
Source:Vaccine
Author(s): Tanja Karvonen, Kari Auranen, Markku Kuusi, Tuija Leino
ObjectivesWe describe the current epidemiology of acute and chronic hepatitis B infections in Finland. We estimate the total incidence of chronic hepatitis B following from the current incidence of acute infections and the influx of chronic carriers of hepatitis B associated with net immigration. We evaluate the incidence of hepatitis B infections preventable by a universal vaccination programme among infants.MethodsWe analysed hepatitis B cases reported to the National Infectious Disease Register during 2004–2012 and used pre-developed methods to adjust for acute asymptomatic infections. We estimated the projected incidence of chronic infection by applying age-specific risks of chronic infection to the estimated incidence of acute infection. We estimated the influx of chronic carriers associated with immigration by utilising data on immigration during 2004–2012 and the WHO regional estimates of carriage prevalence.ResultsThe estimated incidence of acute hepatitis B infection in Finland, adjusted for asymptomatic infections, was 1.67 per 100,000 per year (95% Crl 1.43–1.94) which is 4.2-fold to the register-based incidence. The estimated lifetime risks of acute and chronic hepatitis B infections were 0.13% and 0.01%, respectively. We estimated that annually seven new chronic infections would result from infections acquired in Finland. These new chronic infections accounted for 1.2% of the total incidence of chronic infections. We estimated that eventually three chronic infections per year would be potentially preventable by a universal infant vaccination programme.ConclusionsPartly due to the fact that hepatitis B infections in neonates and in children are rare, a very limited number of chronic hepatitis B infections resulted from infection acquired within the country. A vast majority of chronic hepatitis B infections occurred among foreign-born persons and were therefore not preventable by a universal infant immunisation programme in Finland. Even with a targeted immunisation programme, the incidence of hepatitis B infection has remained low.



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Dendritic Spine Classification using Shape and Appearance Features based on Two-Photon Microscopy

Publication date: Available online 18 December 2016
Source:Journal of Neuroscience Methods
Author(s): Muhammad Usman Ghani, Fitsum Mesadi, Sümeyra Demir Kanık, Ali Özgür Argunşah, Anna Felicity Hobbiss, Inbal Israely, Devrim Ünay, Tolga Taşdizen, Müjdat Çetin
BackgroundNeuronal morphology and function are highly coupled. In particular, dendritic spine morphology is strongly governed by the incoming neuronal activity. The first step towards understanding the structure-function relationships is to classify spine shapes into the main spine types suggested in the literature. Due to the lack of reliable automated analysis tools, classification is mostly performed manually, which is a time-intensive task and prone to subjectivity.New MethodWe propose an automated method to classify dendritic spines using shape and appearance features based on challenging two-photon laser scanning microscopy (2PLSM) data. Disjunctive Normal Shape Models (DNSM) is a recently proposed parametric shape representation. We perform segmentation of spine images by applying DNSM and use the resulting representation as shape features. Furthermore, we use Histogram of Oriented Gradients (HOG) to extract appearance features. In this context, we propose a kernel density estimation (KDE) based framework for dendritic spine classification, which uses these shape and appearance features.ResultsOur shape and appearance features based approach combined with Neural Network (NN) correctly classifies 87.06% of spines on a dataset of 456 spines.Comparison with Existing MethodsOur proposed method outperforms standard morphological feature based approaches. Our KDE based framework also enables neuroscientists to analyze the separability of spine shape classes in the likelihood ratio space, which leads to further insights about nature of the spine shape analysis problem.ConclusionsResults validate that performance of our proposed approach is comparable to a human expert. It also enable neuroscientists to study shape statistics in the likelihood ratio space.



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Contribution of the HNE-Immunohistochemistry to Modern Pathological Concepts of Major Human Diseases

Publication date: Available online 18 December 2016
Source:Free Radical Biology and Medicine
Author(s): Kamelija Zarkovic, Antonia Jakovcevic, Neven Zarkovic
Excessive production of reactive oxygen species can induce peroxidation of the polyunsaturated fatty acids thus generating reactive aldehydes like 4-hydroxy-2-nonenal (HNE), denoted as "the second messenger of free radicals". Because HNE has high binding affinity for cysteine, histidine and lysine it forms relatively stable and hardly metabolized protein adducts. By changing structure and function of diverse structural and regulatory proteins, HNE achieves not only cytotoxic, but also regulatory functions in various pathophysiological processes. Numerous animal model studies and clinical trials confirmed HNE as one of the crucial factors in development and progression of many disorders, in particular of cancer, (neuro)degenerative, metabolic and inflammatory diseases.Since HNE has multiple biological effects and is in the living system usually bound to proteins and peptides, many research groups work on development of specific immunochemical methods targeting the HNE-histidine adducts as major bioactive marker of lipid peroxidation, following the research pathway initiated by Hermann Esterbauer, who discovered HNE in 60's. Such immunohistochemical studies did not only prove the high biomedical importance of HNE, but have also given new insights into major diseases of the modern man. Immunohistochemical studies have shown reversibility of formation of the HNE-protein adducts, as well as differential onset of the HNE-mediated lipid peroxidation between age- associated atherosclerosis and photoaging, revealing eventually selective anti-cancer effects of HNE produced by non-malignant cells in vicinity of cancer.This review summarizes some of the HNE-histidine immunohistochemistry findings we believe are of broad biomedical interest and could inspire new studies in the field.



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BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma

Publication date: February 2017
Source:Human Pathology, Volume 60
Author(s): Stephanie M. McGregor, James McElherne, Agata Minor, Jennifer Keller-Ramey, Ryan Dunning, Aliya N. Husain, Wickii Vigneswaran, Carrie Fitzpatrick, Thomas Krausz
BRCA-associated protein 1 (BAP1) immunohistochemistry (IHC) and CDKN2A (p16) fluorescence in situ hybridization (FISH) have shown clinical utility in confirming the diagnosis of malignant pleural mesothelioma (MPM), but the role for using these 2 markers to guide clinical management is not yet clear. Although p16 loss is predictive of poor prognosis, there is controversy as to whether BAP1 loss is predictive of a more favorable prognosis; how these results interact with one another has not been explored. We performed CDKN2A FISH on a previously published tissue microarray on which we had performed BAP1 IHC, revealing combined BAP1/p16 status for 93 MPM cases. As expected, BAP1 IHC in combination with CDKN2A FISH resulted in high sensitivity (84%) and specificity (100%) for MPM, and p16 loss was an independent predictor of poor survival (hazard ratio, 2.2553; P = .0135). There was no association between BAP1 loss and p16 loss, as 26%, 28%, 30%, and 16% of overall cases demonstrated loss of BAP1 alone, loss of p16 alone, loss of both BAP1 and p16, or neither abnormality, respectively. Although multivariate analysis demonstrated that BAP1 IHC is not an independent predictor of prognosis, when viewed in combination with homozygous CDKN2A deletion, risk stratification was evident. More specifically, patients with CDKN2A disomy and loss of BAP1 expression had improved outcomes compared with those with CDKN2A disomy and retained BAP1 expression (hazard ratio, 0.2286; P = .0017), and this finding was notably evident among epithelioid cases. We conclude that BAP1 IHC provides prognostic information within the context of CDKN2A FISH that may have clinical utility beyond diagnosis.



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Modifying the One-Minute Preceptor Model for Use in the Emergency Department with a Critically Ill Patient

Publication date: Available online 16 December 2016
Source:The Journal of Emergency Medicine
Author(s): Kimberly Sokol




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Response

Publication date: Available online 16 December 2016
Source:The Journal of Emergency Medicine
Author(s): Susan E. Farrell, Sally Santen




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Tuberous sclerosis: Inside and outside

Publication date: Available online 16 December 2016
Source:Medical Journal Armed Forces India
Author(s): Manoj Gopinath, Deepak Vashisht, G.S. Madan




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Use of corticosteroids in acute respiratory distress syndrome: Perspective from an Indian intensive care unit

Publication date: Available online 16 December 2016
Source:Medical Journal Armed Forces India
Author(s): Naveen G.S. Chandra, Saraschandra Vallabhajosyula, Barkur A. Shastry, Shashaank Vallabhajosyula, Saarwaani Vallabhajosyula, Kavita Saravu
BackgroundAcute respiratory distress syndrome (ARDS) causes overwhelming inflammation, which serves as a potential target for corticosteroids. Despite extensive Western literature, there are no Indian studies evaluating steroids in ARDS.MethodsThis was a retrospective study at an Indian intensive care unit (ICU) on ARDS patients. Demographic, clinical, laboratory, and imaging parameters were collected. Patients were divided into cohorts based on steroid use, and some received high-dose (2mg/kg/day), whereas others received low-dose (1mg/kg/day) steroids. Primary outcomes were in-hospital mortality and secondary outcomes included need for and duration of invasive mechanical ventilation (IMV), IMV-free days, ICU length of stay (LOS), and total LOS. Two-tailed p<0.05 was considered statistically significant.ResultsDuring the 20-month period, 95 patients [median age 37 (30–47) years; 48 (50.5%) males] met our inclusion criteria. Steroid use was noted in 48 (50.5%) patients [11 (22.9%) low-dose and 37 (77.1%) high-dose]. Baseline characteristics of the cohorts, including ARDS severity indices, were comparable. Of these 95 patients, 70 (73.7%) had sepsis, but microbiological diagnosis was positive only in 17 (17.9%) patients. Steroid use did not significantly influence mortality [odds ratio (OR) 0.6 (0.3–1.4)] or need for IMV [OR 1.0 (0.4–2.6)]. There were no differences in outcomes of IMV-free days, ICU LOS, or total LOS. These outcomes were comparable between the high-dose and low-dose steroid users.ConclusionsSteroid use and comparison of low-dose vs. high-dose steroids did not influence outcomes associated with ARDS in the Indian population.



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Device-Associated Healthcare-Associated Infections (DA-HAI) and the caveat of multiresistance in a multidisciplinary intensive care unit

Publication date: Available online 16 December 2016
Source:Medical Journal Armed Forces India
Author(s): Inam Danish Khan, Atoshi Basu, Sheshadri Kiran, Shaleen Trivedi, Priyanka Pandit, Anupam Chattoraj
BackgroundDevice-Associated Healthcare-Associated Infections (DA-HAI), including Ventilator-Associated Pneumonia (VAP), Central-Line-Associated Blood Stream Infection (CLABSI), and Catheter-Related Urinary Tract Infection (CAUTI), are considered as principal contributors to healthcare hazard and threat to patient safety as they can cause prolonged hospital stay, sepsis, and mortality in the ICU. The study intends to characterize DA-HAI in a tertiary care multidisciplinary ICU of a teaching hospital in eastern India.MethodsThis prospective outcome-surveillance study was conducted among 2157 ICU patients of a 760-bedded teaching hospital in Eastern India. Clinical, laboratory and environmental surveillance, and screening of HCPs were conducted using the US Centers for Disease Control and Prevention (CDC)'s National Healthcare Safety Network (NHSN) definitions and methods.ResultsWith 8824 patient/bed/ICU days and 14,676 device days, pooled average device utilization ratio was 1.66, total episodes of DA-HAI were 114, and mean monthly rates of DA-HAI, VAP, CLABSI, and CAUTI were 4.75, 2, 1.4, and 1.25/1000 device days. Most common pathogens isolated from DA-HAI patients were Klebsiella pneumoniae (24.6%), Escherichia coli (21.9%), and Pseudomonas aeruginosa (20.2%). All Acinetobacter baumanii, >80% K. pneumoniae and E. coli, and >70% P. aeruginosa were susceptible only to colistin and tigecycline. One P. aeruginosa isolate was panresistant.ConclusionMean rates of VAP, CLABSI, and CAUTI were 14.4, 8.1, and 4.5 per 1000 device days, which are comparable with Indian and global ICUs. Patients and HCPs form important reservoirs of infection. Resolute conviction and sustained momentum in Infection Control Initiatives are an essential step toward patient safety.



