MicroRNAs function as key regulators in various human cancers, including breast cancer (BC). MiR-361-5p has been proved to be a tumor suppressor in colorectal cancer and gastric cancer in our previous study. I...
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Δευτέρα 13 Νοεμβρίου 2017
MiR-361-5p inhibits glycolytic metabolism, proliferation and invasion of breast cancer by targeting FGFR1 and MMP-1
Cover Image
The cover image, by Jianjian Qiu et al., is based on the Original Article 18F-Fluoromisonidazole positron emission tomography/CT-guided volumetric-modulated arc therapy-based dose escalation for hypoxic subvolume in nasopharyngeal carcinomas: A feasibility study, DOI: 10.1002/hed.24925.
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Issue Information - Contents
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Elevated mitochondrial DNA copy numbers in pediatric acute lymphoblastic leukemia: A potential biomarker for predicting inferior survival
Abstract
Background
Studies on mitochondrial DNA copy number reveal an increase or decrease in copy number that appears to be cancer specific, but data on acute lymphoblastic leukemia have been inconsistent regarding the significance of changes in mitochondrial DNA copies. The purpose of this pilot study was to analyze mitochondrial DNA copy number and mitochondrial DNA integrity.
Procedure
Copy number and mitochondrial deletion ratios were estimated in the bone marrow of 51 patients and peripheral blood of 30 healthy controls using quantitative real-time PCR. The copy number values were correlated with prognostic markers in patients.
Results
Significantly increased mitochondrial DNA copy number (P-value < 0.0001) and increased mitochondrial deletion ratios (P-value = 0.0018) were observed in patients compared with controls. The copy numbers were significantly decreased in patients after chemotherapy (P-value = 0.0232). Patients with higher copy numbers exhibited significantly inferior survival than patients with lower copy numbers (for event-free survival, P-value = 0.04 and overall survival, P-value = 0.1175).
Conclusions
Significant decreases in mitochondrial DNA copy number with therapy indicates that copy number could be evaluated as a potential marker for therapeutic efficacy and a higher mitochondrial DNA copy number could be a poor prognostic marker.
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Acute chest syndrome among children hospitalized with vaso-occlusive crisis: A nationwide study in the United States
Abstract
Purpose
Acute chest syndrome (ACS) is a common complication among pediatric inpatients with sickle cell disease and vaso-occlusive crisis (VOC). However, little is known about the factors associated with ACS complication. The present study assessed the epidemiological features of children hospitalized with VOC and ascertained factors associated with ACS complication.
Methods
Hospital discharge records of patients with VOC aged <20 years were obtained for the years 2003, 2006, 2009, and 2012 from the Kids' Inpatient Database. Data were weighted to estimate the annual hospitalization rates with respect to gender and race/ethnicity in the United States. Multivariable logistic regression was conducted to ascertain factors associated with ACS complication after adjusting for patient and hospital characteristics.
Results
The total annual hospitalizations for VOC increased from 22,511 in 2003 to 24,292 in 2012. Multivariable logistic regression analysis showed that children aged 5–9 years had 2.59 times higher odds of ACS than children aged 15–19 years (95% confidence interval [CI], 2.32–2.88). Comorbidity of asthma (odds ratio [OR], 1.42; 95% CI, 1.31–1.54) and obstructive sleep apnea (OR, 1.70; 95% CI, 1.31–2.20) were associated with ACS development. ACS was also associated with male gender and the summer and fall seasons.
Conclusion
We reported nationwide estimates of the annual hospitalization rate for childhood VOC in the United States and demonstrated the major risk factors associated with ACS complication. Vigilance is needed for ACS complications in high-risk VOC admissions.
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Tumor predisposition syndromes: The challenge of de novo mutations
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Who is responsible for delivering palliative care to children with cancer?
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A Two-Faced mSWI/SNF Subunit: Dual Roles for ARID1A in Tumor Suppression and Oncogenicity in the Liver
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Jordan E. Otto, Cigall Kadoch
In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit ARID1A in the development and progression of hepatocellular carcinoma (HCC).
Teaser
In this issue of Cancer Cell, Sun et al. describe context-dependent oncogenic and tumor-suppressive functions for the mammalian SWI/SNF (BAF) complex subunit, ARID1A, in the development and progression of hepatocellular carcinoma (HCC).from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AIrD8y
Early GalNAc O-Glycosylation: Pushing the Tumor Boundaries
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Joana Gomes, Stefan Mereiter, Ana Magalhães, Celso A. Reis
Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14.
Teaser
Glycosylation alterations are frequently observed in cancer cells and shape tumor progression. In this issue of Cancer Cell, Nguyen et al. show that GALNT1 relocation from Golgi to endoplasmic reticulum drives liver tumor growth and invasion, due to enhanced glycosylation and consequential activation of the extracellular matrix-degrading metalloproteinase MMP14.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yAjFfU
Does CSF1R Blockade Turn into Friendly Fire?
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Tim F. Greten
In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts.
Teaser
In this issue of Cancer Cell, Kumar et al. describe how CSF1R blockade induces not only an expected deprivation of tumor-associated macrophages, but also an accumulation of tumor-infiltrating polymorphonuclear mononuclear cells caused by Cxcl-1 released from cancer-associated fibroblasts.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AHEbgf
Pontine Infantile Glioma Simplified
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Vijay Ramaswamy, Michael D. Taylor
In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer.
Teaser
In this issue of Cancer Cell, Pathania et al. report sporadic childhood histone K27M mutant malignant glioma mouse models that faithfully recapitulate the human tumor phenotypes. Beyond emphasizing the importance of correct timing in mouse modeling of cancer, these models will facilitate research to effectively treat this lethal childhood cancer.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yBIOap
Molecular Landscape of Non-Muscle Invasive Bladder Cancer
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Joshua J. Meeks, Seth P. Lerner
In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling. Tumors from female patients have a higher frequency of KDM6A mutations.
Teaser
In this issue of Cancer Cell, Hurst et al. report an integrated analysis of non-invasive (stage Ta) bladder cancer. Two genomic subtypes are distinguished by chromosome 9q loss, resulting in increased AKT/PI3K/mTOR signaling and increased risk of recurrence. Tumors from female patients have a higher frequency of KDM6A mutations.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AI22wk
Oncogene-Stimulated Congestion at the KEAP1 Stress Signaling Hub Allows Bypass of NRF2 and Induction of NRF2-Target Genes that Promote Tumor Survival
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): John D. Hayes, Albena T. Dinkova-Kostova
In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif.
Teaser
In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yBIoAR
Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Hugues de Thé, Pier Paolo Pandolfi, Zhu Chen
Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.
