T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Ilaria Marigo, Serena Zilio, Giacomo Desantis, Bernhard Mlecnik, Andrielly H.R. Agnellini, Stefano Ugel, Maria Stella Sasso, Joseph E. Qualls, Franz Kratochvill, Paola Zanovello, Barbara Molon, Carola H. Ries, Valeria Runza, Sabine Hoves, Amélie M. Bilocq, Gabriela Bindea, Emilia M.C. Mazza, Silvio Bicciato, Jérôme Galon, Peter J. Murray, Vincenzo Bronte
Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8⁺ cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1⁺ myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.

Graphical abstract

Teaser

Marigo et al. show that nitric oxide produced by Tip-DCs, a subset of tumor-infiltrating myeloid cells, is important for tumor control by adoptive cell therapy (ACT). Tip-DCs require the CD40-CD40L pathway but not CSF-1R; CSF-1R blockade reduces immunosuppressive macrophages and improves tumor control by ACT.


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Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Arabella Young, Shin Foong Ngiow, Deborah S. Barkauskas, Erin Sult, Carl Hay, Stephen J. Blake, Qihui Huang, Jing Liu, Kazuyoshi Takeda, Michele W.L. Teng, Kris Sachsenmeier, Mark J. Smyth
Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors. In a two-way mixed leukocyte reaction using a fully human anti-CD73, we demonstrated that Fc receptor binding augmented the production of proinflammatory cytokines.

Graphical abstract

Teaser

Young et al. show that blockade of CD73 and A2AR, two components of the adenosinergic pathway, has more potent anti-tumor activity than blockade of either, partly due to increased CD73 expression in the absence of A2AR. Moreover, anti-CD73 antibodies require the FcR binding domain for optimal anti-tumor activity.


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Tipping the Balancing ACT

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Shari Pilon-Thomas, Brian Ruffell
Adoptive cell transfer therapy has emerged as a powerful treatment for metastatic melanoma, but efficacy is limited by an inhospitable tumor microenvironment. In this issue of Cancer Cell, Marigo et al. demonstrate that therapy requires induced expression of nitric oxide synthase 2 in monocyte-derived dendritic cells.

Teaser

Adoptive cell transfer therapy has emerged as a powerful treatment for metastatic melanoma, but efficacy is limited by an inhospitable tumor microenvironment. In this issue of Cancer Cell, Marigo et al. demonstrate that therapy requires induced expression of nitric oxide synthase 2 in monocyte-derived dendritic cells.


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Physiologic Expression of Sf3b1K700E Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Esther A. Obeng, Ryan J. Chappell, Michael Seiler, Michelle C. Chen, Dean R. Campagna, Paul J. Schmidt, Rebekka K. Schneider, Allegra M. Lord, Lili Wang, Rutendo G. Gambe, Marie E. McConkey, Abdullah M. Ali, Azra Raza, Lihua Yu, Silvia Buonamici, Peter G. Smith, Ann Mullally, Catherine J. Wu, Mark D. Fleming, Benjamin L. Ebert
More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1^K700E. Sf3b1^K700E mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1^K700E myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3′ splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1^K700E to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1^K700E-expressing cells. Thus, SF3B1^K700E expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.

Graphical abstract

Teaser

Obeng et al. generate knockin mice with Sf3b1^K700E, a prevalent mutation in myelodysplastic syndrome (MDS). Sf3b1^+/K700E mice display characteristics of MDS. Mouse and human MDS cells expressing SF3B1^K700E exhibit aberrant 3′ splice-site selection, and SF3B1^K700E sensitizes cells to a spliceosome modulator.


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Lactate Dehydrogenase B Controls Lysosome Activity and Autophagy in Cancer

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Lucie Brisson, Piotr Bański, Martina Sboarina, Coralie Dethier, Pierre Danhier, Marie-Joséphine Fontenille, Vincent F. Van Hée, Thibaut Vazeille, Morgane Tardy, Jorge Falces, Caroline Bouzin, Paolo E. Porporato, Raphaël Frédérick, Carine Michiels, Tamara Copetti, Pierre Sonveaux
Metabolic adaptability is essential for tumor progression and includes cooperation between cancer cells with different metabolic phenotypes. Optimal glucose supply to glycolytic cancer cells occurs when oxidative cancer cells use lactate preferentially to glucose. However, using lactate instead of glucose mimics glucose deprivation, and glucose starvation induces autophagy. We report that lactate sustains autophagy in cancer. In cancer cells preferentially to normal cells, lactate dehydrogenase B (LDHB), catalyzing the conversion of lactate and NAD⁺ to pyruvate, NADH and H⁺, controls lysosomal acidification, vesicle maturation, and intracellular proteolysis. LDHB activity is necessary for basal autophagy and cancer cell proliferation not only in oxidative cancer cells but also in glycolytic cancer cells.