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Flow cytometric detection of minimal residual disease in B-lineage acute lymphoblastic leukemia by using “MRD lite” panel

Publication date: Available online 16 December 2016
Source:Medical Journal Armed Forces India
Author(s): Tathagata Chatterjee, Venkatesan Somasundaram
BackgroundNormal B lymphoid precursors that express CD19, CD10, and/or CD34 are highly sensitive to corticosteroids and after two weeks of remission-induction therapy, they form less than 0.01% of the bone marrow population. More than 0.01% of such cells indicate minimal residual disease (MRD). MRD "lite" panel uses only three antibodies, namely CD19, CD10, and CD34 for MRD detection in cases of B-lineage acute lymphoblastic leukemia (B-ALL) expressing CD19, CD10, and/or CD34 by flow cytometry.MethodsFifteen cases of B-ALL were studied for MRD at Day 19 of remission-induction therapy by employing a simplified MRD detection protocol using a 3-color fluorochrome conjugated antibody panel (CD19, CD10, and CD34) on bone marrow aspirate samples.ResultsAll cases at diagnosis expressed CD19, CD10, and CD34. Of fifteen patients, five (33.33%) were MRD negative with less than 0.01% of mononuclear cells and remaining ten cases (66.66%) were MRD positive, with the level of 0.01% to less than 0.1% cells.ConclusionThe MRD assay used in this study is a simplified method for detecting MRD at Day 19 of remission-induction therapy for B-lineage ALL. This MRD assay is an effective and useful methodology in cases of B-ALL expressing CD19, CD10, and/or CD34 by flow cytometry.



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Ampelopsin attenuates lipopolysaccharide-induced inflammatory response through the inhibition of the NF-κB and JAK2/STAT3 signaling pathways in microglia

Publication date: March 2017
Source:International Immunopharmacology, Volume 44
Author(s): Leihua Weng, He Zhang, Xiaoxi Li, Hui Zhan, Fan Chen, Lijuan Han, Yun Xu, Xiang Cao
Increasing evidence suggests that microglia are a major cellular contributor to neuroinflammation. The present study investigated whether Ampelopsin (Amp), a type of flavanonol derivative from Ampelopsis grossedentata, may exert an anti-inflammatory effect on lipopolysaccharide (LPS)-induced BV2 and primary microglia cells. We found that pre-treatment of microglia cells with Amp before LPS with a non-cytotoxic concentration range decreased the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Amp also suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels. In addition, LPS-induced production of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) was obviously reduced by Amp. Our mechanistic study indicated that Amp suppressed LPS-induced activation of the IκB/NF-κB inflammation pathway without affecting changes in the phosphorylation levels of mitogen-activated protein kinases (MAPKs) in BV2 cells. Further studies revealed that Amp markedly reduced the phosphorylation levels of JAK2-STAT3 and STAT3 nuclear translocation. Overall, our data suggest that Amp can suppress the LPS-induced inflammatory response of microglial cells, indicating that Amp has potential for the treatment of inflammation-mediated neurodegenerative diseases.



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Nutritionally relevant concentrations of resveratrol and hydroxytyrosol mitigate oxidative burst of human granulocytes and monocytes and the production of pro-inflammatory mediators in LPS-stimulated RAW 264.7 macrophages

Publication date: February 2017
Source:International Immunopharmacology, Volume 43
Author(s): Elisabetta Bigagli, Lorenzo Cinci, Sara Paccosi, Astrid Parenti, Mario D'Ambrosio, Cristina Luceri
The health benefits of bio-active phenolic compounds have been largely investigated in vitro at concentrations which exceed those reachable in vivo. We investigated and compared the anti-inflammatory effects of resveratrol, hydroxytyrosol and oleuropein at physiologically relevant concentrations by using in vitro models of inflammation.Human granulocytes and monocytes were stimulated with phorbol myristate acetate (PMA) and the ability of resveratrol, hydroxytyrosol and oleuropein to inhibit the oxidative burst and CD11b expression was measured. Nitric oxide (NO), prostaglandin E2 (PGE2) levels, COX-2, iNOS, TNFα, IL-1β and miR-146a expression and activation of the transcription factor Nrf2 were evaluated in macrophages RAW 264.7 stimulated with LPS (1μg/ml) for 18h, exposed to resveratrol, hydroxytyrosol and oleuropein (5 and 10μM). Synergistic effects were explored as well, together with the levels of PGE2, COX-2 and IL-1β expression in macrophages after 6h of LPS stimulation. PGE2 and COX-2 expression were also assessed on human monocytes.All the tested compounds inhibited granulocytes oxidative burst in a concentration dependent manner and CD11b expression was also significantly counteracted by resveratrol and hydroxytyrosol. The measurement of oxidative burst in human monocytes produced similar effects being resveratrol more active. Hydroxytyrosol and resveratrol inhibited the production of NO and PGE2 but did not reduce iNOS, TNFα or IL-1β gene expression in LPS-stimulated RAW 264.7 for 18h. Resveratrol slightly decreased COX-2 expression after 18h but not after 6h, but reduced PGE2 levels after 6h. Resveratrol and hydroxytyrosol 10μM induced NRf2 nuclear translocation and reduced miR-146a expression in LPS treated RAW 264.7.Overall, we reported an anti-inflammatory effect of resveratrol and hydroxytyrosol at low, nutritionally relevant concentrations, involving the inhibition of granulocytes and monocytes activation, the modulation of miR-146a expression and the activation of Nrf2. A regular dietary intake of resveratrol and hydroxytyrosol may be a useful complementary strategy to control inflammatory diseases.



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CD14++ CD16− monocytes are the main source of 11β-HSD type 1 after IL-4 stimulation

Publication date: February 2017
Source:International Immunopharmacology, Volume 43
Author(s): Vidya Kunnathully, Macarena Gomez-Lira, Giulio Bassi, Fabio Poli, Elisa Zoratti, Valentina La Verde, Luca Idolazzi, Davide Gatti, Ombretta Viapiana, Silvano Adami, Maurizio Rossini
The anti-inflammatory actions of IL-4 are well established through earlier findings. However, the exact mechanism it uses to downregulate the pro-inflammatory cytokine production through monocytes and macrophages is poorly understood. In this study, we examined the effect of IL-4 in the induction of 11β-HSD1 in the two main classes of monocytes, CD14⁺⁺ CD16⁻ (CD14) and CD14⁺ CD16⁺ (CD16). Peripheral Blood Mononuclear Cells (PBMCs) were isolated from 17 healthy donors and were sorted into CD14 and CD16 subpopulations using cell sorting. Effect of IL-4 on 11β-HSD1-enzyme activity was measured in sorted and unsorted monocytes using Homogeneous Time-Resolved Fluorescence (HTRF) and M1/M2 polarization analysis was performed by flow cytometry. Our results indicate that CD14 cells are the major source of 11β-HSD1 enzyme after IL-4 stimulation and that M2 phenotype is not a pre-requisite for its synthesis.



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Digital PCR assessment of MGMT promoter methylation coupled with reduced protein expression optimises prediction of response to alkylating agents in metastatic colorectal cancer patients

Publication date: January 2017
Source:European Journal of Cancer, Volume 71
Author(s): Andrea Sartore-Bianchi, Filippo Pietrantonio, Alessio Amatu, Massimo Milione, Andrea Cassingena, Silvia Ghezzi, Marta Caporale, Rosa Berenato, Chiara Falcomatà, Alessio Pellegrinelli, Alberto Bardelli, Michele Nichelatti, Federica Tosi, Filippo De Braud, Federica Di Nicolantonio, Ludovic Barault, Salvatore Siena
BackgroundO(6)-methylguanine-DNA-methyltransferase (MGMT) is a repair protein, and its deficiency makes tumours more susceptible to the cytotoxic effect of alkylating agents. Five clinical trials with temozolomide or dacarbazine have been performed in metastatic colorectal cancer (mCRC) with selection based on methyl-specific PCR (MSP) testing with modest results. We hypothesised that mitigated results are consequences of unspecific patient selection and that alternative methodologies for MGMT testing such as immunohistochemistry (IHC) and digital polymerase chain reaction (PCR) could enhance patient enrolment.Patients and methodsFormalin-fixed paraffin embedded archival tumour tissue samples from four phase II studies of temozolomide or dacarbazine in MGMT MSP-positive mCRCs were analysed by IHC for MGMT protein expression and by methyl-BEAMing (MB) for percentage of promoter methylation. Pooled data were then retrospectively analysed according to objective response rate, progression-free survival (PFS) and overall survival (OS).ResultsOne hundred and five patients were included in the study. Twelve had achieved partial response (PR) (11.4%), 24 stable disease (SD; 22.9%) and 69 progressive disease (PD; 65.7%). Patients with PR/SD had lower IHC scores and higher MB levels than those with PD. MGMT expression by IHC was negatively and MB levels positively associated with PFS (p < 0.001 and 0.004, respectively), but not with OS. By combining both assays, IHC low/MB high patients displayed an 87% reduction in the hazard of progression (p < 0.001) and a 77% in the hazard for death (p = 0.001).ConclusionIn mCRC selected for MGMT deficiency by MSP, IHC and MB testing improve clinical outcome to alkylating agents. Their combination could enhance patient selection in this setting.



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Calibration and response of an agarose gel based passive sampler to record short pulses of aquatic organic pollutants

Publication date: 1 April 2017
Source:Talanta, Volume 165
Author(s): Angel Belles, Claire Alary, Yann Aminot, James W. Readman, Christine Franke
A passive sampler inspired from previous devices was developed for the integrative sampling of a broad range of contaminants in the water column. Our primary objective was to improve the performance of the device to provide accurate and averaged pollutant water concentrations. For this purpose, an agarose diffusive gel was used as the boundary layer that drives the analyte uptake rate. Contrary to conventional passive samplers, the developed device does not require the sampling rates to be corrected for exposure conditions (e.g. hydrodynamic flow) because the diffusive gel boundary layer selected was sufficiently large to control the pollutant diffusion rate from the aqueous phase. The compounds diffusion coefficients in agarose gel and the gel thickness are the only required data to accurately calculate the time weighted averaged water concentration of pollutants. The performance of the developed sampler was evaluated in the laboratory under two contamination scenarios and in the field in 8 contrasting exposure sites for a selection of 16 emerging pollutants and pesticides. The results show that detection limits of this method are environmentally relevant and allow the determination of the averaged pollutant concentrations. Additionally, the ability of the device to sense very short contamination pulses (5–320min) was evaluated through a theoretical approach and laboratory tests. Results show that the device is suitable for sampling contamination pulses as short as 5min without deviation from the actual average concentrations of pollutants.