Teaser
Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AJptFG
Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Xuxu Sun, Sam C. Wang, Yonglong Wei, Xin Luo, Yuemeng Jia, Lin Li, Purva Gopal, Min Zhu, Ibrahim Nassour, Jen-Chieh Chuang, Thomas Maples, Cemre Celen, Liem H. Nguyen, Linwei Wu, Shunjun Fu, Weiping Li, Lijian Hui, Feng Tian, Yuan Ji, Shuyuan Zhang, Mahsa Sorouri, Tae Hyun Hwang, Lynda Letzig, Laura James, Zixi Wang, Adam C. Yopp, Amit G. Singal, Hao Zhu
ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.
Graphical abstract
Teaser
Sun el al. uncover context-specific roles for the SWI/SNF component Arid1a in liver cancer, where elevated Arid1a promotes tumor initiation through CYP450-mediated oxidative stress, whereas reduced Arid1a in established tumors increases metastasis due to reduced expression of inhibitory factors.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yz2fk6
Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Leire Bejarano, Alberto J. Schuhmacher, Marinela Méndez, Diego Megías, Carmen Blanco-Aparicio, Sonia Martínez, Joaquín Pastor, Massimo Squatrito, Maria A. Blasco
Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM.
Graphical abstract
Teaser
Bejarano et al. show that genetic or chemical inhibition of TRF1 increases telomeric DNA damage and reduces proliferation and stemness independent of telomere length. TRF1 inhibition also inhibits glioblastoma initiation and progression and prolongs survival in genetic and xenograft glioblastoma models.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yBI6df
A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Javier Robles-Valero, L. Francisco Lorenzo-Martín, Mauricio Menacho-Márquez, Isabel Fernández-Pisonero, Antonio Abad, Mireia Camós, María L. Toribio, Lluis Espinosa, Anna Bigas, Xosé R. Bustelo
Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway.
Graphical abstract
Teaser
Robles-Valero et al. find that Vav1 facilitates binding of Cbl-b to the intracellular domain of Notch1 (ICN1) and promotes ICN1 degradation. Loss of Vav1 induces T cell acute lymphoblastic leukemia (T-ALL) by increasing ICN1 signaling, and TLX inhibits Vav1 expression to stimulate ICN1 signaling in TLX+ T-ALL.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yAjEZo
Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Anh Tuan Nguyen, Joanne Chia, Manon Ros, Kam Man Hui, Frederic Saltel, Frederic Bard
Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). In a mouse liver cancer model, expressing an ER-targeted GALNT1 (ER-G1) massively increased tumor expansion, with median survival reduced from 23 to 10 weeks. In vitro cell growth was unaffected, but ER-G1 strongly enabled matrix degradation and tissue invasion. Unlike its Golgi-localized counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumor expansion. Together, our results indicate that GALNTs strongly promote liver tumor growth after relocating to the ER.
Graphical abstract
Teaser
Nguyen et al. find that O-glycosylation increases during liver tumor progression, with increased expression of GALNT1 and glycosylation of ER-associated proteins. In mouse models, expression of GALNT1 in the ER, but not the Golgi, accelerates tumorigenesis and increases invasion through glycosylation of MMP14.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yzhcCB
Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Vinit Kumar, Laxminarasimha Donthireddy, Douglas Marvel, Thomas Condamine, Fang Wang, Sergio Lavilla-Alonso, Ayumi Hashimoto, Prashanthi Vonteddu, Reeti Behera, Marlee A. Goins, Charles Mulligan, Brian Nam, Neil Hockstein, Fred Denstman, Shanti Shakamuri, David W. Speicher, Ashani T. Weeraratna, Timothy Chao, Robert H. Vonderheide, Lucia R. Languino, Peter Ordentlich, Qin Liu, Xiaowei Xu, Albert Lo, Ellen Puré, Chunsheng Zhang, Andrey Loboda, Manuel A. Sepulveda, Linda A. Snyder, Dmitry I. Gabrilovich
Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.
Graphical abstract
Teaser
Kumar et al. show that CSF1R inhibition alters chemokine secretion by cancer-associated fibroblasts, which attracts pro-tumor PMN-MDSCs and results in poor efficacy. Combined inhibition of CSF1R and CXCR2 blocks MDSC recruitment and reduces tumor growth, which is further improved by the addition of anti-PD-1.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yz28oG
An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Asis Palazon, Petros A. Tyrakis, David Macias, Pedro Veliça, Helene Rundqvist, Susan Fitzpatrick, Nikola Vojnovic, Anthony T. Phan, Niklas Loman, Ingrid Hedenfalk, Thomas Hatschek, John Lövrot, Theodoros Foukakis, Ananda W. Goldrath, Jonas Bergh, Randall S. Johnson
Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity.
Teaser
Palazon et al. demonstrate the importance of the HIF-1α/VEGF-A axis in tumor immunity. HIF-1α, but not HIF-2α, drives CD8+ T cell glycolytic metabolism, migration, and effector function, while the HIF-1α transcriptional target VEGF-A contributes to tumor vascularization.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yCxL0g
Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Carolyn D. Hurst, Olivia Alder, Fiona M. Platt, Alastair Droop, Lucy F. Stead, Julie E. Burns, George J. Burghel, Sunjay Jain, Leszek J. Klimczak, Helen Lindsay, Jo-An Roulson, Claire F. Taylor, Helene Thygesen, Angus J. Cameron, Anne J. Ridley, Helen R. Mott, Dmitry A. Gordenin, Margaret A. Knowles
Bladder cancer incurs a higher lifetime treatment cost than other cancers due to frequent recurrence of non-invasive disease. Improved prognostic biomarkers and localized therapy are needed for this large patient group. We defined two major genomic subtypes of primary stage Ta tumors. One of these was characterized by loss of 9q including TSC1, increased KI67 labeling index, upregulated glycolysis, DNA repair, mTORC1 signaling, features of the unfolded protein response, and altered cholesterol homeostasis. Comparison with muscle-invasive bladder cancer mutation profiles revealed lower overall mutation rates and more frequent mutations in RHOB and chromatin modifier genes. More mutations in the histone lysine demethylase KDM6A were present in non-invasive tumors from females than males.
Graphical abstract
Teaser
By analyzing 140 primary patient samples, Hurst et al. identify two genomic subtypes of stage Ta non-invasive bladder cancer. The more genomically unstable subtype is distinguished by loss of chromosome 9q sequences, upregulated mTORC1 signaling, and altered metabolic profile. They also find that females have a higher frequency of KDM6A mutations than males.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AI13vW
SnapShot: Chronic Lymphocytic Leukemia
Publication date: 13 November 2017
Source:Cancer Cell, Volume 32, Issue 5
Author(s): Elisa ten Hacken, Romain Guièze, Catherine J. Wu
Despite the recent advances in the therapeutic management of Chronic Lymphocytic Leukemia (CLL) patients, this common B cell malignancy still remains incurable. This SnapShot provides an overview of CLL biology and therapy, with a focus on genetics and microenvironmental interactions, which contribute to disease progression and therapy resistance. To view this SnapShot, open or download the PDF.