Graphical abstract

Teaser

Brisson et al. show that lactate dehydrogenase B (LDHB) is critical for lysosomal activity and autophagy in cancer cells. Silencing LDHB selectively inhibits the proliferation of both oxidative and glycolytic cancer cells over normal cells, suggesting inhibition of LDHB as a promising anticancer approach.


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Feedback Activation of Leukemia Inhibitory Factor Receptor Limits Response to Histone Deacetylase Inhibitors in Breast Cancer

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Hanlin Zeng, Jia Qu, Nan Jin, Jun Xu, Chenchu Lin, Yi Chen, Xinying Yang, Xiang He, Shuai Tang, Xiaojing Lan, Xiaotong Yang, Ziqi Chen, Min Huang, Jian Ding, Meiyu Geng
Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling. Importantly, JAK1 or BRD4 inhibition sensitizes breast cancer to HDAC inhibitors, implicating combination inhibition of HDAC with JAK1 or BRD4 as potential therapies for breast cancer.

Graphical abstract

Teaser

Zeng et al. show that HDAC inhibitors (HDACi) promote BRD4-mediated activation of LIFR, which in turn activates JAK1-STAT3 signaling and restrains the efficacy of HDACi in breast cancer. Concurrent inhibition of BRD4 or JAK sensitizes breast cancer, in particular the triple-negative subset, to HDACi.


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Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Zhong-Qiang Guo, Tong Zheng, Baoen Chen, Cheng Luo, Sisheng Ouyang, Shouzhe Gong, Jiafei Li, Liu-Liang Mao, Fulin Lian, Yong Yang, Yue Huang, Li Li, Jing Lu, Bidong Zhang, Luming Zhou, Hong Ding, Zhiwei Gao, Liqun Zhou, Guoqiang Li, Ran Zhou, Ke Chen, Jingqiu Liu, Yi Wen, Likun Gong, Yuwen Ke, Shang-Dong Yang, Xiao-Bo Qiu, Naixia Zhang, Jin Ren, Dafang Zhong, Cai-Guang Yang, Jiang Liu, Hualiang Jiang
In the cytoplasm of virtually all clear-cell renal cell carcinoma (ccRCC), speckle-type POZ protein (SPOP) is overexpressed and misallocated, which may induce proliferation and promote kidney tumorigenesis. In normal cells, however, SPOP is located in the nucleus and induces apoptosis. Here we show that a structure-based design and subsequent hit optimization yield small molecules that can inhibit the SPOP-substrate protein interaction and can suppress oncogenic SPOP-signaling pathways. These inhibitors kill human ccRCC cells that are dependent on oncogenic cytoplasmic SPOP. Notably, these inhibitors minimally affect the viability of other cells in which SPOP is not accumulated in the cytoplasm. Our findings validate the SPOP-substrate protein interaction as an attractive target specific to ccRCC that may yield novel drug discovery efforts.

Graphical abstract

Teaser

Using a structure-based design followed by hit optimization, Guo et al. report small-molecule inhibitors that disrupt oncogenic SPOP-mediated pathways by blocking SPOP-substrate interactions and suppress human clear-cell renal cell carcinoma in vitro and in vivo, suggesting the potential of SPOP-targeted therapy.


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Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Najoua Lalaoui, Kay Hänggi, Gabriela Brumatti, Diep Chau, Nhu-Y.N. Nguyen, Lazaros Vasilikos, Lisanne M. Spilgies, Denise A. Heckmann, Chunyan Ma, Margherita Ghisi, Jessica M. Salmon, Geoffrey M. Matthews, Elisha de Valle, Donia M. Moujalled, Manoj B. Menon, Sukhdeep Kaur Spall, Stefan P. Glaser, Jennifer Richmond, Richard B. Lock, Stephen M. Condon, Raffi Gugasyan, Matthias Gaestel, Mark Guthridge, Ricky W. Johnstone, Lenka Munoz, Andrew Wei, Paul G. Ekert, David L. Vaux, W. Wei-Lynn Wong, John Silke




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Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Haidong Tang, Yang Wang, Lukasz K. Chlewicki, Yuan Zhang, Jingya Guo, Wei Liang, Jieyi Wang, Xiaoxiao Wang, Yang-Xin Fu




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IDH1, Histone Methylation, and So Forth

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Virginie Penard-Lacronique, Olivier A. Bernard




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An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Zoi Karoulia, Yang Wu, Tamer A. Ahmed, Qisheng Xin, Julien Bollard, Clemens Krepler, Xuewei Wu, Chao Zhang, Gideon Bollag, Meenhard Herlyn, James A. Fagin, Amaia Lujambio, Evripidis Gavathiotis, Poulikos I. Poulikakos




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Rapid Response to High-Dose, Pulsatile Erlotinib in Afatinib-Refractory Leptomeningeal Carcinomatosis from Adenocarcinoma of the Lung: A Case Report