Graphical abstract

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Radiopharmaceuticals for metastatic bone pain palliation: available options in the clinical domain and their comparisons

Abstract

Bone pain arising due to skeletal metastases is one of the common complications experienced by the majority of patients suffering from prostate, breast and lung cancer at the advanced stage of the disease. These patients are subjected to palliative care in order to improve the quality of their remaining life. With the gradually increasing number of cancer cases, palliation of metastatic bone pain is gaining importance. Bone-seeking radiopharmaceuticals play a pivotal role in the management of cancer pain, particularly in patients with multiple metastases, as these agents are proven to be effective in controlling the bone pain with minimum side effects. Although a plethora of such radiopharmaceuticals have been developed and evaluated in animal models, only a few are regularly used in clinics while some of these agents are at different stages of clinical evaluations. The present article describes only those bone-seeking radiopharmaceuticals, which have been reported to be clinically administered till date, along with their relative merits and drawbacks.

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Young, Healthy South Asians Have Enhanced Lipogenic Sensitivity to Dietary Sugar

Abstract

Objective

South Asians have higher rates of Type 2 diabetes and cardiovascular disease compared to most other racial/ethnic groups. Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar may accelerate the development of these chronic diseases in this population.

Study Design

Hepatic DNL in response to a calorically sweetened beverage was measured in an outpatient setting in 15 South Asians and 15 Caucasians with similar and normal body mass indexes, waist circumferences, glucose tolerance and lipid profiles. Blood was sampled before and hourly for 4 h after the ingestion of a single beverage made with glucose (1.5 g/kg) and fructose (1.5g/kg). The main outcome, DNL, was measured as the increase in %palmitate (16:0) in very low density lipoprotein (VLDL) triglyceride (TG) over 4 h.

Results

After the sugar dose, the increase in %16:0 in VLDL TG was significantly greater in South Asians vs. Caucasians (P=0.01). VLDL and total TG also increased to a significantly greater extent in South Asians (P=0.04 and <0.001, respectively). Although the fasting and post-sugar levels of insulin and glucose did not differ between groups, the DNL response significantly correlated with the insulin response to sugar in South Asians (r=0.56, P=0.03).

Conclusions

Hepatic DNL in response to a sugar challenge was greater in healthy, young South Asians compared to Caucasians despite normal indices of insulin sensitivity, and it correlated with the insulin response. These findings suggest an early, insulin-related, gene-nutrient interaction contributing to the high prevalence of diabetes and coronary disease in this population.

This article is protected by copyright. All rights reserved.

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Focal Gain Control of Thalamic Visual Receptive Fields by Layer 6 Corticothalamic Feedback

The projections between the thalamus and primary visual cortex (V1) are a key reciprocal neural circuit, relaying retinal signals to cortical layers 4 & 6 while being simultaneously regulated by massive layer 6 corticothalamic feedback. Effectively dissecting the influence of this corticothalamic feedback circuit in higher mammals remains a challenge for vision research. By pharmacologically increasing the focal gain of visually driven layer 6 responses of cat V1 in a controlled fashion, we examined the effects of such focal cortical changes on the response amplitudes and spatial structure of the receptive fields (RFs) of individual dorsal lateral geniculate nucleus (dLGN) cells. We found that enhancing visually driven cortical feedback could facilitate or suppress the overall responses of dLGN cells, and such an effect was linked to the orientation preference of the cortical neuron. Related to these selective retinotopic gain changes, enhanced feedback induced the RFs of dLGN cells to expand, contract or shift their spatial focus. Our results provide further evidence for a functional mechanism through which the cortex can selectively gate visual information flow from the thalamus back to the visual cortex.

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A label-free and high-efficient GO-based aptasensor for cancer cells based on cyclic enzymatic signal amplification

Publication date: 15 May 2017
Source:Biosensors and Bioelectronics, Volume 91
Author(s): Kunyi Xiao, Juan Liu, Hui Chen, Song Zhang, Jilie Kong
A label-free and high-efficient graphene oxide (GO)-based aptasensor was developed for the detection of low quantity cancer cells based on cell-triggered cyclic enzymatic signal amplification (CTCESA). In the absence of target cells, hairpin aptamer probes (HAPs) and dye-labeled linker DNAs stably coexisted in solution, and the fluorescence was quenched by the GO-based FÖrster resonance energy transfer (FRET) process. In the presence of target cells, the specific binding of HAPs with the target cells triggered a conformational alternation, which resulted in linker DNA complementary pairing and cleavage by nicking endonuclease-strand scission cycles. Consequently, more cleaved fragments of linker DNAs with more the terminal labeled dyes could show the enhanced fluorescence because these cleaved DNA fragments hardly combine with GOs and prevent the FRET process. Fluorescence analysis demonstrated that this GO-based aptasensor exhibited selective and sensitive response to the presence of target CCRF-CEM cells in the concentration range from 50 to 10⁵ cells. The detection limit of this method was 25 cells, which was approximately 20 times lower than the detection limit of normal fluorescence aptasensors without amplification. With high sensitivity and specificity, it provided a simple and cost-effective approach for early cancer diagnosis.



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A green and facile approach for synthesizing imine to develop optical biosensor for wide range detection of bilirubin in human biofluids

Publication date: 15 May 2017
Source:Biosensors and Bioelectronics, Volume 91
Author(s): Sundaram Ellairaja, Kathiravan Shenbagavalli, Sarkaraisamy Ponmariappan, Vairathevar Sivasamy Vasantha
Bilirubin, a key biomarker for the jaundice and its clinical diagnosis needs a better analytical tool. A novel and simple fluorescent platform based on (2,2′-((1E,1′E)-((6-bromopyridine-2,3-diyl) bis(azanylylidene)) bis(methanylylidene diphenol) (BAMD) was designed. BAMD showed a remarkable fluorescent intensity with a very good quantum yield of 0.85 and lifetime of 870ps. Hence, it was applied for the determination of bilirubin using both colorimetric and fluorimetric techniques in physiological and basic pH. Under optimized experimental conditions, the probe detects bilirubin selectively in the presence of other interfering biomolecules and metal ions. The linear range of detection is 1pM–500µM at pH=7.4 and LOD is 2.8 and 3.3 pM at pH=7.4 and 9.0, respectively, which were reported so far. The probe detects the bilirubin through FRET mechanism. The practical application of the probe was successfully tested in the human blood and urine samples. Based on all above advantages, this simple idea can be applied to design a simple clinical diagnostic tool for jaundice.



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Visual colorimetric sensor array for discrimination of antioxidants in serum using MnO2 nanosheets triggered multicolor chromogenic system

Publication date: 15 May 2017
Source:Biosensors and Bioelectronics, Volume 91
Author(s): Wei Huang, Yuequan Deng, Yi He
Here we report a unique visual colorimetric sensor array for discrimination of antioxidants in serum based on MnO2 nanosheets-3,3′,5,5′-tetramethylbenzidine (TMB) multicolor chromogenic system. The absorbance values of the system at 370, 450, and 650nm provide three cross-reactive sensing elements. The presence of antioxidant will inhibit the reaction between TMB and MnO2 nanosheets due to the presence of the competitive reaction of MnO2 nanosheets and antioxidants. Different antioxidants containing uric acid, glutathione, ascorbic acid, cysteine, and melatonin have distinct reducing ability, producing a differential inhibition of MnO2 nanosheets-TMB system, and therefore generating distinct colorimetric response patterns at 370, 450, and 650nm. The obtained patterns for each antioxidant at a concentration of 20μM were successfully discriminated using principal component analysis both in buffer and when spiked into fetal bovine serum (FBS). The identification accuracy of 45 unknown samples was found to be 100%. Remarkably, this sensor assay can visually discriminate antioxidants in diluted FBS with the naked eye.

Graphical abstract

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Development of a colloidal gold immunochromatographic strip for rapid detection of Streptococcus agalactiae in tilapia

Publication date: 15 May 2017
Source:Biosensors and Bioelectronics, Volume 91
Author(s): Wu Wen-de, Li Min, Chen Ming, Li Li-ping, Wang Rui, Chen Hai-lan, Chen Fu-Yan, Mi Qiang, Liang Wan-wen, Chen Han-zhong
A colloidal gold immunochromatographic strip was developed for rapid detection of Streptococcus agalactiae (S. agalactiae) infection in tilapia. The monoclonal antibodies (mAb) 4C12 and 3A9 were used to target S. agalactiae as colloidal gold-mAb conjugate and captured antibody, respectively. The colloidal gold immunochromatographic strip was assembled via routine procedures. Optimal pH and minimum antibody levels in the reaction system for gold colloidal-mAb 4C12 conjugation were pH 7.4 and 18μg/mL, respectively. Optimal concentrations of the captured antibody 3A9 and goat anti-mouse antibody were 0.6mg/mL and 2mg/mL, respectively. The sensitivity of the strip for detecting S. agalactiae was 1.5×10⁵ colony forming units (CFU). No cross-reaction was observed with other commonly encountered bacteria, including Pseudomonas fluorescens, Aeromonas hydrophila, Vibrio anguillarum and Streptococcus iniae. The assay time for S. agalactiae was less than 15min. Tilapia samples artificially infected with S. agalactiae were tested using the newly developed strip. The results indicated that blood, brain, kidney, spleen, metanephros and intestine specimens of infected fish can be used for S. agalactiae detection. The validity of the strip was maintained for 6 months at 4°C. These findings suggested that the immunochromatographic strip was effective for spot and rapid detection of S. agalactiae infected tilapia.



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The characteristics of steel slag and the effect of its application as a soil additive on the removal of nitrate from aqueous solution

Abstract

This study examined the characteristics of nitrate removal from aqueous solution by steel slag and the feasibility of using steel slag as a soil additive to remove nitrate. Steel slag adsorbents were characterized by X-ray fluorescence (XRF), X-ray diffraction (XRD), scanning electron microscopy (SEM) and infrared spectrum (IR spectrum). Adsorption isotherms and kinetics were also analysed. Various parameters were measured in a series of batch experiments, including the sorbent dose, grain size of steel slag, reaction time, initial concentration of nitrate nitrogen, relationship between Al, Fe and Si ions leached from the steel slag and residual nitrate in the aqueous solution. The nitrate adsorbing capacity increased with increasing amounts of steel slag. In addition, decreasing the grain diameter of steel slag also enhanced the adsorption efficiency. Nitrate removal from the aqueous solution was primarily related to Al, Fe, Si and Mn leached from the steel slag. The experimental data conformed to second-order kinetics and the Freundlich isothermal adsorption equation, indicating that the adsorption of nitrate by steel slag is chemisorption under the action of monolayer adsorption. Finally, it was determined that using steel slag as a soil additive to remove nitrate is a feasible strategy.

http://ift.tt/2gXQlLH

Microwave-assisted enhancement of milkweed ( Calotropis procera L.) leaves as an eco-friendly source of natural colorants for textile

Abstract

Application of natural colorants to textile fabrics has gained worldwide public acceptance due to the hazardous nature of synthetic dyes. Present study investigated the microwave's mediated extraction of natural colorants from leaves of milkweed (Calotropis procera L.) as well as their application to cotton fabrics assisted with biochemical mordants. Dye extraction from C. procera leaves was carried out in various mediums (alkali and aqueous), and the extracted dye as well as cotton fabrics was irradiated with microwaves for 2, 4, 6, 8, or 10 min. Effect of various temperature regimes and sodium chloride (NaCl) concentrations was also evaluated on the color strength of dyed cotton fabrics. The results revealed that extraction of natural colorants was enhanced when microwave radiations were applied for 4 min by using alkali as an extraction medium as compared to aqueous one. Optimum dyeing of cotton fabrics was achieved by using NaCl at a temperature of 55 °C. Among the chemical mordants, iron was effective for better color strength when used as pre- and post-mordant. Among the studied bio-mordants, extract of Acacia nilotica bark significantly improved the color strength and fastness properties as pre-mordant and Curcuma longa tuber as post-mordant. It was concluded that extract of C. procera leaves was a potential source of natural colorants and a high level of dye was obtained upon irradiation of alkali-solubilized extract for 4 min. Application of NaCl at concentration of 3 g/100 mL and temperature treatment of 55 °C significantly improved the color strength of dyed cotton fabrics.

http://ift.tt/2hdQuGQ

Characteristics of the overflow pollution of storm drains with inappropriate sewage entry

Abstract

To probe the overflow pollution of separate storm drains with inappropriate sewage entries, in terms of the relationship between sewage entries and the corresponding dry-weather and wet-weather overflow, the monitoring activities were conducted in a storm drainage system in the Shanghai downtown area (374 ha). In this study site, samples from inappropriately entered dry-weather sewage and the overflow due to storm pumps operation on dry-weather and wet-weather days were collected and then monitored for six water quality constituents. It was found that overflow concentrations of dry-weather period could be higher than those of wet-weather period; under wet-weather period, the overflow concentrations of storm drains were close to or even higher than that of combined sewers. Relatively strong first flush mostly occurred under heavy rain that satisfied critical rainfall amount, maximum rainfall intensity, and maximum pumping discharge, while almost no first flush effect or only weak first flush effect was found for the other rainfall events. Such phenomenon was attributed to lower in-line pipe storage as compared to that of the combined sewers, and serious sediment accumulation within the storm pipes due to sewage entry. For this kind of system, treating a continuous overflow rate is a better strategy than treating the maximum amount of early part of the overflow. Correcting the key inappropriate sewage entries into storm drains should also be focused.