Teaser
Despite the recent advances in the therapeutic management of Chronic Lymphocytic Leukemia (CLL) patients, this common B cell malignancy still remains incurable. This SnapShot provides an overview of CLL biology and therapy, with a focus on genetics and microenvironmental interactions, which contribute to disease progression and therapy resistance. To view this SnapShot, open or download the PDF.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AIS4uP
Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders
Endothelin-converting enzyme-like 1 (ECEL1, also termed DINE in rodents), a membrane-bound metalloprotease, has been identified as a gene responsible for distal arthrogryposis (DA). ECEL1-mutated DA is generally ...
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Early Education and Employment Outcomes After Cancer in Adolescents and Young Adults
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Atmospheric mercury species measurements across the Western Mediterranean region: Behaviour and variability during a 2015 research cruise campaign
Publication date: January 2018
Source:Atmospheric Environment, Volume 173
Author(s): Jessica Castagna, Mariantonia Bencardino, Francesco D'Amore, Giulio Esposito, Nicola Pirrone, Francesca Sprovieri
In the framework of the ongoing MEDOCEANOR measurements program, an oceanographic cruise campaign was carried out during summer 2015 in the Western sector of Mediterranean Sea basin, on-board the research vessel "Minerva Uno" of the Italian National Research Council (CNR). The overall goal was to investigate the dynamic patterns of mercury in the Marine Boundary Layer (MBL) and the main factors affecting mercury behaviour at both coastal and offshore locations. The mean concentrations of the recorded Hg species were 1.6 ± 0.5 ngm−3, 11.8 ± 15.0 pgm−3, and 2.4 ± 1.1 pgm−3, respectively for GEM, GOM, and PBM. Moreover, during the measurement period typical fair-weather conditions of the Mediterranean summer were encountered with high levels of solar radiation and temperature that favoured photochemical reactions. Atmospheric pollutants such as ozone, sulphur oxides and nitrogen oxides and other meteorological parameters were in addition recorded and jointly discussed with selected mercury events in terms of their spatio-temporal variations. Changes in air pollutant concentrations were also argued in the light of their likely influencing sources, among which, anthropogenic activities, such as the mercury cell chlor-alkali complex in Tuscany, Italy, and natural influence, like volcanic ashes, detected around the Aeolian area and the in-situ production of reactive gaseous mercury within the Marine Boundary Layer.
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Composition and sources of carbonaceous aerosols in Northern Europe during winter
Publication date: January 2018
Source:Atmospheric Environment, Volume 173
Author(s): M. Glasius, A.M.K. Hansen, M. Claeys, J.S. Henzing, A.D. Jedynska, A. Kasper-Giebl, M. Kistler, K. Kristensen, J. Martinsson, W. Maenhaut, J.K. Nøjgaard, G. Spindler, K.E. Stenström, E. Swietlicki, S. Szidat, D. Simpson, K.E. Yttri
Sources of elemental carbon (EC) and organic carbon (OC) in atmospheric aerosols (carbonaceous aerosols) were investigated by collection of weekly aerosol filter samples at six background sites in Northern Europe (Birkenes, Norway; Vavihill, Sweden; Risoe, Denmark; Cabauw and Rotterdam in The Netherlands; Melpitz, Germany) during winter 2013. Analysis of 14C and a set of molecular tracers were used to constrain the sources of EC and OC. During the four-week campaign, most sites (in particular those in Germany and The Netherlands) were affected by an episode during the first two weeks with high concentrations of aerosol, as continental air masses were transported westward. The analysis results showed a clear, increasing north to south gradient for most molecular tracers. Total carbon (TC = OC + EC) at Birkenes showed an average concentration of 0.5 ± 0.3 μg C m−3, whereas the average concentration at Melpitz was 6.0 ± 4.3 μg C m−3. One weekly mean TC concentration as high as 11 μg C m−3 was observed at Melpitz. Average levoglucosan concentrations varied by an order of magnitude from 25 ± 13 ng m−3 (Birkenes) to 249 ± 13 ng m−3 (Melpitz), while concentrations of tracers of fungal spores (arabitol and mannitol) and vegetative debris (cellulose) were very low, showing a minor influence of primary biological aerosol particles during the North European winter. The fraction of modern carbon generally varied from 0.57 (Melpitz) to 0.91 (Birkenes), showing an opposite trend compared to the molecular tracers and TC. Total concentrations of 10 biogenic and anthropogenic carboxylic acids, mainly of secondary origin, were 4–53 ng m−3, with the lowest concentrations observed at Birkenes and the highest at Melpitz. However, the highest relative concentrations of carboxylic acids (normalized to TC) were observed at the most northern sites. Levels of organosulphates and nitrooxy organosulphates varied more than two orders of magnitude, from 2 to 414 ng m−3, between individual sites and samples. The three sites Melpitz, Rotterdam and Cabauw, located closest to source regions in continental Europe, showed very high levels of organosulphates and nitrooxy organosulphates (up to 414 ng m−3) during the first two weeks of the study, while low levels (<7 ng m−3) were found at all sites except Melpitz during the last week. The large variation in organosulphate levels probably reflects differences in the presence of acidic sulphate aerosols, known from laboratory studies to accelerate the formation of these compounds. On average, the ratio of organic sulphate to inorganic sulphate was 1.5 ± 1.0% (range 0.1–3.4%). Latin-hypercube source apportionment techniques identified biomass burning as the major source of OC for all samples at all sites (typically >40% of TC), while use and combustion of fossil fuels was the second most important source. Furthermore, EC from biomass burning accounted for 7–16% of TC, whereas EC from fossil sources contributed to <2–23% of TC, of which the highest percentages were observed for low-concentration aerosol samples. Unresolved non-fossil sources (such as cooking and biogenic secondary organic aerosols) did not account for more than 5–12% of TC. The results confirm that wood combustion is a major source to OC and EC in Northern Europe during winter.
Graphical abstract
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Spatial inter-comparison of Top-down emission inventories in European urban areas
Publication date: January 2018
Source:Atmospheric Environment, Volume 173
Author(s): Marco Trombetti, Philippe Thunis, Bertrand Bessagnet, Alain Clappier, Florian Couvidat, Marc Guevara, Jeroen Kuenen, Susana López-Aparicio
This paper presents an inter-comparison of the main Top-down emission inventories currently used for air quality modelling studies at the European level. The comparison is developed for eleven European cities and compares the distribution of emissions of NOx, SO2, VOC and PPM2.5 from the road transport, residential combustion and industry sectors. The analysis shows that substantial differences in terms of total emissions, sectorial emission shares and spatial distribution exist between the datasets. The possible reasons in terms of downscaling approaches and choice of spatial proxies are analysed and recommendations are provided for each inventory in order to work towards the harmonisation of spatial downscaling and proxy calibration, in particular for policy purposes. The proposed methodology may be useful for the development of consistent and harmonised European-wide inventories with the aim of reducing the uncertainties in air quality modelling activities.