Leptomeningeal carcinomatosis occurred in an old female patient who was on a standard dose of afatinib for the treatment of her non-small cell lung cancer harboring an epidermal growth factor receptor gene mutation sensitive to tyrosine kinase inhibitors when extracranial lesions were still under control. Shifting to high-dose, pulsatile erlotinib dramatically saved her from the devastating condition in a very short period of time. Inadequate afatinib concentration in cerebrospinal fluid is reasonably suspected, and there is a call for clinical trials testing high-dose afatinib in leptomeningeal carcinomatosis.
Case Rep Oncol 2016;9:537–542

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Bilateral Choroidal Metastases from Lung Adenocarcinoma: A Case Report

The most common malignancy of the eye is metastatic tumors, with choroidal metastases being the majority of them. In women, breast cancer is the most common cause of orbital metastases, and in men, it is lung cancer. Despite the fact that there are efficient treatment options for orbital metastases, the benefit of procedures to detect choroidal metastases is debatable due to the quick progression and poor prognosis of lung cancer. In choroidal metastases resulting from lung cancer, patients are usually presented with decreased sight. Defects in the field of vision, flashes of light and floating bodies generally follow. Treatment options of choroidal metastases include many methods including laser photocoagulation, cryotherapy, chemotherapy, radiotherapy, surgical resection, enucleation and photodynamic therapy. There are reports emphasizing radiotherapy as the most efficient treatment option. In this case report, we sum up the case of a male patient presenting with blurry vision in both eyes, who was subsequently detected to have bilateral choroidal metastatic tumor and was diagnosed with primary lung adenocarcinoma.
Case Rep Oncol 2016;9:530–536

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Diagnosis of Jejunal Metastases from Lung Cancer Using Capsule Endoscopy

Gastrointestinal metastases from lung cancer are rare and usually asymptomatic. We report a case of small bowel metastases from primary lung cancer revealed by abdominal pain and severe recurrent anaemia. The diagnosis was obtained with capsule endoscopy. This non-invasive procedure thus represents a valuable method contributing to a rapid and detailed diagnosis while reducing underdiagnosis, and it should thus be considered for lung cancer patients complaining of abdominal symptoms, which may indeed be related to gastrointestinal metastases.
Case Rep Oncol 2016;9:526–529

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Using force: experiences of Belgian police officers

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Ethnic minority households and residential segregation: how important is the household composition to understand where minorities live?

Despite the importance of life cycle and household characteristics for residential mobility, these factors are seldom considered in the extensive field of ethnic residential segregation research. This study integrates the household composition of ethnic minorities into the spatial assimilation theory, the ethnic enclave theory and the self-segregation theory. We investigate the relationship between the type of household and living in a concentration neighbourhood for Turkish and North-African origin households. Moreover, we distinguish between both higher-educated and lower-educated people. For these purposes, we use a selection of the Belgian census data of 2011 (N=126,451). We used multilevel binary logistic regression analyses comparing families with children, childless couples and single and living alone households. We find clear associations between living in a Turkish of North-African concentration neighbourhood and the household type: families with children are more likely to live in concentration neighbourhoods than childless couples. Moreover, only lower educated families with children are more likely to live in concentration neighbourhoods than lower educated singles. Higher educated families are equally likely to live in a non-concentration neighbourhood as higher educated single and living alone households.

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The perceived intra-frame dynamic range in a cinema environment

When considering a higher contrast and brightness range in cinema, it's important to understand the limits of the Human Visual System (HVS) under cinema specific conditions. A user experiment with 36 participants was conducted in a cinema theatre. We assessed how the perceivable dynamic range evolved with different background gray levels and with the presence of local highlights in the image; how the size, position and intensity of these highlights affected the results. We found that the perceptual visibility of details in black depends greatly upon the image composition and the average luminance of a given image or image sequence. We found that in a fully dark frame, the average person can detect black details down to .005 Cd/m². However, if a 1% gray background in the central field of view is presented this rises to .009 Cd/m². and with a 10% gray background the black level threshold further increases to .015 Cd/m². In addition to the limitations of the HVS, one needs to consider the limitations of a theatrical projection setup where bright elements in the image via reflections on the walls, ceiling, floor, seats and audience contaminate the black elements of the image.

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Selling green militarization: the discursive (re)production of militarized conservation in the Virunga National Park, Democratic Republic of the Congo

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De diverse en complexe rol van media in een democratische samenleving

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De waardering van voorraden bij aankoop in bulk met doorverkoop per stuk

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Distances

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Experimental assessment of the inhalation zone of standing, sitting and sleeping persons

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Een geschenk uit de (Chinese) hemel

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Animamix: de nieuwe esthetiek van de 21ste eeuw

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Kunst en erfgoed: gescheiden werelden?