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Green mitigation strategy for cultural heritage: bacterial potential for biocide production

Abstract

Several biosurfactants with antagonistic activity are produced by a variety of microorganisms. Lipopeptides (LPPs) produced by some Bacillus strains, including surfactin, fengycin and iturin are synthesized nonribosomally by mega-peptide synthetase (NRPS) units and they are particularly relevant as antifungal agents. Characterisation, identification and evaluation of the potentials of several bacterial isolates were undertaken in order to establish the production of active lipopeptides against biodeteriogenic fungi from heritage assets. Analysis of the iturin operon revealed four open reading frames (ORFs) with the structural organisation of the peptide synthetases. Therefore, this work adopted a molecular procedure to access antifungal potential of LPP production by Bacillus strains in order to exploit the bioactive compounds synthesis as a green natural approach to be applied in biodegraded cultural heritage context. The results reveal that the bacterial strains with higher antifungal potential exhibit the same morphological and biochemical characteristics, belonging to the genera Bacillus. On the other hand, the higher iturinic genetic expression, for Bacillus sp. 3 and Bacillus sp. 4, is in accordance with the culture antifungal spectra. Accordingly, the adopted methodology combining antifungal screening and molecular data is represent a valuable tool for quick identification of iturin-producing strains, constituting an effective approach for confirming the selection of lipopeptides producer strains.

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Catalytic oxidation of 1,2-DCBz over V 2 O 5 /TiO 2 -CNTs: effect of CNT diameter and surface functional groups

Abstract

A series of V₂O₅/TiO₂-carbon nanotube (CNT) catalysts were prepared and tested to decompose gaseous 1,2-dichlorobenzene (1,2-DCBz). Several physicochemical methods, including nitrogen adsorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and H₂ temperature-programmed reduction (TPR) were employed to characterise their physicochemical properties. To better understand the effect of CNT properties on the reactivity of V₂O₅/TiO₂-CNT catalysts, the 1,2-DCBz residue remaining in the off-gas and on the catalyst surface were both collected and analysed. The results indicate that the outer diameter and the surface functional groups (hydroxide radical and carboxyl) of CNTs significantly influence upon the catalytic activity of CNT-containing V₂O₅/TiO₂ catalysts: the CNT outer diameter mainly affects the aggregation of CNTs and the π-π interaction between the benzene ring and CNTs, while the introduction of –OH and –COOH groups by acid treatment can further enlarge specific surface area (SSA) and contribute to a higher average oxidation state of vanadium (V _aos) and supplemental surface chemisorbed oxygen (O_ads). In addition, the enhanced mobility of lattice oxygen (O_latt) also improves the oxidation ability of the catalysts.

http://ift.tt/2gXY6RO

Prevention of Thrombosis in the Hypercoagulable Microsurgery Patient: A Novel Anticoagulation Protocol

Hypercoagulable conditions are often considered to be relative contraindications to free flap reconstruction. This paper presents and critically examines a novel anticoagulation regimen developed to address this disease state.

http://ift.tt/2gXvoAB

Phenotypic approaches to obstructive sleep apnoea- New pathways for targeted therapy

People develop obstructive sleep apnoea (OSA) for different reasons. The ability to understand these reasons, easily identify them in individual patients, and develop therapies that target one or more of these reasons are the keys to unlocking new approaches for the treatment of OSA. In line with this approach, recent advances in OSA pathogenesis using upper airway and respiratory phenotyping techniques have identified four key causes of OSA. A narrow or collapsible upper airway ('impaired anatomy') is the primary cause.

http://ift.tt/2gXzQzh

How does general anaesthesia affect the circadian clock?

Post-operative patients experience sleep disturbances. Animal studies demonstrate that general anaesthesia (GA) can disrupt circadian rhythms and cause changes in the molecular clock, indicating that anaesthesia contributes to post-operative circadian disruption. Here we review the effect of anaesthesia on the circadian clock and its rhythms in order to summarise current findings outline commonalities between studies and propose mechanisms by which effects may be mediated.Key points: (1) GA has strong effects on the main neurotransmitter systems linked with circadian control (GABA/NMDA) and may act by interfering with light-entrainment of the clock.

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MicroRNA-712 restrains macrophage pro-inflammatory responses by targeting LRRK2 leading to restoration of insulin stimulated glucose uptake by myoblasts

Publication date: February 2017
Source:Molecular Immunology, Volume 82
Author(s): Malathi Talari, Tapan Kumar Singh Nayak, Vasundhara Kain, Phanithi Prakash Babu, Parimal Misra, Kishore V.L. Parsa
Chronic inflammatory diseases such as insulin resistance, Type 2 diabetes, neurodegenerative diseases etc., are shown to be caused due to imbalanced activation states of macrophages. MicroRNAs which are transcriptional/post-transcriptional regulators of gene expression drive several pathophysiological processes including macrophage polarization. However the functional role of microRNAs in regulating inflammation induced insulin resistance is ill defined. In our current study we observed that the expression of miR-712 was reduced in macrophages exposed to LPS and IFN-γ. Ectopic expression of miR-712 in RAW 264.7 mouse macrophages impaired the expression of iNOS protein and secretion of pro-inflammatory cytokines such as TNF-α, IL-6 and IFN-β which in turn led to improved insulin stimulated glucose uptake in co-cultured L6 myoblasts. Mechanistically, we identified that miR-712 targets the 3′UTR of a potent inflammatory gene LRRK2 and dampens the phosphorylation of p38 and ERK1/2 kinases. Taken together, our data underscore the regulatory role of miR-712 in restoring insulin stimulated glucose uptake by myoblasts through down-regulating macrophage mediated inflammatory responses.



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TRPM1 (melastatin) expression is an independent predictor of overall survival in clinical AJCC stage I and II melanoma patients

Abstract

BACKGROUND

The expression of TRPM1 (melastatin) mRNA is an independent marker, as measured by radioactive in situ hybridization (RISH), of disease-free survival in primary cutaneous melanoma (PM). The aim of the study was to determine if chromogenic in situ hybridization (CISH) can reproduce results examining diagnostic and prognostic utility of TRPM1 mRNA expression in melanocytic proliferations as measured by RISH.

METHODS

The expression of TRPM1 mRNA was detected by CISH in melanocytic nevi (MN, n = 61), PM (n = 145), and metastatic melanomas (MM, n = 15).

RESULTS

A progressive loss of TRPM1 was found moving from MN to PM to MM. The histologic stepwise model of melanoma progression revealed that loss of TRPM1 occurred at the transition of RGP PM to VGP PM. As a diagnostic marker, TRPM1 gradient loss showed 93.8% sensitivity and 52.4% specificity for PM. Loss of TRPM1 mRNA correlated with melanoma aggressiveness markers and was independent predictor of disease-free and overall survival. The corresponding survival curves for degree of melanoma pigmentation matched those for degree of loss of TPRM1 mRNA.

CONCLUSION

Loss of TRPM1 mRNA expression appears to be a crucial event in the progression of melanoma to a more malignant, metastatic phenotype.

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Are linear AChR epitopes the real culprit in ocular myasthenia gravis?

Publication date: Available online 16 December 2016
Source:Medical Hypotheses
Author(s): Xiaorong Wu, Erdem Tüzün
Extraocular muscle weakness occurs in most of the myasthenia gravis (MG) patients and it is often the initial complaint. Approximately 10-20% of MG patients with extraocular muscle weakness display only ocular symptoms and rest of the patients subsequently develop generalized muscle weakness. It is not entirely clear why some MG patients develop only ocular symptoms and why extraocular muscle weakness almost always precedes generalized muscle weakness. These facts are often explained by increased susceptibility of extraocular muscles due to their reduced endplate safety factor and lower complement inhibitor expression. Findings of a recently developed animal model of ocular MG suggest that additional factors might be in play. While immunization of HLA transgenic and wild-type (WT) mice with the native acetylcholine receptor (AChR) pentamer carrying conformational epitopes generates severe generalized muscle weakness, immunization of the same mouse strains with recombinant unfolded AChR subunits containing linear epitopes induces ptosis with or without mild generalized muscle weakness. Notably, immunization of mice with deficient T helper cell-mediated antigen presentation with recombinant AChR subunits or whole native AChR pentamer also induces ocular symptoms, AChR-reactive B cells and AChR antibodies. Based on these findings, we hypothesize that ocular symptoms observed in the earlier stages of MG might be triggered by linear and non-conformational AChR epitopes expressed by thymic cells or invading microorganisms. This initial AChR autoimmunity might be managed by T cell-independent and B cell mediated mechanisms yielding low affinity AChR antibodies. These antibodies are putatively capable of inducing muscle weakness only in extraocular muscles which have increased vulnerability due to their inherent biological properties. After this initial attack, as AChR bearing immune complexes form and the immune system gains access to the native AChR expressed by muscle and thymic myoid cells, a more robust anti-AChR autoimmunity develops giving way to high affinity AChR antibodies, thymic germinal center formation and severe generalized muscle weakness. Accurate characterization of chain if events leading to ocular and generalized symptoms in MG might enable development of novel therapeutics that might prevent the transition from mild ocular symptoms to severe generalized weakness in earlier stages of the disease.



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Datasets for next-generation sequencing of DNA and RNA from urine and plasma of patients with prostate cancer

Publication date: February 2017
Source:Data in Brief, Volume 10
Author(s): A.S. Nikitina, E.I. Sharova, S.A. Danilenko, O.V. Selezneva, T.B. Butusova, A.O. Vasiliev, A.V. Govorov, E.A. Prilepskaya, D.Y. Pushkar, E.S. Kostryukova
Current prostate cancer (PCa) diagnostic tests suffer from insufficient sensitivity and specificity. Novel biomarkers that can be detected by minimally invasive methods are of a particular value. Here we provide two datasets. The first one is on the whole transcriptome profiling by RNA-seq of urine and plasma obtained from patients with PCa and benign prostatic hyperplasia (BPH). The second one represents targeted sequencing of DNA from urine and plasma of patients with PCa and BPH. Both datasets are available at NCBI Sequence Read Archive under Accession No. SRP093707 and No. SRP093842 respectively.