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Vaccines We Need But Don't Have
Viral Immunology , Vol. 0, No. 0.
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Association of Single-Nucleotide Polymorphisms in Immune-Related Genes with Development of Dengue Hemorrhagic Fever in a Mexican Population
Viral Immunology , Vol. 0, No. 0.
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Enhanced CD103 Expression and Reduced Frequencies of Virus-Specific CD8+ T Cells Among Airway Lymphocytes After Influenza Vaccination of Mice Deficient in Vitamins A + D
Viral Immunology , Vol. 0, No. 0.
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Neurokinin 1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant
Future Oncology, Ahead of Print.
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Nivolumab in recurrent/metastatic head and neck cancers
Future Oncology, Ahead of Print.
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Image-guided surgery and therapy for lung cancer: a critical review
Future Oncology, Ahead of Print.
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Proteasome-associated deubiquitinases and cancer
Abstract
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types. Simultaneously, the elevated protein synthesis rate of cancer cells and consequential accumulation of misfolded proteins drives UPS addiction, thus sensitizing them to UPS inhibitors. This sensitivity along with the potential of stabilizing pro-apoptotic signaling pathways makes the proteasome an attractive clinical target for the development of novel therapies. Targeting of the catalytic 20S subunit of the proteasome is already a clinically validated strategy in multiple myeloma and other cancers. Spurred on by this success, promising novel inhibitors of the UPS have entered development, targeting the 20S as well as regulatory 19S subunit and inhibitors of deubiquitinating and ubiquitin ligase enzymes. In this review, we outline the manner in which deregulation of the UPS can cause cancer to develop, current clinical application of proteasome inhibitors, and the (pre-)clinical development of novel inhibitors of the UPS.
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Neurokinin 1 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant
Future Oncology, Ahead of Print.
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Nivolumab in recurrent/metastatic head and neck cancers
Future Oncology, Ahead of Print.
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Image-guided surgery and therapy for lung cancer: a critical review
Future Oncology, Ahead of Print.
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Predictability of orthodontic movement with orthodontic aligners: a retrospective study
The aim of this study was to evaluate the predictability of F22 aligners (Sweden & Martina, Due Carrare, Italy) in guiding teeth into the positions planned using digital orthodontic setup.
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Therapeutic Impact of Nanoparticle Therapy Targeting Tumor Associate Macrophages
Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest anti-angiogenic therapy induced hypoxia can induce tumor "stemness' as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor associated macrophages (TAMs). As such TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) Nps deplete tumor associated macrophages in both solid tumor and ascites models of ovarian cancer. As a therapeutic these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to anti-angiogenic therapy, (ii) prevent antiangiogenic therapy induced increases in cancer stem-like cells in both murine and human tumor cell models, and (iii) prevent anti-angiogenic therapy induced increases in VEGF-C (iv) prevent anti-angiogenic therapy induce BRCA1 gene expression. Combine this work strongly supports the development of TAM targeted nanoparticle therapy.
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The Mutational Landscape of Gastrointestinal Malignancies as Reflected by Circulating Tumor DNA
We aimed to assess the utility of a novel, non-invasive method of detecting genomic alterations in patients with gastrointestinal malignancies i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N=55 (26%)), appendiceal adenocarcinoma (N=46 (22%)), hepatocellular carcinoma (N=31 (15%)), and pancreatic ductal adenocarcinoma (N=25 (12%)). The majority of patients (58%) had >1 characterized alteration (excluded variants of unknown significance). The median number of characterized alterations was 1 (range, 0-13). The number of detected alterations per patient varied between different cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had >1 characterized alteration(s) versus 24% of appendiceal adenocarcinoma patients (11/46). The median percent ctDNA among characterized alterations was 2.50% (interquartile range, 0.76-8.96%). Overall, 95% of patients (117/123) had distinct molecular portfolios with 143 unique characterized alterations within 56 genes. Overall concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue-biopsy (N = 105 patients) in the four most common alterations (KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Of the 123 patients with characterized alterations, >99% (122/123) had one or more alterations potentially actionable by experimental or approved drugs. These observations suggest that many patients with gastrointestinal tumors, including difficult-to-biopsy malignancies like hepatocellular cancers, frequently have discernible and pharmacologically tractable ctDNA alterations.
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Response and resistance to paradox breaking BRAF inhibitor in melanomas in vivo and ex vivo
FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox breaking RAF inhibitor (PLX8394) has been designed. Here we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenib-resistant BRAF splice-variant expressing tumors and reduced splice-variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test efficacy of therapeutic agents.
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Clinical application of circulating tumor DNA in the genetic analysis of patients with advanced GIST
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. While circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance. But the concordance was strong for patients with tumor size>10cm or Ki-67>5%. Tumor size, mitotic figure, Ki-67 and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients.
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IMMU-140, a novel SN-38-antibody-drug conjugate targeting HLA-DR, mediates dual cytotoxic effects in hematological cancers and malignant melanoma
HLA-DR is a member of the MHC class II antigen family expressed on hematological and solid tumors. Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development. IMMU-140 is an anti-HLA-DR antibody-drug conjugate comprised of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti-HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR-expressing tumors. In vitro, IMMU-140 had dual-therapeutic mechanisms, as evidenced by its retention of non-overlapping anti-HLA-DR non-classical apoptotic signaling and classical apoptosis mediated by its SN-38 payload. In seven human disease models (acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], multiple myeloma [MM], acute myeloid leukemia [AML], diffuse large B-cell lymphoma [DLBCL], Hodgkin lymphoma [HL], and melanoma), IMMU-140 provided significant therapeutic efficacy compared to controls, in vivo and in 3D spheroid models. Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared to parental IMMU-114. Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects, IMMU-140 therapy mediated >80% improvement in survival. Therapy was well-tolerated, as demonstrated by no marked loss in body weight. Combined with doxorubicin, IMMU-140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity. The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development.
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Ceritinib enhances the efficacy of trametinib in BRAF/NRAS-wild type melanoma cell lines
Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both 3D spheroid culture and long-term colony formation experiments. Co-administration of ceritinib and trametinib led to robust inhibition of tumor growth in an in vivo xenograft BRAF/NRAS-WT melanoma model; this was not due to ALK inhibition by ceritinib. Mechanistic studies showed the ceritinib-trametinib combination to increase suppression of MAPK and TORC1 signaling. Similar results were seen when BRAF/NRAS-WT melanoma cells were treated with a combination of trametinib and the TORC1/2 inhibitor INK128. We next used mass spectrometry-based chemical proteomics and identified known and new ceritinib targets, such as IGF1R and ACK1, respectively. Validation studies suggested that ceritinib could suppress mTORC1 signaling in the presence of trametinib through inhibition of IGF1R and/or ACK1 in a cell line-dependent manner. Together our studies demonstrated that combining a specific inhibitor (trametinib) with a more broadly targeted agent (ceritinib) has efficacy against tumors with heterogeneous mutational profiles.