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Shanghai biennale: translocalmotion

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Worldwide clinical experience with a new dual-chamber implantable cardioverter defibrillator system

Introduction: Management of atrial tachyarrhythmias represents a significant challenge in patients with implantable cardioverter defibrillators (ICDs). Drug therapy of these arrhythmias is limited by moderate efficacy, ventricular proarrhythmia, and drug-device interactions. This study tested the safety and efficacy of a new dual-chamber ICD to detect and treat atrial as well as ventricular tachyarrhythmias, Methods and Results: A dual-chamber ICD (Medtronic 7250 Jewel AF) was implanted in 293 of 303 patients at 49 centers in Europe, Canada, and North America. Specific data were collected at implant and during a mean follow-up period of 7.9 +/- 4.7 months. There were no clinically evident failures to detect and treat ventricular arrhythmias. In patients with at least one of the dual-chamber detection criteria activated, 1,056 of 1,192 episodes of ventricular tachycardia or fibrillation detected were judged to be appropriate (89 % positive predictive accuracy). Therapy efficacy was 100 % in the ventricular fibrillation zone and 98 % in the ventricular tachycardia zone. Positive predictive accuracy for detection of atrial episodes was 95 % (1,052/1,107), For episodes classified as atrial tachycardia by the device, the efficacy of atrial antitachycardia pacing and high-frequency (50-Hz) burst pacing was 55% and 17%, respectively. High-frequency burst pacing terminated 16.8% of episodes classified as atrial fibrillation, and atrial defibrillation had an estimated efficacy of 76 %. The actuarial estimates of 6-month complication-free survival and total survival were 88 % and 94 %, respectively. Conclusion: This novel dual-chamber ICD is capable of safely and effectively discriminating atrial from ventricular tachyarrhythmias and of treating atrial tachyarrhythmias without compromising detection and treatment of ventricular tachyarrhythmias.

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Ongewone ventrikeltachykardie tijdens nierdialyse

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Clustered double-strand breaks in heterochromatin perturb DNA repair after high linear energy transfer irradiation

Publication date: Available online 13 September 2016
Source:Radiotherapy and Oncology
Author(s): Yvonne Lorat, Sara Timm, Burkhard Jakob, Gisela Taucher-Scholz, Claudia E. Rübe
Background and purposeHigh linear energy transfer (LET) radiotherapy offers superior dose conformity and biological effectiveness compared with low-LET radiotherapy, representing a promising alternative for radioresistant tumours. A prevailing hypothesis is that energy deposition along the high-LET particle trajectories induces DNA lesions that are more complex and clustered and therefore more challenging to repair. The precise molecular mechanisms underlying the differences in radiobiological effects between high-LET and low-LET radiotherapies remain unclear.Material and MethodsHuman fibroblasts were irradiated with high-LET carbon ions or low-LET photons. At 0.5h and 5h post exposure, the DNA-damage pattern in the chromatin ultrastructure was visualised using gold-labelled DNA-repair factors. The induction and repair of single-strand breaks, double-strand breaks (DSBs), and clustered lesions were analysed in combination with terminal dUTP nick-end labelling of DNA breaks.ResultsHigh-LET irradiation induced clustered lesions with multiple DSBs along ion trajectories predominantly in heterochromatic regions. The cluster size increased over time, suggesting inefficient DSB repair. Low-LET irradiation induced many isolated DSBs throughout the nucleus, most of which were efficiently rejoined.ConclusionsThe clustering of DSBs in heterochromatin following high-LET irradiation perturbs efficient DNA repair, leading to greater biological effectiveness of high-LET irradiation versus that of low-LET irradiation.



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Membrane-bound stem cell factor is the major but not only driver of fibroblast-induced murine skin mast cell differentiation

Abstract

The maintenance and modulation of cutaneous mast cell (MC) numbers is held to be important for skin immune responses to allergens and pathogens. The increase of MC numbers in the skin is achieved by proliferation and the differentiation of precursor to mature MCs. Fibroblast-derived SCF is thought to be the major skin MC growth factor and it potently induces MC proliferation. The mechanisms of fibroblast-induced skin MC differentiation, including the role of SCF, however, remain insufficiently characterized and understood. Using cocultures of immature murine MCs and fibroblasts we found that the adhesion of immature MCs to fibroblasts via VCAM-1 and α₄β₇ integrin is very important for subsequent differentiation, which is driven by fibroblast membrane-bound SCF and additional fibroblast-derived membrane-bound signals. Thus, our results show that fibroblast-induced MC differentiation is induced by direct cell-cell contact and involves both Kit-dependent and -independent pathways. Our findings add to the understanding of how immature mast cells mature in murine skin and encourage further analyses of the underlying mechanisms, which may result in novel targets for the modulation of skin mast cell driven diseases.

This article is protected by copyright. All rights reserved.

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Metabolism of melatonin in the skin: why is it important?