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Modulation of Signaling Mechanisms in the Heart by Thioredoxin 1

Publication date: Available online 16 December 2016
Source:Free Radical Biology and Medicine
Author(s): Narayani Nagarajan, Shinichi Oka, Junichi Sadoshima
Myocardial ischemia/reperfusion and heart failure are the major cardiac conditions in which an imbalance between oxidative stress and anti-oxidant mechanisms is observed. The myocardium has endogenous reducing mechanisms, including the thioredoxin (Trx) and glutathione systems, that act to scavenge reactive oxygen species (ROS) and reduce oxidized proteins. The Trx system consists of Trx, Trx reductase (TrxR), and an electron donor, NADPH, where Trx is maintained in a reduced state in the presence of TrxR and NADPH. Trx1, a major isoform of Trx, is abundantly expressed in the heart and exerts its oxidoreductase activity through conserved Cys32 and Cys35, reducing oxidized proteins through thiol disulfide exchange reactions. In this review, we will focus on molecular targets of Trx1 in the heart, including transcription factors, microRNAs, histone deactylases, and protein kinases. We will then discuss how Trx1 regulates the functions of its targets, thereby affecting the extent of myocardial injury caused by myocardial ischemia/reperfusion and the progression of heart failure.



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Use of electric field sensors for recording respiration, heart rate, and stereotyped motor behaviors in the rodent home cage

Publication date: Available online 16 December 2016
Source:Journal of Neuroscience Methods
Author(s): Donald J. Noble, Camden J. MacDowell, Michael L. McKinnon, Tamra I. Neblett, William N. Goolsby, Shawn Hochman
BackgroundNumerous environmental and genetic factors can contribute significantly to behavioral and cardiorespiratory variability observed experimentally. Affordable technologies that allow for noninvasive home cage capture of physio-behavioral variables should enhance understanding of inter-animal variability including after experimental interventions.New methodWe assessed whether EPIC electric field sensors (Plessey Semiconductors) embedded within or attached externally to a rodent's home cage could accurately record respiration, heart rate, and motor behaviors.Comparison with existing methodsCurrent systems for quantification of behavioral variables require expensive specialty equipment, while measures of respiratory and heart rate are often provided by surgically implanted or chronically affixed devices.ResultsSensors accurately encoded imposed sinusoidal changes in electric field tested at frequencies ranging from 0.5–100Hz. Mini-metronome arm movements were easily detected, but response magnitude was highly distance dependent. Sensors accurately reported respiration during whole-body plethysmography. In anesthetized rodents, PVC tube-embedded sensors provided accurate mechanical detection of both respiratory and heart rate. Comparable success was seen in naturally behaving animals at rest or sleeping when sensors were attached externally. Video-verified motor behaviors (sniffing, grooming, chewing, and rearing) were detectable and largely separable by their characteristic voltage fluctuations. Larger movement-related events had comparably larger voltage dynamics that easily allowed for a broad approximation of overall motor activity. Spectrograms were used to quickly depict characteristic frequencies in long-lasting recordings, while filtering and thresholding software allowed for detection and quantification of movement-related physio-behavioral events.ConclusionsEPIC electric field sensors provide a means for affordable non-contact home cage detection of physio-behavioral variables.



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Phase I study of stereotactic body radiation therapy for peripheral T2N0M0 non-small cell lung cancer (JCOG0702): Results for the group with PTV⩾100cc

Publication date: Available online 16 December 2016
Source:Radiotherapy and Oncology
Author(s): Rikiya Onimaru, Hiroshi Onishi, Taro Shibata, Masahiro Hiraoka, Satoshi Ishikura, Katsuyuki Karasawa, Yukinori Matsuo, Masaki Kokubo, Yoshiyuki Shioyama, Haruo Matsushita, Yoshinori Ito, Hiroki Shirato
PurposeA dose escalation study to determine the recommended dose (RD) with stereotactic body radiation therapy (SBRT) for peripheral T2N0M0 non-small cell carcinomas (NSCLC) was conducted. The results of the group with PTV⩾100cc are reported in this paper.Materials and methodsThe continual reassessment method (CRM) was used to determine the dose level that patients should be assigned to and to estimate the maximum tolerated dose (MTD). Dose limiting toxicity (DLT) was Grade 3 or higher radiation pneumonitis (RP), and Grade 2 or higher RP was used as a surrogate DLT. The RD was equal to the MTD. The dose was prescribed at D95 of the PTV.ResultsThirteen patients were accrued. More patients should have been enrolled but we decided not to prolong the study period. No patients experienced Grade 3 RP. Two patients experienced Grade 2 RP at 50Gy in 4 fractions. The predicted MTD was 50.2Gy. The posterior probability of the Grade 2 RP frequency over 40% was 5.3% for the dose level of 50Gy. The RD was determined to be 50Gy.ConclusionsThe RD was determined to be 50Gy in 4 fractions in this population.



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Seasonal behavior of carbonyls and source characterization of formaldehyde (HCHO) in ambient air

Publication date: March 2017
Source:Atmospheric Environment, Volume 152
Author(s): K.H. Lui, Steven Sai Hang Ho, Peter K.K. Louie, C.S. Chan, S.C. Lee, Di Hu, P.W. Chan, Jeffrey Chi Wai Lee, K.F. Ho
Gas-phase formaldehyde (HCHO) is an intermediate and a sensitive indicator for volatile organic compounds (VOCs) oxidation, which drives tropospheric ozone production. Effective photochemical pollution control strategies demand a thorough understanding of photochemical oxidation precursors, making differentiation between sources of primary and secondary generated HCHO inevitable. Spatial and seasonal variations of airborne carbonyls based on two years of measurements (2012–2013), coupled with a correlation-based HCHO source apportionment analysis, were determined for three sampling locations in Hong Kong (denoted HT, TC, and YL). Formaldehyde and acetaldehyde were the two most abundant compounds of the total quantified carbonyls. Pearson's correlation analysis (r > 0.7) implies that formaldehyde and acetaldehyde possibly share similar sources. The total carbonyl concentration trends (HT < TC < YL) reflect location characteristics (urban > rural). A regression analysis further quantifies the relative primary HCHO source contributions at HT (∼13%), TC (∼21%), and YL (∼40%), showing more direct vehicular emissions in urban than rural areas. Relative secondary source contributions at YL (∼36%) and TC (∼31%) resemble each other, implying similar urban source contributions. Relative background source contributions at TC could be due to a closed structure microenvironment that favors the trapping of HCHO. Comparable seasonal differences are observed at all stations. The results of this study will aid in the development of a new regional ozone (O3) control policy, as ambient HCHO can enhance O3 production and also be produced from atmospheric VOCs oxidation (secondary HCHO).



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Laboratory mechanical parameters of composite resins and their relation to fractures and wear in clinical trials—A systematic review

Publication date: Available online 16 December 2016
Source:Dental Materials
Author(s): Siegward D. Heintze, Nicoleta Ilie, Reinhard Hickel, Alessandra Reis, Alessandro Loguercio, Valentin Rousson
ObjectiveTo evaluate a range of mechanical parameters of composite resins and compare the data to the frequency of fractures and wear in clinical studies.MethodsBased on a search of PubMed and SCOPUS, clinical studies on posterior composite restorations were investigated with regard to bias by two independent reviewers using Cochrane Collaboration's tool for assessing risk of bias in randomized trials. The target variables were chipping and/or fracture, loss of anatomical form (wear) and a combination of both (summary clinical index). These outcomes were modelled by time and material in a linear mixed effect model including random study and experiment effects. The laboratory data from one test institute were used: flexural strength, flexural modulus, compressive strength, and fracture toughness (all after 24-h storage in distilled water). For some materials flexural strength data after aging in water/saliva/ethanol were available. Besides calculating correlations between clinical and laboratory outcomes, we explored whether a model including a laboratory predictor dichotomized at a cut-off value better predicted a clinical outcome than a linear model.ResultsA total of 74 clinical experiments from 45 studies were included involving 31 materials for which laboratory data were also available. A weak positive correlation between fracture toughness and clinical fractures was found (Spearman rho=0.34, p=0.11) in addition to a moderate and statistically significant correlation between flexural strength and clinical wear (Spearman rho=0.46, p=0.01). When excluding those studies with "high" risk of bias (n=18), the correlations were generally weaker with no statistically significant correlation. For aging in ethanol, a very strong correlation was found between flexural strength decrease and clinical index, but this finding was based on only 7 materials (Spearman rho=0.96, p=0.0001). Prediction was not consistently improved with cutoff values.SignificanceCorrelations between clinical and laboratory outcomes were moderately positive with few significant results, fracture toughness being correlated with clinical fractures and flexural strength with clinical wear. Whether artificial aging enhances the prognostic value needs further investigations.



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Talimogene Laherparepvec (T-VEC) and Other Oncolytic Viruses for the Treatment of Melanoma

Abstract

Many mammalian viruses have properties that can be commandeered for the treatment of cancer. These characteristics include preferential infection and replication in tumor cells, the initiation of tumor cell lysis, and the induction of innate and adaptive anti-tumor immunity. Furthermore, viruses can be genetically engineered to reduce pathogenicity and increase immunogenicity resulting in minimally toxic therapeutic agents. Talimogene laherparepvec (T-VEC; Imlygic™), is a genetically modified herpes simplex virus, type 1, and is the first oncolytic virus therapy to be approved for the treatment of advanced melanoma by the US FDA. T-VEC is attenuated by the deletion of the herpes neurovirulence viral genes and enhanced for immunogenicity by the deletion of the viral ICP47 gene. Immunogenicity is further supported by expression of the human granulocyte–macrophage colony-stimulating factor (GM-CSF) gene, which helps promote the priming of T cell responses. T-VEC demonstrated significant improvement in durable response rate, objective response rate, and progression-free survival in a randomized phase III clinical trial for patients with advanced melanoma. This review will discuss the optimal selection of patients for such treatment and describe how therapy is optimally delivered. We will also discuss future directions for oncolytic virus immunotherapy, which will likely include combination T-VEC clinical trials, expansion of T-VEC to other types of non-melanoma skin cancers, and renewed efforts at oncolytic virus drug development with other viruses.

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Validation of a next generation sequencing panel for detection of hotspot cancer mutations in a clinical laboratory

Publication date: Available online 16 December 2016
Source:Pathology - Research and Practice
Author(s): Reza Shahsiah, Jenefer DeKoning, Saeed Samie, Seyed Ziaeddin Latifzadeh, Zahra Mehdizadeh Kashi
Recent advances in sequencing technologies have enabled us to scrutinize the versatile underlying mechanisms of cancer more precisely. However, adopting these new sophisticated technologies is challenging for clinical labs as it involves complex workflows, and requires validation for diagnostic purposes. The aim of this work is towards the analytical validation of a next generation sequencing (NGS) panel for cancer hotspot mutation analysis.Characterized formalin-fixed paraffin-embedded (FFPE) samples including biopsy specimens and cell-lines were examined by NGS methods utilizing the Ion Torrent™ Oncomine™ Focus DNA Assay and the PGM™ platform. Important parameters for somatic mutations including the threshold for differentiation of a positive and a negative result, coverage, sensitivity, specificity, and limit of detection (LoD) were analyzed.Variant calls with coverage of <100x were found to be inaccurate. The limit of detection for identifying hotspot mutations was determined to be 4.3%. The sensitivity and specificity of the method were 96.1% and 97.8% respectively. No statistically significant difference was found between different gene targets in terms of performance of hotspot frequency measurement for the subset tested. In every validation study, the number of samples, the manner of sample selection, and the number and type of variants play a role in the outcome. Therefore, these parameters should be assessed according to the clinical needs of each laboratory undertaking the validation.