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Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response Targeted Therapies in Breast Cancer
Disruption of Cyclin Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and poly(ADP-ribose) polymerase 1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by immunohistochemistry (IHC) in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer specific survival taking HER2 status into account, however absent CDK12 protein expression significantly correlated with a triple negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK and gamma-H2AX, suggesting a novel mechanism of CDK12 associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in BC is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple negative breast cancers.
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In upcoming issues...
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How to suction pancreatic juice from the duodenum: Endoscope, catheter, or cap-assisted?
Pancreatic cancer is associated with a very poor prognosis. The American Cancer Society estimates that in 2017, about 53,670 people will receive a diagnosis of pancreatic cancer and about 43,090 people will die of the disease. It is predicted that pancreatic cancer will be the second leading cause of cancer death in the United States by 2030.1 Although the 5-year relative survival is as low as 8% for all stages, the 5-year relative survival for localized tumor is 29%.2 Therefore, surgical resection of the tumor at an early stage is the only cure.
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ERCP: Time to take the lead off?
Multiple studies have shown ERCP to generate significant doses of ionizing radiation. Yet, with the exception of the pregnant patient, most endoscopists performing ERCP are not precisely aware of, much less concerned about, the ionizing radiation generated. It's just another day in the ERCP suite, and what counts is the procedural outcome: Was cannulation of the targeted duct accomplished, and was the therapeutic intervention successfully executed? Historically, the radiation exposure from ERCP to the patient has been perceived as trivial and—even when longer fluoroscopy times are needed—as a necessary tradeoff to reap the advantages of ERCP over more invasive and risky radiologic and surgical alternatives.
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Response:
We thank Dr Cotton1 for his insightful comments on the recent American Society for Gastrointestinal Endoscopy (ASGE) guideline document on privileging and credentialing in GI endoscopy as it pertains to competence in ERCP.2 The first issue raised in this letter relates to the number of the ERCPs that a trainee must complete before competency can be assessed and the lack of data on this subject in the published literature. We would like to clarify that the intent of this statement was to ensure that trainees complete at least 200 supervised independent ERCP procedures.
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Response:
We appreciate the thoughtful comments of Dr Agrawal1 regarding the Multi-Society Task Force (MSTF) recommendations on colorectal cancer screening.2 Dr Agrawal suggests that the MSTF should advise patients to ask prospective colonoscopists for their rate of adequate preparations. Dr Agrawal cites the ≥85% target for adequate preparations, which he attributes to the American College of Gastroenterology (ACG). This target, although endorsed by the ACG, was first presented by the MSTF.3 Thus, we strongly agree that colonoscopists should measure rates of adequate bowel preparation (defined by the use of bowel preparation descriptors or scores consistent with adequacy plus adherence to screening or surveillance recommendations appropriate to the examination findings) and make changes when needed to exceed this target.
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Zeroing in on endoscopic and histologic mucosal healing to reduce the risk of colorectal neoplasia in inflammatory bowel disease
The past 2 decades have witnessed unprecedented advances in our understanding of the causes and pathogenesis of inflammatory bowel disease (IBD). Taken together with an expanding therapeutic armamentarium, this has emboldened the definitions of disease control, placing greater emphasis on achieving mucosal healing than on clinical remission alone. What can now be achieved through abrogation of immunoinflammatory events such as reduction in disease relapse, hospitalization, surgery, and colorectal neoplasia (CRN) has redefined our perceptions of meaningful disease control.
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Information for readers
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Continuing Medical Education Exam: December 2017
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Choledocholithiasis: Should EUS replace MRCP in patients at intermediate risk?
Choledocholithiasis is a common adverse event of gallstones, occurring in 10% to 20% of patients undergoing cholecystectomy.1 Although ERCP is considered the criterion standard for diagnosis and management of choledocholithiasis, the diagnostic role of this modality is limited by its invasive nature and risk for adverse events such as post-ERCP pancreatitis (PEP).2 Pancreatitis is the most common adverse event of ERCP and is estimated to be responsible for 150 million dollars of health care expenditures annually in the United States.
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Pancreatic function testing for the early diagnosis of chronic pancreatitis
Chronic pancreatitis is a syndrome.1 Not all disease syndromes have a single specific diagnostic test that corroborates the diagnosis but instead rely on a combination of clinical, laboratory, imaging, and pathologic characteristics in various combinations to define the disease (eg, systemic lupus erythematosus). Chronic pancreatitis occurs in patients with genetic, environmental, and other risk factors; has a diversity of mechanisms; and is associated with a wide variety of clinical features. In the past, chronic pancreatitis was defined only by the presence of specific morphologic changes (imaging features such as pancreatic calcification, or histologic characteristics demonstrating fibrosis) or by functional changes (gland failure with pancreatic exocrine or endocrine insufficiency).
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PiCaSSO: a predictive score for endoscopic findings in ulcerative colitis that sounds like art but is all science
Treatment goals in inflammatory bowel disease are in the process of a profound transformation. Clinical measures defined by patient symptoms and noninvasive testing, although useful in practice, are inadequate for monitoring response to therapy and likelihood of relapse. Mucosal healing is fast becoming the ultimate treatment goal in inflammatory bowel disease and is now an accepted outcome measure for clinical trials because it leads to better patient outcomes.1 Mucosal healing in Crohn's disease, as defined by the absence of mucosal erosion and ulceration, did lead to durable clinical remission but did not show lower rates of surgery.
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Covered self-expanding metal stents: a promising therapy for difficult stone disease
We read with great interest the article by Hartery et al1 entitled "Covered self-expanding metal stents for the management of common bile duct stones." This retrospective study evaluated the safety and efficacy of inserting covered self-expanding metal stents (CSEMSs) alongside "difficult" stones in 44 patients at 2 tertiary referral centers. After the work by Cerefice et al2 in 2011, this is the second case series in the literature that has evaluated this modality in treating difficult stones after failed endoscopic extraction.
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Covered bridge over troubled strictures
In this current issue of Gastrointestinal Endoscopy, Tal et al1 compare 2 different approaches for the treatment of anastomotic biliary strictures (ABSs) after orthotopic liver transplantation (OLT). The authors report the results of their prospective open-label 2-arm study comparing multiple plastic stents (MPSs) with covered self-expandable metal stents (cSEMSs). On the basis of these results, patients who undergo cSEMS placement for ABSs require fewer ERCP interventions (median ERCP sessions, 2; range, 2-12) than do patients undergoing MPS placement (median ERCP sessions, 4; range, 3-12; P < .001).