Abstract

Melatonin is produced in almost all living taxa and is probaly 2-3 billion years old. Its pleiotropic activities are related to its local concentration that is secondary to its local synthesis, delivery from distant sites and metabolic or non-enzymatic consumption. This consumption generates metabolites through indolic, kynuric and cytochrome P450 (CYP) mediated hydroxylations and O-demethylation or non-enzymatic processes, with potentially diverse phenotypic effects. While melatonin acts through receptor dependent and independent mechanism, receptors for melatonin metabolites remain to be identified, while their receptor independent activities are well documented. The human skin with its main cellular components including malignant cells can both produce and rapidly metabolize melatonin in cell type and context dependent fashion. The predominant metabolism in human skin occurs through indolic, CYP-mediated and kynuric pathways with main metabolites represented by 6-hydroxymelatonin, N¹-acetyl-N²-formyl-5-methoxykynuramine (AFMK), N¹-acetyl-5-methoxykynuramine (AMK), 5-methoxytryptamine, 5-methoxytryptophol and 2-hydroxymelatonin. AFMK, 6-hydroxymelatonin, 2-hydroxymelatonin and probably 4-hydroxymelatonin can potentially be produced in epidermis through UVB-induced non-enzymatic melatonin transformation. The skin metabolites are also the same as those produced in lower organisms and plants indicating phylogenetic conservation across diverse species and adaptation by skin of the primordial defense mechanism. Since melatonin and its metabolites counteract or buffer environmental stresses to maintain its homeostasis through broad-spectrum activities, both melatoninergic and degradative pathways must be precisely regulated, because local concentration of melatonin and its metabolites will decide about the nature of phenotypic regulations. These can be receptor mediated or represent non-receptor regulatory mechanisms.

This article is protected by copyright. All rights reserved.

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Construct validity and responsiveness of Movakic: An instrument for the evaluation of motor abilities in children with severe multiple disabilities

Publication date: December 2016
Source:Research in Developmental Disabilities, Volume 59
Author(s): Sonja M. Mensch, Michael A. Echteld, Heleen M. Evenhuis, Eugène A.A. Rameckers
Movakic is a newly developed instrument for measurement of motor abilities in children with severe multiple disabilities, with a satisfactory feasibility and content validity and good inter-observer and test-retest reliability.The objective of this study was to investigate its construct validity and responsiveness to change.Sixty children with severe multiple disabilities (mean age 7.7 years, range 2–16) were measured using Movakic six times during 18 months. Construct validity was assessed by correlating Movakic scores with expert judgment. In order to assess responsiveness, scores during 3-months intervals were compared (mean score-changes and intraclass correlations) during which some children experienced meaningful events influencing motor abilities and during which others experienced no such event.Forty-five percent of children had a lower cognitive development level than 6-month, 52% had Gross Motor Function Classification System level V and 37% had level IV. For 27 children all measurements were completed, six children dropped out. Construct validity was good (r=0.50–0.71). Responsiveness was demonstrated by significantly larger score changes after events than when such events did not occur.Movakic is a valid instrument for measuring motor abilities in children with severe multiple disabilities. Results suggest responsiveness to change in motor abilities after meaningful events.



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Serum Procalcitonin: An Independent Predictor of Clinical Outcome in Health Care-Associated Pneumonia

Background: Early prediction of the clinical outcomes for health care-associated pneumonia (HCAP) patients is challenging. Objectives: This is the first study to evaluate procalcitonin (PCT) as a predictor of outcomes in HCAP patients. Methods: We conducted an observational study based on data for HCAP patients prospectively collected between 2011 and 2014. Outcome variables were intensive care unit (ICU) admission and 30-day mortality. PCT was categorized into three groups: 2.0 ng/ml. We analysed multiple variables including age, sex, comorbidities, clinical findings, and PCT group to assess their association with outcomes. Results: Of 245 HCAP patients, 99 (40.4%) were admitted to an ICU and 44 (18.0%) died within 30 days. The median PCT level was significantly higher in the ICU admission (1.19 vs. 0.4 ng/ml; p 2.0 ng/ml) was strongly associated with ICU admission [odds ratio 3.734, 95% confidence interval (CI) 1.753-7.951; p = 0.001] and 30-day mortality (hazard ratio 2.254, 95% CI 1.250-5.340; p = 0.035). In receiver operating characteristic analysis, PCT had a poor discrimination power regarding ICU admission [0.695 of the area under the curve (AUC)] and a fair discrimination power regarding 30-day mortality in HCAP patients (0.768 of the AUC). Conclusions: High PCT on admission was strongly associated with ICU admission and 30-day mortality in HCAP patients. However, application of PCT alone seems to be limited to predicting outcomes.
Respiration

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Im Gedenken an Professor Dr. Dr. Michael Wannenmacher

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Evaluation of a New Brain Tissue Probe for Cerebral Blood Flow Monitoring in an Experimental Pig Model.