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Temporal and Racial Differences Associated with Atopic Dermatitis Staphylococcusaureus and Encoded Virulence Factors.

Related Articles

Temporal and Racial Differences Associated with Atopic Dermatitis Staphylococcusaureus and Encoded Virulence Factors.

mSphere. 2016 Nov-Dec;1(6):

Authors: Merriman JA, Mueller EA, Cahill MP, Beck LA, Paller AS, Hanifin JM, Ong PY, Schneider L, Babineau DC, David G, Lockhart A, Artis K, Leung DY, Schlievert PM

Abstract
Atopic dermatitis (AD) is an inflammatory skin condition strongly associated with Staphylococcus aureus colonization and infection. S. aureus strains shift in populations in ~10-year intervals depending on virulence factors. Shifts in S. aureus virulence factors may in part explain the racial differences observed in the levels of prevalence and severity of AD. AD S. aureus isolates collected from 2011 to 2014 (103 isolates) and in 2008 (100 isolates) were examined for the prevalence of genes encoding superantigens (SAgs). The strains from 2011 to 2014 were obtained from AD patients as a part of the National Institute of Allergy and Infectious Diseases (NIAID) Atopic Dermatitis Research Network (ADRN). The prevalence of SAg genes was investigated temporally and racially. The enterotoxin gene cluster (EGC) was more prevalent in the 2011-2014 AD isolates than in the 2008 AD isolates. The prevalences of virulence factor genes were similar in European American (EA) and Mexican American (MA) patients but differed in 6 of 22 SAg genes between EA and African American (AA) or MA and AA isolates; notably, AA isolates lacked tstH, the gene encoding toxic shock syndrome toxin 1 (TSST-1). The presence of tstH and sel-p (enterotoxin-like P) was associated with decreased clinical severity and increased blood eosinophils, respectively. The EGC is becoming more prevalent, consistent with the previously observed 10 years of cycling of S. aureus strains. Race-specific S. aureus selection may account for differences in virulence factor profiles. The lack of TSST-1-positive (TSST-1(+)) AD S. aureus in AA is consistent with the lack of AAs acquiring TSST-1-associated menstrual toxic shock syndrome (TSS). IMPORTANCE Monitoring pathogen emergence provides insight into how pathogens adapt in the human population. Secreted virulence factors, important contributors to infections, may differ in a manner dependent on the strain and host. Temporal changes of Staphylococcus aureus toxigenic potential, for example, in encoding toxic shock syndrome toxin 1 (TSST-1), contributed to an epidemic of TSS with significant health impact. This study monitored changes in atopic dermatitis (AD) S. aureus isolates and demonstrated both temporal and host infection differences according to host race based on secreted superantigen potential. The current temporal increase in enterotoxin gene cluster superantigen prevalence and lack of the gene encoding TSST-1 in AAs predict differences in infection types and presentations.

PMID: 27981233 [PubMed - in process]

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Cancer-testis antigen expression in synovial sarcoma: NY-ESO-1, PRAME, MAGEA4 and MAGEA1

Publication date: Available online 16 December 2016
Source:Human Pathology
Author(s): Kunio Iura, Akira Maekawa, Kenichi Kohashi, Takeaki Ishii, Hirofumi Bekki, Hiroshi Otsuka, Yuichi Yamada, Hidetaka Yamamoto, Katsumi Harimaya, Yukihide Iwamoto, Yoshinao Oda
Synovial sarcoma (SS) is regarded as a relatively chemosensitive sarcoma, but the prognosis of advanced SSs remains poor. Here we identified highly expressed cancer-testis antigens that could be promising immunotherapy targets for SS, using a previously conducted cDNA microarray, and we assessed the clinicopathological or prognostic relationships of these antigens in SS. We compared the gene expression profiles of 11 synovial sarcomas with those of three normal adipose tissues. Among the up-regulated cancer-testis antigens, we analyzed PRAME, MAGEA1 and MAGEA4 and another cancer-testis antigen (NY-ESO-1) together, by immunohistochemistry and real-time polymerase chain reaction (PCR) in 108 synovial sarcomas. Immunohistochemically, NY-ESO-1, PRAME, MAGEA4 and MAGEA1 were positive in 66/108 (61%), 93/108 (86%), 89/108 (82%) and 16/108 (15%) SSs, respectively, and 104/108 (96%) of the SSs showed the immunohistochemical expression of ≥1 of NY-ESO-1, PRAME and MAGEA4. Moreover, the high expression of ≥1 of these three antigens was observed in 83% of the SSs. High expression of NY-ESO-1 and MAGEA4 was significantly correlated with the presence of necrosis and advanced clinical stage. The immunohistochemical expression of these cancer-testis antigens was not correlated with prognosis, but the coexpression of NY-ESO-1, PRAME and MAGEA4 was significantly associated with adverse prognosis. The real-time PCR results were closely related to the immunohistochemical results: NY-ESO-1 (P = .0019), PRAME (P = .039), MAGEA4 (P = .0149), MAGEA1 (P = .0766). These data support the potential utility of NY-ESO-1, PRAME and MAGEA4 as immunotherapy targets and ancillary prognostic parameters, suggesting the possible benefit of the combined use of these cancer-testis antigens as an SS immunotherapy target.



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Clinicopathological characteristics of invasive gastric Helicobacter pylori

Publication date: March 2017
Source:Human Pathology, Volume 61
Author(s): Jonathan Dudley, Tad Wieczorek, Martin Selig, Hoiwan Cheung, Jeanne Shen, Robert Odze, Vikram Deshpande, Lawrence Zukerberg
Helicobacter pylori organisms have been observed deep within the stomach mucosa with an "intracellular" appearance, although the clinicopathological characteristics of such cases remain poorly understood. We analyzed 18 cases of deep mucosal H pylori and associated clinical (sex, age, history of H pylori infection, or proton pump inhibitor [PPI] use, medications, smoking, alcohol use, comorbidities, treatment response) and pathological (presence of lymphoid aggregates, intestinal metaplasia, PPI effect, active and/or chronic inflammation, quantity of invasive versus surface H pylori) characteristics. Electron microscopy was performed on 6 cases with the highest burden of invasive H pylori. Within our sample, 3 of 16 had a history of H pylori infection, 10 of 15 were receiving PPIs at the time of biopsy, and 12 of 13 had a negative posttreatment follow-up. Histology revealed that invasive H pylori were more commonly associated with chronic inflammation, in both the antrum (15/15 chronic, 8/15 acute) and fundus (17/18 chronic, 8/18 acute). Electron microscopy showed organisms within intercellular and luminal spaces, but no intracellular organisms. Deep mucosal H pylori often have an intracellular appearance but are contained within intercellular and luminal spaces and are responsive to standard therapy.



http://ift.tt/2hFrhIX

B-cell post-transplant lymphoproliferative disorder isolated to the central nervous system is EBV-positive and lacks p53 and Myc expression by immunohistochemistry

Publication date: Available online 16 December 2016
Source:Human Pathology
Author(s): Andrew Sundin, Bartosz J. Grzywacz, Sophia Yohe, Michael A. Linden, Elizabeth L. Courville
In this retrospective study from one institution, we performed a clinicopathologic study of a cohort of patients with post-transplant lymphoproliferative disorder (PTLD) confined to the central nervous system. We also identified a comparison cohort of patients with de novo primary diffuse large B-cell lymphoma of the central nervous system. We performed a detailed morphologic review, evaluated Epstein–Barr Virus (EBV) by in-situ hybridization, and interpreted a panel of immunohistochemical stains in a subset of cases including Hans classification markers (CD10, BCL6, MUM1), p53, CD30, myc, and BCL2. All 17 of the post-transplant and none of the 11 de novo cases were EBV-positive (P<.005). Morphologic patterns identified in the PTLD cases were monomorphic diffuse large B-cell lymphoma pattern (10 patients) and "T-cell rich" pattern (7 patients). The monomorphic post-transplant cases were more likely to be myc negative (P=.015) and CD30 positive (P<.005) than the de novo cases, and showed a similarly low rate of p53 positivity by immunohistochemistry. No prognostic factors for overall survival were identified. Central nervous system PTLD is EBV positive, typically lacks p53 and myc expression by immunohistochemistry, and can present with numerous background T-lymphocytes.



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Does the gross prosector impact pT3 subclassification or lymph node counts in bladder cancer?

Publication date: Available online 16 December 2016
Source:Human Pathology
Author(s): Eric M. Tretter, Joshua J. Ebel, Kamal S. Pohar, Debra L. Zynger
Gross prosector analysis of perivesicular adipose tumor invasion is the sole differentiator between pT3 substages, and gross evaluation is critical to lymph node identification. Gross prosector impact on pT3 subclassification and lymph node counts in cystectomy specimens resected for bladder cancer has not been previously analyzed. Both pT3 subclassification and total number of lymph nodes removed at radical cystectomy for bladder cancer are considered important components of the pathology report; however, both have controversial prognostic significance. Our objective was to assess the impact of the gross prosector on pT3 substaging and lymph node count. Pathology reports from 560 cystectomy cases performed for primary bladder cancer were reviewed. Educational interventions were conducted regarding cystectomy gross prosector documentation. Gross prosectors did not document the presence or absence of macroscopic perivesicular adipose invasion in 17% of cases. There was a decrease in the frequency of cases lacking documentation after educational intervention (33% to 5%, P<.01). The majority of pT3 cases lacking documentation were classified as pT3a (75%). The percent of pT3 cases classified as pT3a decreased after intervention (68% to 35%, P<.01). Over-counting of lymph nodes by gross prosectors was more common than under-counting (22% vs. 2%). Pathology residents and prosectors with lower caseloads had more uncounted lymph packets (P<.01). In conclusion, we demonstrated an impact of the gross prosector on pT3 substaging and lymph node counts within bladder cancer resection specimens. This novel variable may confound the relationship of these parameters upon oncologic outcomes and should be incorporated into quality assurance programs.



http://ift.tt/2hFAEbt

Expression of cathepsins V and S in thymic epithelial tumors

Publication date: February 2017
Source:Human Pathology, Volume 60
Author(s): Shizuka Kiuchi, Utano Tomaru, Akihiro Ishizu, Makoto Imagawa, Takayuki Kiuchi, Sari Iwasaki, Akira Suzuki, Noriyuki Otsuka, Takahiro Deguchi, Tomohiro Shimizu, Katsuji Marukawa, Yoshihiro Matsuno, Masanori Kasahara
Cathepsins are a group of proteolytic enzymes of the endosomal/lysosomal pathway involved in the thymic development of T cells restricted by major histocompatibility complex class II molecules. In the normal thymus, cathepsin V (CTV) and cathepsin S (CTS) are expressed in cortical and medullary epithelial cells, respectively. To investigate whether cathepsins could serve as a diagnostic marker, we performed immunohistochemical analysis for CTV and CTS in 77 cases of thymic epithelial tumors. Almost all cases (59/60) of thymoma expressed CTV, whereas 28 of 60 cases of thymoma expressed CTS. Notably, CTS was expressed in most cases of type A and type AB thymomas, but not in type B thymoma. The expression of cathepsins in type AB thymoma showed a clear correlation with histologic features; CTV was found predominantly in the type B component, and CTS was frequently expressed in the type A component. In thymic carcinoma, CTV was expressed in less than half cases (7/17), and the ratio of CTS-positive cases was equivalent to that of thymoma (8/17). Cases of CTV-negative thymic carcinoma tended to have a higher incidence of recurrence than did CTV-positive cases. Although further studies with a larger number of cases are required to confirm the utility of cathepsin immunostaining, CTV and CTS appear to serve as auxiliary diagnostic and/or prognostic markers in thymic epithelial tumors.