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Inadequate bowel preparation rates should be considered before screening colonoscopy is recommended
Rex et al1 provided a comprehensive update of the U.S. Multi-Society Task Force of Colorectal Cancer recommendations on colon cancer screening. They cite good evidence in support of a sequential approach based on colonoscopy, first based on sensitivity and cost effectiveness. The authors also discuss tools for patients (and primary care physicians) to judge whether colonoscopy is performed at a high level. These include asking about adenoma detection rate, cecal intubation rate, and use of split-dosing bowel preparation.
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ASGE guidelines for ERCP competence
I applaud the continuing efforts of the American Society for Gastrointestinal Endoscopy (ASGE) to improve the quality of endoscopy in the United States, and thus I read the latest comprehensive guidelines with interest.1 The section on ERCP has 2 surprising conclusions.
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Factors influencing cerebral aneurysm obliteration and reliability of indocyanine green video-angiography
Abstract
Background
Indocyanine green video-angiography (ICG-V) is commonly used for intraoperative confirmation of aneurysm obliteration following clipping. However, direct puncture of the aneurysm wall occasionally results in blood leakage in patients for whom ICG-V has indicated complete closure. Therefore, the present study aimed to determine the reliability of ICG-V for confirming complete aneurysm closure, and to elucidate the factors underlying aneurysm obliteration and the occurrence of false-negative ICG-V findings.
Methods
Between June 2012 and June 2016, 89 patients (107 aneurysms total) undergoing aneurysm clipping were examined using ICG-V to confirm aneurysm closure. In ICG-V-negative cases, further confirmation of complete aneurysm closure was obtained via direct puncture of the aneurysm wall, except in cases where this procedure was deemed unsafe. To elucidate the possible causes of ICG-V inaccuracies, positive, negative, and false-negative ICG-V findings were compared in terms of aneurysm location (maximum height and length), neck width (parallel and orthogonal directions to the branching vessels), wall thickness around the neck, bifurcation angle, and direction of the clipping closure line. Statistical analyses were performed using the Welsh's t test and Chi-square test.
Results
Intraoperative ICG-V detected seven cases of incomplete aneurysm closure (6.5%), defined as positive ICG-V findings. Following direct aneurysm wall puncture, nine patients (8.4%) exhibited false-negative ICG-V findings. A Chi-square test revealed that false-negative ICG-V findings were significantly influenced by the presence of heterogeneous arteriosclerosis, and wall thickening at the clipping site, which were subjectively defined by the surgeon and confirmed by an independent observer, depending on the wall color and hardness, respectively.
Conclusions
Although ICG-V is useful for intraoperative confirmation of aneurysm obliteration, our findings further highlight the risk of false-negative ICG-V findings. Acknowledgement of risk factors is crucial for efficient detection of false-negative ICG-V findings.
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Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer
Summary
Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.
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ACS NSQIP risk calculator reliability in head and neck oncology: The effect of prior chemoradiation on NSQIP risk estimates following laryngectomy
To determine whether inclusion of chemoradiation history increases estimated risk for complications following total laryngectomy using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Surgical Risk Calculator.
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Effects of somatosensory electrical stimulation on motor function and cortical oscillations
Few patients recover full hand dexterity after an acquired brain injury such as stroke. Repetitive somatosensory electrical stimulation (SES) is a promising method to promote recovery of hand function. However...
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A composite robotic-based measure of upper limb proprioception
Proprioception is the sense of the position and movement of our limbs, and is vital for executing coordinated movements. Proprioceptive disorders are common following stroke, but clinical tests for measuring i...
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Progressive practice promotes motor learning and repeated transient increases in corticospinal excitability across multiple days
Source:Brain Stimulation
Author(s): L. Christiansen, M.J. Madsen, E. Bojsen-Møller, R. Thomas, J.B. Nielsen, J. Lundbye-Jensen
BackgroundA session of motor skill learning is accompanied by transient increases in corticospinal excitability(CSE), which are thought to reflect acute changes in neuronal connectivity associated with improvements in sensorimotor performance. Factors influencing changes in excitability and motor skill with continued practice remain however to be elucidated.Objective/HypothesisHere we investigate the hypothesis that progressive motor practice during consecutive days can induce repeated transient increases in corticospinal excitability and promote motor skill learning.MethodsChanges in motor performance and CSE were assessed during 4 consecutive days of skill learning and 8 days after the last practice session. CSE was assessed as area under recruitment curves(RC) using transcranial magnetic stimulation(TMS). Two groups of participants(n = 12) practiced a visuomotor tracking-task with task difficulty progressively increased with individual proficiency(PPG) or with the same task level throughout all 4 days(NPPG).ResultsProgressive practice resulted in superior motor learning compared to NPPG(p < 0.001). Whereas NPPG displayed increased CSE following only the first day of practice(p < 0.001), progressive motor practice was accompanied by increases in CSE on both the first and the final session of motor practice(p = 0.006). Eight days after ended practice, the groups showed similar CSE, but PPG maintained superior performance at a skilled task level and transfer task performance(p < 0.005,p = 0.029).ConclusionThe results demonstrate that progressive practice promotes both motor learning and repeated increases in CSE across multiple days. While changes in CSE did not relate to learning our results suggest that they signify successful training. Progressive practice is thus important for optimizing neurorehabilitation and motor practice protocols in general.
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Ohrmuschelplastik der Dysplasie Grad I
Laryngo-Rhino-Otol 2017; 96: 797-807
DOI: 10.1055/s-0043-119044
Die Korrektur der Ohrmuscheldysplasie Grad I gehört zu den häufigsten ästhetischen Eingriffen im HNO-Gebiet. In den allermeisten Fällen liegt eine komplexe Pathologie von Anthelix, Cavum conchae und/oder Lobulus vor. Der Operateur muss deshalb nach einer genauen Analyse der Pathologie aus den verschiedenen Korrekturmöglichkeiten nach dem „Baukastenprinzip" die für das spezielle Problem geeignetsten Operationstechniken auswählen können.
[...]
Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Nasenmuscheloperation: Welche olfaktorischen Leistungen werden eingeschränkt
Laryngo-Rhino-Otol 2017; 96: 753-754
DOI: 10.1055/s-0043-119601
Konstantinidis I et al. Intranasal trigeminal function in patients with empty nose syndrome. Laryngoscope 2017;127: 1263–1267 Das trigeminale System vermittelt die Wahrnehmung des nasalen Luftflusses. Eine griechische Arbeitsgruppe hat nun in einer Studie untersucht, inwieweit bei „Syndrom der leeren Nase"-Patienten (Empty Nose Syndrome, ENS) die geschädigte intranasale Trigeminusfunktion Teil einer paradoxen Nasenatmungsbehinderung ist.