BACKGROUND: Bedside monitoring of cerebral blood flow (CBF) may provide new insights into the pathophysiology of brain injury, allow early detection of secondary ischemia, and help guide therapy. OBJECTIVE: To evaluate a new brain tissue probe for serial CBF monitoring using near-infrared spectroscopy and indocyanine green dye dilution (NeMo Probe) compared with the existing thermal diffusion probe (QFlow 500 Probe). METHODS: In 7 pigs, the NeMo Probe and QFlow 500 Probe were inserted into the subcortical white matter. Parallel measurements were recorded during (1) baseline, (2) hypotension, (3) hypertension, and (4) hyperventilation. Thereafter, protocol points 1 through 4 were repeated once. The Spearman correlation (rs), Bland-Altman plot, concordance rate, and coefficient of variation were used for statistical analysis. RESULTS: There was poor agreement between 56 pairs of absolute CBF values (rs = 0.52, P

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Glycated albumin: from biochemistry and laboratory medicine to clinical practice

Abstract

This review summarizes current knowledge about glycated albumin. We review the changes induced by glycation on the properties of albumin, the pathological implications of high glycated albumin levels, glycated albumin quantification methods, and the use of glycated albumin as a complementary biomarker for diabetes mellitus diagnosis and monitoring and for dealing with long-term complications. The advantages and limits of this biomarker in different clinical settings are also discussed.

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Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease

Abstract

The long-term effect of therapeutic diets in obesity treatment is a challenge at present. The current study aimed to evaluate the long-term effect of a very low-calorie-ketogenic (VLCK) diet on excess adiposity. Especial focus was set on visceral fat mass, and the impact on the individual burden of disease. A group of obese patients (n = 45) were randomly allocated in two groups: either the very low-calorie-ketogenic diet group (n = 22), or a standard low-calorie diet group; (n = 23). Both groups received external support. Adiposity parameters and the cumulative number of months of successful weight loss (5 or 10 %) over a 24-month period were quantified. The very low-calorie-ketogenic diet induced less than 2 months of mild ketosis and significant effects on body weight at 6, 12, and 24 months. At 24 months, a trend to regress to baseline levels was observed; however, the very low-calorie-ketogenic diet induced a greater reduction in body weight (−12.5 kg), waist circumference (−11.6 cm), and body fat mass (−8.8 kg) than the low-calorie diet (−4.4 kg, −4.1 cm, and −3.8 kg, respectively; p < 0.001). Interestingly, a selective reduction in visceral fat measured by a specific software of dual-energy x-ray absorptiometry (DEXA)-scan (−600 g vs. −202 g; p < 0.001) was observed. Moreover, the very low-calorie-ketogenic diet group experienced a reduction in the individual burden of obesity because reduction in disease duration. Very low-calorie-ketogenic diet patients were 500 months with 5 % weight lost vs. the low-calorie diet group (350 months; p < 0.001). In conclusion, a very low-calorie-ketogenic diet was effective 24 months later, with a decrease in visceral adipose tissue and a reduction in the individual burden of disease.

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Belian feasibility study on clinical biology analyses used in a contect of rare disease and reference laboratories

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X-ray micro-CT applied to natural building materials and art objects

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Tachycardie avec complexes ventriculaires larges et alternance des complexes QRS et des intervalles RR

A patient with sustained monomorphic ventricular tachycardia developed a second tachycardia of incessant character with alternating RR-interval and alternating QRS-complexes after treatment with amiodarone. A retrograde His bundle deflection was recorded during the latter arrhythmia, that was induced as well with atrial as with ventricular stimulation. The "alternating" tachycardia could be explained by alternating bundle branch reentry and alternating conduction in the myocardium. This view is supported by the finding of an alternating mid-diastolic potential. This case report introduces a new electrocardiographic entity in the spectrum of wide QRS-tachycardias.

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Design and Development of a Proactive Rapid Response System.

Timely identification of patient deterioration can prompt intervention and prevent the escalation of care and unplanned intensive care admissions. However, both personal experience and professional literature reveals that staff nurses in the acute care setting may not notice subtle signs of patient deterioration or may be reluctant to activate the rapid response system. To overcome these barriers, a proactive rapid response system with early warning signs was created and studied. Using a quasi-experimental design, data were collected from two medical-surgical nursing units at one large tertiary medical center over a 6-month period. One unit used the new rapid response system and early warning sign criteria with real-time data entry and trigger activation. A second unit served as the control and relied on the nurse for rapid response system activation. Findings revealed that the use of the newly developed rapid response system demonstrated significantly greater sensitivity to subtle signs of patient deterioration and prompted early evaluation and intervention. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Nurses' Satisfaction With Using Nursing Information Systems From Technology Acceptance Model and Information Systems Success Model Perspectives: A Reductionist Approach.

Nursing information systems can enhance nursing practice and the efficiency and quality of administrative affairs within the nursing department and thus have been widely considered for implementation. Close alignment of human-computer interaction can advance optimal clinical performance with the use of information systems. However, a lack of introduction of the concept of alignment between users' perceptions and technological functionality has caused dissatisfaction, as shown in the existing literature. This study provides insight into the alignment between nurses' perceptions and how technological functionality affects their satisfaction with Nursing Information System use through a reductionist perspective of alignment. This cross-sectional study collected data from 531 registered nurses in Taiwan. The results indicated that "perceived usefulness in system quality alignment," "perceived usefulness in information quality alignment," "perceived ease of use in system quality alignment," "perceived ease of use in information quality alignment," and "perceived ease of use in service quality alignment" have significantly affected nurses' satisfaction with Nursing Information System use. However, "perceived usefulness in service quality alignment" had no significant effect on nurses' satisfaction. This study also provides some meaningful implications for theoretical and practical aspects of design. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Paeonol Suppresses Neuroinflammatory Responses in LPS-Activated Microglia Cells