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Clinicopathological features of a kindred with SCG5-GREM1–associated hereditary mixed polyposis syndrome

Publication date: February 2017
Source:Human Pathology, Volume 60
Author(s): Thomas Plesec, Kathryn Brown, Charles Allen, Carol A. Burke, James Church, Matthew Kalady, Lisa LaGuardia, Margaret O'Malley, Brandie Heald
Since first characterized in 1997, patients with hereditary mixed polyposis syndrome (HMPS) have been difficult to identify because of lack of well-established diagnostic criteria. Recently, HMPS was found to be caused by a duplication on chromosome 15 spanning the 3′ end of the SCG5 gene and a region upstream of the GREM1 locus. Clinical testing for the duplication is available; however, the clinical characteristics of hereditary mixed polyposis to support testing are ill defined. The clinicopathological findings of 10 HMPS patients with confirmed germline SCG5-GREM1 duplication were reviewed. Mean age at presentation was 33.3 years. Fifty-one colonoscopies yielded 207 polyp specimens, all of which were reexamined. Adenomas (n = 80) and a fairly unique polyp composed of a mixture of hyperplastic polyp and inflammatory polyp–type changes (n = 74) were the most common findings; however, other polyps, including hyperplastic (n = 28), mixed inflammatory polyp/adenoma (n = 8), inflammatory polyp (n = 7), prolapse-type polyp (n = 6), and lymphoid aggregates (n = 4), were encountered. None of the patients developed colorectal malignancy during surveillance, demonstrated extracolonic manifestations, or underwent colectomy on follow-up (mean, 26.2 years). SCG5-GREM1 duplication–associated polyposis is characterized by a few polyps per endoscopy with a mixture of phenotypes, most commonly adenoma and nondysplastic mixed hyperplastic/inflammatory polyps. Nine of 10 patients had at least 1 mixed hyperplastic-inflammatory polyp, which is the characteristic lesion of SCG5-GREM1 duplication–associated HMPS.



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Loss of BRCA1-associated Protein 1 (BAP1) expression is rare in non–small cell lung cancer

Publication date: February 2017
Source:Human Pathology, Volume 60
Author(s): Daniel Owen, Brandon S. Sheffield, Diana Ionescu, Andrew Churg
BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene involved in regulation of the cell cycle, cellular differentiation, repair of DNA damage, and apoptosis. In the distinction of malignant mesothelioma from benign mesothelial proliferations, immunohistochemical loss of BAP1, the protein expressed by the BAP1 gene, has proven highly specific for malignant mesothelioma. However, few studies have investigated the rate of BAP1 loss in tumors that commonly metastasize to the pleura. Our objective is to determine the rate of BAP1 loss in non–small cell lung cancer (NSCLC). Immunohistochemistry for BAP1 was performed using tissue microarrays containing 133 confirmed cases of NSCLC (80 of lung adenocarcinoma and 53 of squamous cell carcinoma). Cases were interpreted as showing BAP1 loss if nuclear staining was completely absent in all tumor cells and present in stromal and inflammatory cells that served as internal controls. Cases showing no BAP1 staining in the internal controls were excluded. After exclusion of 32 cases for technical reasons, only 1 case of pulmonary adenocarcinoma of 101 cases of NSCLC (69 adenocarcinoma and 32 squamous cell carcinoma; 1.0% of cases) showed BAP1 loss. We conclude that loss of BAP1 expression is a rare event in NSCLC. Therefore, BAP1 is a potentially useful addition to the immunohistochemical markers used to distinguish mesothelioma from pleural metastasis of NSCLC.



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High expression of heat shock protein 10 (HSP10) correlates negatively with estrogen/progesterone receptor status and predicts poor prognosis in invasive ductal breast carcinoma

Publication date: Available online 16 December 2016
Source:Human Pathology
Author(s): Shuzhou Chu, Qiuyuan Wen, Zhenzhen Qing, Jiadi Luo, Weiyuan Wang, Lingjiao Chen, Juan Feng, Lina Xu, Hongjing Zang, Songqing Fan
Heat shock proteins (HSPs) usually are associated with stress response and tolerance. HSP10 is a co-chaperone for HSP60, which is involved in the mitochondrial protein-folding machinery. To the best of our knowledge, the expression of HSP10 protein in invasive ductal breast carcinoma (IDBC) has never been reported. In the present study, HSP10 expression in 242 cases of IDBC and 46 cases of noncancerous breast tissues was detected by immunohistochemistry staining. High expression was significantly more common in IDBC than in noncancerous breast tissues (P<.001). Also, high expression was significantly more common in poorly differentiated than in well- and moderately differentiated IDBC (P=.023). Furthermore, high expression correlated negatively with estrogen receptor (ER) and progesterone receptor (PR) expression (P=.031 and P=.042, respectively). The most interesting result of the study was that high expression of HSP10 was significantly associated with shorter overall survival by both univariate and multivariate analysis (P=.013 and P=.036, respectively). In conclusion, we report for the first time that high expression of HSP10 protein is negatively associated with ER/PR status and might be a novel independent biomarker for poor prognosis in IDBC.



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Estrogen receptor α (ERα) status evaluation using RNAscope in situ hybridization: A reliable and complementary method for IHC in breast cancer tissues

Publication date: Available online 16 December 2016
Source:Human Pathology
Author(s): Xiuwei Yu, Shipeng Guo, Weihong Song, Tingxiu Xiang, Chengcheng Yang, Kai Tao, Lin Zhou, Yijia Cao, Shengchun Liu
Estrogen receptor α (ERα) plays a significant role in the development of breast cancer and has been used clinically as an endocrine therapeutic target. Currently, clinical laboratories use immunohistochemistry (IHC) to determine the ERα status of patients in order to distinguish those who would benefit from endocrine therapy. This method is highly subjective, requires a large amount of tumor tissue, and may generate false-negative results. To improve the detection of ERα, we used a new RNA in situ hybridization technique (RNAscope) and compared its use with IHC in 72 breast cancer tissues (47 ERα positive and 25 ERα negative). Then we evaluated ERα mRNA by RT-qPCR with RNAscope. An unobvious difference was found between RT-qPCR and IHC but a positive correlation was found between RNAscope and IHC. In addition, breast cancer is a highly heterogeneous cancer, and RNAscope could easily reveal the heterogeneity in breast cancer. Moreover, we found that some ERα IHC-based negative and RNAscope-based positive test results were detected as positive after testing with IHC again. Our findings suggest that RNAscope may be a complementary method for improving the detection of patient ERα status and has potential clinical utility.



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The Effect of Limited (Tertiary) Gleason Pattern 5 on the New Prostate Cancer Grade Groups

Publication date: Available online 16 December 2016
Source:Human Pathology
Author(s): Alexander S Baras, Joel B. Nelson, Misop Han, Anil V. Parwani, Jonathan I. Epstein
The risk of recurrence for prostatic adenocarcinoma following prostatectomy, as detected by prostate specific antigen (PSA) or other modalities, is based primarily on Gleason score along with pathologic tumor stage and surgical margin status. Recent large multi-institutional data spanning the last decade have supported modification of risk of recurrence stratification based on Grade Groups: Grade Group 1 (3+3=6), Grade Group 2 (3+4=7), Grade Group 3 (4+3=7), Grade Group 4 (4+4=8), and Grade Group 5 (Gleason scores 9 and 10). Using currently accepted grading definitions of grade patterns and grading rules, this study examines how the introduction of a limited, less than 5%, Gleason pattern 5 component at prostatectomy affects prognosis and fits into the Grade Group schema and reporting. The aggregate data from two independent major academic medical centers comprised of 7606 patient records were analyzed with respect to biochemical recurrence free survival. The presence of a limited (tertiary) Gleason pattern 5 component in the context of Gleason score 3+4=7 (Grade Group 2) and 4+3=7 (Grade Group 3) imparts an intermediate prognosis relative to the next highest Grade Group. As such, we suggest that an additional comment and designation to the Grade Groups be provided reflecting the increased risk of recurrence in such cases (such as Grade Group 2+ or 3+). In contrast, the presence of limited (less than 5%) Gleason pattern 5 in the context of Gleason score 4+4=8 imparts a poor prognosis equivalent to Grade Group 5 and therefore should be reported as Grade Group 5.



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“Sarcomatoid” carcinomas of the lung: a clinicopathologic study of 86 cases with a new perspective on tumor classification

Publication date: Available online 16 December 2016
Source:Human Pathology
Author(s): Annikka Weissferdt, Neda Kalhor, Arlene M Correa, Cesar A Moran
Pulmonary sarcomatoid carcinoma includes a heterogenous group of tumors which is difficult to diagnose and treat. We report the clinicopathological features of 86 such tumors, including 74 pleomorphic and 12 spindle cell carcinomas, and propose a novel approach to the classification of these neoplasms in an attempt to better guide patient management. The patients were 47 males and 39 females aged 36 to 87 years (mean, 63 years) who primarily presented with shortness of breath, cough and chest pain. Eighty-six percent of patients had a smoking history. Histologically, the pleomorphic carcinomas consisted of spindle and/or giant cells with varying proportions of conventional non-small cell carcinoma in the form of adenocarcinoma (n=29), squamous cell carcinoma (n=10) or large cell carcinoma (n=18); seventeen cases contained a mix of spindle and giant cells only. The 12 spindle cell carcinomas consisted of spindle cells only. Based on the combined histopathological and immunohistochemical features of these tumors we were able to reanalyze the spectrum of these lesions and reclassify them accordingly. Statistical analysis revealed an overall survival at 3, 5 and 10 years of 42.9%, 34.6% and 23.5%, respectively, and a median survival of 15 months. Log rank test showed that in multivariate analysis only pathological T stage was a factor associated with prognosis. The current classification of pulmonary sarcomatoid carcinomas precludes optimal triaging of these tumors with the risk of denying patients access to novel treatment. Our proposal for a reclassification of these tumors would more accurately guide patient management and facilitate targeted therapies.