[...]
Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Ungewöhnlicher Verlauf eines stumpfen Traumas der Halsregion im Rahmen eines Sportunfalles
Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-119757
Georg Thieme Verlag KG Stuttgart · New York
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Narrow Band Imaging (NBI) zur Früherkennung von Zweitkarzinomen
Laryngo-Rhino-Otol 2017; 96: 754-755
DOI: 10.1055/s-0043-119566
Tirelli G et al. Follow-up of oral and oropharyngeal cancer using narrow-band imaging and high-definition television with rigid endoscope to obtain an early diagnosis of second primary tumors: a prospective study. Eur Arch Otorhinolaryngol 2017; 274: 2529–2536 Italienische Wissenschaftler testeten, inwieweit nach einer Behandlung von oralen Karzinomen und Tumoren des Oropharynx mit einer starren Endoskopie mit NBI-Licht Zweittumore oder lokale Rezidive besser detektierbar sind als mit Weißlicht-Endoskopie (WLE). Darüber hinaus untersuchten sie inwieweit vorherige Radiotherapie, Läsionsseite und Lernkurve die NBI-Leistung zur Detektion mukosaler Gefäßveränderungen tangiert.
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Georg Thieme Verlag KG Stuttgart · New York
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Idiopathische subglottische Stenose: Rezidivwahrscheinlichkeit unverändert
Laryngo-Rhino-Otol 2017; 96: 755-756
DOI: 10.1055/s-0043-119935
Aarnæs MT et al. Idiopathic subglottic stenosis: an epidemiological single-center study. Eur Arch Otorhinolaryngol 2017; 274: 2225–2228 Wissenschaftler der HNO-Klinik der Universität Oslo untersuchten Inzidenz, Management und Behandlungsergebnisse der idiopathischen subglottischen Stenose.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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Aus der Gutachtenpraxis: Die Begutachtung der Facialisparese in der österreichischen privaten Unfallversicherung
Laryngo-Rhino-Otol 2017; 96: 792-796
DOI: 10.1055/s-0043-119592
Georg Thieme Verlag KG Stuttgart · New York
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Koniotomie
Laryngo-Rhino-Otol 2017; 96: 757-758
DOI: 10.1055/s-0043-119561
Georg Thieme Verlag KG Stuttgart · New York
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Fragen für die Facharztprüfung
Laryngo-Rhino-Otol 2017; 96: 808-809
DOI: 10.1055/s-0043-119804
Georg Thieme Verlag KG Stuttgart · New York
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Hörverlust und Sprachverstehen im Alter
Laryngo-Rhino-Otol 2017; 96: 759-764
DOI: 10.1055/s-0043-119388
Das Verstehen von Sprache bei Hintergrundgeräuschen bereitet vielen älteren Menschen Probleme. In der klinischen Praxis wird diese Qualität des Hörvermögens durch Sprachtests im Störgeräusch untersucht. Die Studie HÖRSTAT setzte den Göttinger Satztest (GÖSA) im Störgeräusch zusätzlich zur Tonaudiometrie und einer Befragung bei einer Zufallsstichprobe aus der Allgemeinbevölkerung ein. Wie erwartet nahm der Anteil Schwerhörender ab ca. 60 Jahren stark zu. Bei Ausschluss sehr hoher Hörverluste waren im Alter von 60–85 Jahren jedoch 68 % von 553 Probanden nach dem WHO-Kriterium als normalhörend einzustufen. Von diesen erreichte im GÖSA allerdings nur jeder Dritte annähernd das Sprachverstehen im Störgeräusch junger Normalhörender. Die Selbsteinschätzung des Hörvermögens folgte dabei nur eingeschränkt der messbaren Verschlechterung. Ab einem Alter von ca. 70 Jahren wurden die eigenen Hör-Fähigkeiten eher über- und die Defizite unterschätzt.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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Kommentar der Schriftleitung
Laryngo-Rhino-Otol 2017; 96: 750-751
DOI: 10.1055/s-0043-122090
Georg Thieme Verlag KG Stuttgart · New York
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Automated quantification of steatosis: agreement with stereological point counting
Steatosis is routinely assessed histologically in clinical practice and research. Automated image analysis can reduce the effort of quantifying steatosis. Since reproducibility is essential for practical use, ...
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Tablet-based sublingual immunotherapy for respiratory allergy
Publication date: Available online 13 November 2017
Source:Allergologia et Immunopathologia
Author(s): L. Prieto
Allergic respiratory disease represents a significant and expanding health problem worldwide. The gold standard of therapeutic intervention is still grucocorticosteroids, although they are not effective in all patients and may cause side effects. Allergen Immunotherapy has been administrated as subcutaneous injections for treatment of allergic rhinoconjunctivitis and asthma and has been practiced for the past century. Sublingual immunotherapy (SLIT) tablets are now available for grass- or ragweed-induced rhinoconjunctivitis and will be available in Spain for house dust mite (HDM)-induced rhinoconjunctivitis and asthma in the next months. In this review, new developments in the field of tablet-based SLIT for respiratory allergy are summarized, with special emphasis on HDM-induced allergic rhinitis and asthma. SLIT tablets are the best-documented immunotherapy products on the market and represent a more patient-friendly concept because they can be self-administrated at home.
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The effect of reducing EEG electrode number on the visual interpretation of the human expert for neonatal seizure detection
Optimising neuro-critical care in the newborn has become a high priority issue in paediatrics (Abend et al. 2011; Bonifacio et al. 2011; Glass et al. 2016). One of the key challenges in neuro-critical care is to provide brain monitoring that is continuous and uninterrupted in settings where personnel are changing constantly, neurophysiological support is limited, and an array of other medical devices are competing for cotside attention and placements. These practical considerations have led neonatologists to use a biparietal (P3-P4), or more recently, a two-channel (centro/fronto-parietal) derivation, to provide a measurement of neurological function (van Rooij et al.