Abstract

In this work, we assessed the anti-inflammatory effects of paeonol (PAE) in LPS-activated N9 microglia cells, as well as its underlying molecular mechanisms. PAE had no adverse effect on the viability of murine microglia N9 cell line within a broad range (0.12∼75 μM). When N9 cell line was activated by LPS, PAE (0.6, 3, 15 μM) significantly suppressed the release of proinflammatory products, such as nitric oxide (NO), interleukin-1β (IL-1β), and prostaglandin E2 (PGE2), demonstrated by the ELISA assay. Moreover, the levels of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were significantly reduced in PAE-treated N9 microglia cells. We also examined some proteins involved in immune signaling pathways and found that PAE treatment significantly decreased the expression of TLR4, MyD88, IRAK4, TNFR-associated factor 6 (TRAF6), p-IkB-α, and NF-kB p65, as well as the mitogen-activated protein kinase (MAPK) pathway molecules p-P38, p-JNK, and p-ERK, indicating that PAE might act on these signaling pathways to inhibit inflammatory responses. Overall, we found that PAE had anti-inflammatory effect on LPS-activated N9 microglia cells, possibly via inhibiting the TLR4 signaling pathway, and it could be a potential drug therapy for inflammation-associated neurodegenerative diseases.

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Evaluating osteological ageing from digital data

Abstract

Age at death estimation of human skeletal remains is one of the key issues in constructing a biological profile both in forensic and archaeological contexts. The traditional adult osteological methods evaluate macroscopically the morphological changes that occur with increasing age of specific skeletal indicators, such as the cranial sutures, the pubic bone, the auricular surface of the ilium and the sternal end of the ribs. Technologies such as computed tomography and laser scanning are becoming more widely used in anthropology, and several new methods have been developed. This review focuses on how the osteological age-related changes have been evaluated in digital data. First, the 3D virtual copies of the bones have been used to mimic the appearance of the dry bones and the application of the traditional methods. Secondly, the information directly extrapolated from CT scans has been used to assess qualitatively or quantitatively the changes of the trabecular bones, the thickness of the cortical bones, and to perform morphometric analyses. Lastly, the most innovative approach has been the mathematical quantification of the changes of the pelvic joints, calculating the complexity of the surface. The importance of new updated reference datasets, created thanks to the use of CT scanning in forensic settings, is also discussed.

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Of skin and bone: did Langerhans cells and osteoclasts evolve from a common ancestor?

Abstract

Skin Langerhans cells are antigen-presenting cells of the interfollicular epidermis and the upper part of the hair follicle, whereas osteoclasts are specialized bone-resorbing macrophages. Although at first view these two cell types appear to have little in common, a closer analysis reveals shared features, and when taking into account their surrounding environment, a hypothesis can be developed that Langerhans cells and osteoclasts have evolved from a common ancestral cell type. In this mini-review, we have compared the ontogenetic features of Langerhans cells and osteoclasts from a genetic and a functional point of view, an issue that so far has been overlooked. The gene programs that control cell differentiation, and the body parts where they reside, present surprising similarities. Whereas the function of osteoclasts in bone degradation has been established since the first vertebrates, Langerhans cells may have undergone a stepwise adaptation from aquatic to terrestrial life. Their cell function co-evolved with the imperatives of the skin to protect against physical impact, heat, water loss and pathogens, which implied the capacity of Langerhans cells to associate with skin appendages and to develop immunostimulatory functions. For the highly versatile and efficient immune system of modern vertebrates, Langerhans cells may be a memory of the past.

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“Lull pgm System” for Autologous Fat Grafting: A Simple Closed System with Minimal Equipment and No Extra Cost

Summary: The "Lull pgm system" is a closed system for purifying harvested fat. It processes the collected tissue safely without any additional cost. The system was conceived by referring to the targets described in the literature with the aim of creating a simple system that guarantees a high standard of purification and requires minimal equipment that is available in every operating room. Cost must be always considered: even the most prosperous hospitals must keep within tight annual budgets. "Lull" can be used instead of expensive devices or disposable kits, without substantially increasing the operating time. The system has been used in clinical practice for many plastic reconstructive procedures and has obtained positive results and patient satisfaction, and no contraindications or disadvantages have been observed.