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Inhibition of endoplasmic reticulum stress by neuregulin-1 protects against myocardial ischemia/reperfusion injury

Publication date: Available online 16 December 2016
Source:Peptides
Author(s): Shan-Juan Fang, Peng-Yang Li, Chun-Mei Wang, Yi Xin, Wei-Wei Lu, Xiao-Xia Zhang, Song Zuo, Chang-Sheng Ma, Chao-Shu Tang, Shao-Ping Nie, Yong-Fen Qi
Neuregulin-1 (NRG-1), an endogenously produced polypeptide, is the ligand of cardiomyocyte ErbB receptors, with cardiovascular protective effects. In the present study, we explored whether the cardioprotective effect of NRG-1 against I/R injury is mediated by inhibiting myocardial endoplasmic reticulum (ER) stress. In vitro, NRG-1 directly inhibited the upregulation of ER stress markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12 induced by the ER stress inducers tunicamycin or dithiothreitol in both neonatal and adult ventricular myocytes. Attenuating ErbB signals by an ErbB inhibitor AG1478 or ErbB4 knockdown and preincubation with phosphoinositide 3-kinase inhibitors all reversed the effect of NRG-1 inhibiting ER stress in cultured neonatal rat cardiomyocytes. Concurrently, cardiomyocyte ER stress and apoptosis induced by hypoxia-reoxygenation were decreased by NRG-1 treatment in vitro. Furthermore, in an in vivo rat model of myocardium ischemia/reperfusion (I/R), intravenous NRG-1 administration significantly decreased ER stress and myocardial infarct size induced by I/R. NRG-1 could protect the heart against I/R injury by inhibiting myocardial ER stress, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway.



http://ift.tt/2hubUCF

Pharmacokinetics of lenalidomide during high cut-off dialysis in a patient with multiple myeloma and renal failure

Abstract

Introduction

High cut-off dialysis, increasingly used in multiple myeloma patients, is susceptible to influence anticancer drug elimination. We report about lenalidomide disposition in a patient on high cut-off dialysis for renal failure secondary to myeloma cast nephropathy.

Methods

The patient received a higher dosage of lenalidomide (5 mg b.i.d.), owing to concerns about a potential decrease in lenalidomide exposure during dialysis sessions. A set of blood samples was taken in order to develop a pharmacokinetic model accounting for lenalidomide concentrations in this setting.

Results

According to our model, the area under the curve was 3273 µg h/L, i.e., 60% higher than expected under usual dosage (25 mg q.d.) with normal renal function. Despite this, the patient did not develop major hematological toxicity.

Conclusions

Lenalidomide doses of 5 mg b.i.d. led to high exposure in a patient with renal failure undergoing high cut-off dialysis. Yet, the dosage of 5 mg q.d. recommended in conventional dialysis would probably be adequate in such patients.

http://ift.tt/2hS35nj

Salivary oxidative stress biomarkers in chronic periodontitis and acute coronary syndrome

Abstract

Objectives

The study aimed at assessing oxidative stress (OS) biomarker levels in the saliva of patients with chronic periodontitis (CP) and acute coronary syndrome (ACS) and establishing their correlation to periodontal parameters and markers for cardiovascular events.

Materials and methods

The present study enrolled 24 patients with ACS and CP (the ACSCP group), 24 patients with ACS only (the ACS group), 24 patients with CP only (the CP group), and 24 healthy controls. Plaque index (PI), gingival index, bleeding on probing, probing pocket depth (PPD), and clinical attachment loss were recorded. Markers for cardiovascular events included serum high sensitivity C-reactive protein (hsCRP) and plasma fibrinogen. 8-Hydroxydeoxyguanosine (8-OHdG), protein carbonyl (PC), malondialdehyde (MDA), and total antioxidant capacity (TAOC) were used as OS biomarkers.

Results

Salivary 8-OHdG, MDA, and PC levels were significantly higher in the ACSCP, ACS, and CP groups than in healthy controls (p < 0.05). There were significant correlations between salivary PC levels and PI or PPD (p < 0.05) as well as between salivary 8-OHdG levels and all periodontal parameters (p < 0.05). TAOC levels in saliva were correlated to both serum hsCRP and plasma fibrinogen (p < 0.05). Salivary MDA levels were correlated to all periodontal parameters and biomarkers for cardiovascular events (p < 0.05).

Conclusions

Salivary OS biomarker levels were higher in diseased groups compared to control. They also correlated to clinical periodontal parameters and markers for cardiovascular events in ACS patients, with or without CP.

Clinical relevance

Salivary OS biomarkers could potentially serve as diagnostic tools for cardiovascular and/or periodontal diseases.

http://ift.tt/2gVGtRf

A TMS/high-density-EEG paradigm for genetic generalized epilepsy: a new diagnostic and prognostic tool?

Publication date: Available online 16 December 2016
Source:Clinical Neurophysiology
Author(s): Fabio Ferrarelli




http://ift.tt/2hu4RtF

A New Technology, a New Application, and a Long Road Ahead

Publication date: Available online 16 December 2016
Source:Clinical Neurophysiology
Author(s): Seward B. Rutkove




http://ift.tt/2hFnoRP

Pseudocarcinomatous Epithelial Hyperplasia Induced by Imiquimod: A Mimic of Cutaneous Squamous Cell Carcinoma.

No abstract available

http://ift.tt/2hbwjtm

Complications With New Oral Anticoagulants Dabigatran and Rivaroxaban in Cutaneous Surgery.

No abstract available

http://ift.tt/2gVj2sR

Implantable Body Jewelry and Methods for Their Removal.

No abstract available

http://ift.tt/2hbkWS6

Reconstruction of a Lateral Upper Lip Defect.

No abstract available

http://ift.tt/2hZjhip

Neuronal chloride and excitability — the big impact of small changes

Publication date: April 2017
Source:Current Opinion in Neurobiology, Volume 43
Author(s): Joseph V Raimondo, Blake A Richards, Melanie A Woodin
Synaptic inhibition is a critical regulator of neuronal excitability, and in the mature brain the majority of synaptic inhibition is mediated by Cl⁻-permeable GABAA receptors. Unlike other physiologically relevant ions, Cl⁻ is dynamically regulated, and alterations in the Cl⁻ gradient can have significant impact on neuronal excitability. Due to changes in the neuronal Cl⁻ concentration, GABAergic transmission can bidirectionally regulate the induction of excitatory synaptic plasticity and gate the closing of the critical period for monocular deprivation in visual cortex. GABAergic circuitry can also provide a powerful restraining mechanism for the spread of excitation, however Cl⁻ extrusion mechanisms can become overwhelmed and GABA can paradoxically contribute to pathological excitation such as the propagation of seizure activity.



http://ift.tt/2hRIAH9

Reconstruction after Excision of Hidradenitis Suppurativa: Are Skin Grafts Better than Flaps?

Summary: After surgical excision of hidradenitis suppurativa, reconstruction with a skin graft or a flap is performed when primary closure is not possible. However, the recurrence rate is reportedly high even after wide surgical excision. It is still unclear which reconstruction method provides the lowest recurrence rate. In this report, we present a case of intractable hidradenitis suppurativa in the bilateral perineal region. After wide excision and repair with bilateral groin flaps, a unilateral groin flap was replaced with a split-thickness skin graft because of flap necrosis. Although the skin graft repair region has been recurrence free for 4 years postoperatively, other regions with flap repair showed recurrence 1 year postoperatively, leading to reexcision and repair with a split-thickness skin graft. The current case provides an opportunity to reconsider the optimal surgical strategy for hidradenitis suppurativa. Taking into consideration the fact that hair follicles and sweat glands are involved in the etiology of hidradenitis suppurativa, split-thickness skin grafting, which lack cutaneous appendages, may be superior to flap repair or primary closure in terms of recurrence.

http://ift.tt/2gYbqV1

Systemic Allergic Reaction to Red Tattoo Ink Requiring Excision

No abstract available

http://ift.tt/2gXZ8MD

Kisspeptin in the hypothalamus of two rat models of polycystic ovary syndrome

Endocrinology, Early Release.


http://ift.tt/2hJ395h

Roles of RFRP-3 in the daily and seasonal regulation of reproductive activity in female Syrian hamsters

Endocrinology, Early Release.


http://ift.tt/2hEWifW

Minireview: Therapeutic Implications of Epigenetic Signaling in Breast Cancer

Endocrinology, Early Release.


http://ift.tt/2hISjwn

Variations in the bacterial community compositions at different sites in the tomb of Emperor Yang of the Sui Dynasty

Publication date: Available online 16 December 2016
Source:Microbiological Research
Author(s): Zhi Huang, Fei Zhao, Yonghui Li, Jianwei Zhang, Youzhi Feng
To fully understand the bacterial processes in tomb environments, it is necessary to investigate the details of the bacterial communities present under such oligotrophic conditions. Here, high-throughput sequencing based on partial 16S rRNA gene sequences was used to fully evaluate the bacterial communities at different sites in the tomb of Emperor Yang of the Sui Dynasty. We also aimed to identify the soil factors that were significant related to bacterial diversity and community composition. The results showed the presence of a broad taxonomic diversity that included nine major phyla. Actinobacteria, Firmicutes and Proteobacteria dominated the bacterial profiles in all tomb soil samples. However, significant differences between deposited soils (DS) and covering soils (CSA, CSB and CSC) were revealed by chemistry-based principal component analysis (PCA), the number of OTUs, and the Chao 1 and Shannon indexes. At the family level, hierarchically clustered heatmap and LefSe analyses showed differences in the bacterial community compositions at different sampling sites. Notably, CSA contained significant populations of Nocardioidaceae, Pseudonocardiaceae and Streptomycetaceae, which are often reported to be associated with biodeterioration in cave environments. Further, the most abundant group (>10%) in all soil samples was Streptococcaceae, whose abundance decreased from 34.66% to 13.43% with increasing soil depth. The results of redundancy analysis (RDA) and the Monte Carlo permutation test indicated that soil pH and Cu and Mn levels were significantly related to the bacterial communities in this tomb. This research offers new insight into bacterial communities in cave environments and also provides important information for the protection of this historically important tomb.



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Dermatofibrosarcoma Protuberans-Like Tumor With COL1A1 Copy Number Gain in the Absence of t(17;22).

A 57-year-old woman presented with a 3-year history of a progressive firm plaque on the right cheek. Skin biopsies revealed a bland, storiform, spindle-cell proliferation involving the deep dermis and subcutaneous fat. By immunohistochemistry, the tumor cells were diffusely positive for CD34 and caldesmon with multifocal reactivity for epithelial membrane antigen and focal, weak staining for smooth muscle actin. Retinoblastoma protein expression was not detectable in tumor cells by immunohistochemistry. An interphase fluorescence in situ hybridization analysis for platelet-derived growth factor B (PDGFB) gene rearrangement was negative. A single-nucleotide polymorphism array study detected 1) a gain of chromosome segment 17q21.33-q25.3 which overlapped the entire COL1A1 gene with a breakpoint at 17q21.33, approximately 250 Kb centromeric to the 3' end of COL1A1 gene, 2) several segmental gains on chromosome 11, and 3) an RB1 gene locus with normal copy number and allele frequency. Although the current case resembles dermatofibrosarcoma protuberans, it is unique in that it demonstrates a copy number gain of chromosome 17q in the absence of fusion of COL1A1 and PDGFB genes and an unusual immunohistochemical staining profile. The morphologic and molecular findings suggest a novel molecular variant of dermatofibrosarcoma protuberans not detectable with standard fluorescence in situ hybridization for PDGFB rearrangement. This variant appears to respond to imatinib after 9 months of follow-up. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2hbfCOr

Balloon Cell Melanoma and Its Metastasis, a Rare Entity.

Balloon cell melanoma (BCM) with metastasis is a rarely occurring neoplasia. The incidence of BCM is low, and hence, the frequency of these lesions presenting metastasis is even less frequent. This review exposes the balloon cell metastasis cases that have been published and a new case. These cases share the histopathological features but the location of initial melanoma, age and sex vary. It is relevant for the dermatologist and dermatopathologist to keep in mind the diagnosis of BCM and consider the possibility of it metastasizing as nonpigmented skin lesions. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2gVg6wi