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Shaeer’s Technique: A Minimally Invasive Procedure for Monsplasty and Revealing the Concealed Penis

Background: A concealed penis is a condition where part of the penis is invisible below the surface of the prepubic skin. Dermolipectomy can correct this condition, although it involves a long abdominal crease incision, or infrapubic incision around the base of the penis, and a possibility for genital lymphedema. This study describes Shaeer's technique, a minimally invasive method for revealing the concealed penis. Methods: A 1- to 2-cm-long incision was cut over the anterior superior iliac spine (ASIS) on either side. A long curved blunt forceps was inserted from one incision, down to the base of the penis and then up to the contralateral ASIS. A 5-mm wide nonabsorbable tape was picked up by the forceps from 1 incision and pulled through to emerge from the other. Pulling on the tape cephalad pulled the mons pubis and revealed the penis. The tape was sutured to the periosteum overlying the ASIS on either side. Patients were followed up for 18 months for penile length, complications, and overall satisfaction. Results: Twenty patients were operated upon. Preoperatively, flaccid visible length was 3 ± 0.9 cm, and erect visible length was 8 ± 4.6 cm. Postoperatively, the flaccid visible length was 7.1 ± 2.1 cm, with a 57.9% improvement in length (P

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Interdomal Suture through a Nondelivery Endonasal Approach: A New Technique

Background: The use of interdomal sutures for tip refinement is common in open rhinoplasty and in endonasal rhinoplasty using a delivery technique, but there is paucity of reports in the literature regarding the use of interdomal suturing techniques when the nondelivery endonasal approach is chosen. Objective: The authors describe a technique designed to refine the nasal tip with an interdomal suture placed through a nondelivery endonasal approach. Methods: In this study, the authors retrospectively review the cases of 45 patients who underwent endonasal rhinoplasty with the authors' interdomal suturing technique between the years 2011 and 2013. The average age of the patients was 25.3 years. Intercrural sutures (PDS 4.0 straight needle, Cincinnati, Ohio) were placed as mattress-like suture in the tip region, with the knot buried between both alar cartilages. The suture is tightened progressively according to the tip definition and narrowing sought. Results: The patients were followed for 12 months. All of the patients demonstrated a significant reduction in lobule and tip widths. This series had only 1 complication of tip asymmetry that was revised 1 year after the initial operation. There were no cases of infection, allergic reaction, or extrusion of the suture. Conclusions: Despite the lack of a large volume of patients, our study confirms that this technique is indeed an attractive and highly predictable option for achieving adequate tip refinement and definition when using a nondelivery endonasal rhinoplasty.

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Consumer product ingestion and aspiration in children: A 15-year review

Objectives/Hypothesis

Our objectives were to identify consumer product (CP) ingestion and aspiration trends. Our hope is that evaluation of contemporary trends may be useful to physicians and policy makers and further guide preventative measures.

Methods

The Consumer Product Safety Commission's National Electronic Injury Surveillance System was queried for pediatric CP aspiration and ingestion data for the years 2000 to 2014. Data from 2000 to 2004 were compared to 2010 to 2014 data and analyzed for CP and injury occurrence. Injury trends over the past 15 years were identified; patient demographics were analyzed; and patient disposition was reported.

Results

Emergency department visits for pediatric CP ingestion increased 41.4% over the 15-year period analyzed and remained relatively stable for aspiration events. In all, an estimated 1.1 million visits occurred during this time frame. Jewelry overtook coins as the most common CP aspirated (29.3%). Coins remained the most frequent ingestion but comprised a smaller proportion of ingestions in recent years than years past. From 2010 through 2014, children under 5 years of age accounted for 89.4% and 77.8% of CP aspiration and ingestion cases, respectively.

Conclusion

Pediatric aspiration/ingestion remains a frequent occurrence with potentially significant ramifications. Injury demographics and CPs most likely to be involved may represent valuable information to the otolaryngologist who wishes to provide appropriate counseling to patients and parents and continued investigation on injury prevention.

Level of Evidence

4. Laryngoscope, 2016

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Development and validation of a high-fidelity phonomicrosurgical trainer

Objectives

To validate the use of a high-fidelity phonomicrosurgical trainer.

Study Design

A high-fidelity phonomicrosurgical trainer, based on a previously validated model by Contag et al.,¹ was designed with multilayered vocal folds that more closely mimic the consistency of true vocal folds, containing intracordal lesions to practice phonomicrosurgical removal. A training module was developed to simulate the true phonomicrosurgical experience. A validation study with novice and expert surgeons was conducted.

Methods

Novices and experts were instructed to remove the lesion from the synthetic vocal folds, and novices were given four training trials. Performances were measured by the amount of time spent and tissue injury (microflap, superficial, deep) to the vocal fold. An independent Student t test and Fisher exact tests were used to compare subjects. A matched-paired t test and Wilcoxon signed rank tests were used to compare novice performance on the first and fourth trials and assess for improvement.

Results

Experts completed the excision with less total errors than novices (P = .004) and made less injury to the microflap (P = .05) and superficial tissue (P = .003). Novices improved their performance with training, making less total errors (P = .002) and superficial tissue injuries (P = .02) and spending less time for removal (P = .002) after several practice trials.

Conclusion

This high-fidelity phonomicrosurgical trainer has been validated for novice surgeons. It can distinguish between experts and novices; and after training, it helped to improve novice performance.

Level of Evidence

N/A. Laryngoscope, 2016

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