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Roles of Fibroblast Activation Protein and Hepatocyte Growth Factor Expressions in Angiogenesis and Metastasis of Gastric Cancer
Abstract
This study aims to explore the roles of fibroblast activation protein (FAP) and hepatocyte growth factor (HGF) expressions in the angiogenesis and metastasis of gastric cancer (GC). From May 2012 to December 2015, 110 GC patients who received surgical treatment in the First Hospital of Qinhuangdao were selected. The HGF and FAP expressions in 110 cases of GC, 130 cases of normal gastric mucosa and 115 cases of gastric ulcer were detected by streptavidin-perosidase (SP) method. Venous blood HGF level of GC patients was tested by enzyme-linked immunosorbent assay (ELISA). The micro-vessel number of the patients in the three groups were calculated and analyzed. In GC group, positive expression rates of FAP and HGF protein were 61.8% and 67.3% respectively, which were both higher than those in normal gastric mucosa and gastric ulcer groups. The micro-vessel numbers in patients of the normal gastric mucosa and gastric ulcer groups are far less than that in GC group. FAP, HGF and micro-vessel density (MVD) were significantly correlated with infiltration depth, tumor-node-metastasis (TNM) staging, lymph node metastasis (LNM) and distant metastasis. The results of ELISA showed that serum HGF level was related to tumor size, infiltration degree, TNM staging, LNM and distant metastasis. FAP and HGF expressions in GC were positively correlated with MVD, and the expressions of FAP and HGF in GC were in positive correlation. Our study provided evidence that high FAP and HGF expressions may be positively correlated with the angiogenesis and metastasis of GC.
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The association between sleep disturbances of children with anxiety disorders and those of their mothers
Previous research has demonstrated a link between childhood anxiety and sleep problems, but little is known about the link between these difficulties and parental sleep disturbances. The purpose of the current study was to explore the association between anxious children's sleep difficulties and those of their mothers.
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Night-waking and behavior in preschoolers: A developmental trajectory approach
The aim was to study, with a developmental approach, the longitudinal association between night-waking from age 2 to 5–6 years and behavior at age 5–6 years.
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Soft palate reconstruction after radionecrosis: Combined anterolateral thigh adipofascial and nasoseptal flaps
Although radiation-based treatment for nasopharyngeal cancer may achieve excellent long term oncologic results, late effects of therapy may lead to soft tissue radionecrosis and velopharyngeal insufficiency (VPI). Repair of these oro- and nasopharyngeal defects presents a complex reconstructive challenge. We present a case of a long-term survivor treated with chemoradiotherapy for nasopharyngeal cancer who developed progressive dysphagia, velopharyngeal insufficiency, and radionecrosis of the nasopharynx and soft palate, leading to tracheostomy and gastrostomy tube dependence.
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Effect of implant loading protocols on failure and marginal bone loss with unsplinted two-implant-supported mandibular overdentures: systematic review and meta-analysis
The aim of this study was to compare implant failure and radiographic bone level changes with different loading protocols for unsplinted two-implant-supported mandibular overdentures. An electronic search of two databases (PubMed, Cochrane Library) was performed, without language restriction, to identify randomized controlled trials (RCTs) comparing immediate or early versus conventional dental implant loading protocols for unsplinted two-implant-supported mandibular overdentures. Data were extracted independently by two reviewers.
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Correlation between intraoperative proximal segment rotation and post-sagittal split ramus osteotomy relapse: a three-dimensional cone beam computed tomography study
This study evaluated the effects of proximal segment rotation and the extent of mandibular setback on post-sagittal split ramus osteotomy (SSRO) relapse using three-dimensional (3D) analysis. Thirty-one patients diagnosed with a skeletal class III malocclusion who underwent SSRO alone were enrolled in this study. The movements of the mandibular condyles were assessed using cone beam computed tomography (CBCT) and a 3D imaging program at ≤1 month before the operation (T0), 1 week after the operation (T1), and 6 months (T2) and 1year (T3) postoperative.
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Unusual iliac crest stress fracture in a marathoner: A Case Report
This case presentation describes a 50-year-old healthy woman who developed left sided hip pain while training for the Boston Marathon. Magnetic Resonance Imaging (MRI) demonstrates a stress fracture of the left iliac body. This injury is unique in that it did not occur in the setting of low bone mineral density and it does not fall into the current published radiographic categorization based on location of injury. This case illustrates an uncommon and atypical bone stress injury in an endurance athlete.
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Perspective taking and theory of mind in hide and seek
Abstract
Does theory of mind play a significant role in where people choose to hide an item or where they search for an item that has been hidden? Adapting Anderson's "Hide-Find Paradigm" Anderson et al. (Action, Perception and Performance, 76, 907–913, 2014) participants viewed homogenous or popout visual arrays on a touchscreen table. Their task was to indicate where in the array they would hide an item, or to search for an item that had been hidden, by either a friend or a foe. Critically, participants believed that their sitting location at the touchtable was the same as—or opposite to—their partner's location. Replicating Anderson et al., participants tended to (1) select items nearer to themselves on homogenous displays, and this bias was stronger for a friend than foe; and (2) select popout items, and again, more for a friend than foe. These biases were observed only when participants believed that they shared the same physical perspective as their partner. Collectively, the data indicate that theory of mind plays a significant role in hiding and finding, and demonstrate that the hide-find paradigm is a powerful tool for investigating theory of mind in adults.
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Comparing speech and nonspeech context effects across timescales in coarticulatory contexts
Abstract
Context effects are ubiquitous in speech perception and reflect the ability of human listeners to successfully perceive highly variable speech signals. In the study of how listeners compensate for coarticulatory variability, past studies have used similar effects speech and tone analogues of speech as strong support for speech-neutral, general auditory mechanisms for compensation for coarticulation. In this manuscript, we revisit compensation for coarticulation by replacing standard button-press responses with mouse-tracking responses and examining both standard geometric measures of uncertainty as well as newer information-theoretic measures that separate fast from slow mouse movements. We found that when our analyses were restricted to end-state responses, tones and speech contexts appeared to produce similar effects. However, a more detailed time-course analysis revealed systematic differences between speech and tone contexts such that listeners' responses to speech contexts, but not to tone contexts, changed across the experimental session. Analyses of the time course of effects within trials using mouse tracking indicated that speech contexts elicited fewer x-position flips but more area under the curve (AUC) and maximum deviation (MD), and they did so in the slower portions of mouse-tracking movements. Our results indicate critical differences between the time course of speech and nonspeech context effects and that general auditory explanations, motivated by their apparent similarity, be reexamined.
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Acoustic Analysis of Soccer Fans in Acute Phonotrauma After the Match
Acute phonotrauma is the result of sound production by shouting or straining one's voice. In this study, we aimed to investigate the acute changes in the vocal folds and voices of soccer fans who voluntarily applied to our clinic after the soccer match where they engaged in acute phonotrauma. There are no other studies in the literature conducted on a similar sample group.
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Editorial Board
Source:Practical Radiation Oncology, Volume 7, Issue 6
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Table of Contents
Source:Practical Radiation Oncology, Volume 7, Issue 6
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Prophylactic rtPA in the Prevention of Line-associated Thrombosis and Infection in Short Bowel Syndrome.
Background: Central venous access devices (CVADs) are essential for total parenteral nutrition administration in patients with short bowel syndrome (SBS). However, they are fraught with complications including infection and venous thromboembolism (VTE), which increases associated morbidity and mortality in this population. There is evidence linking the development of CVAD-associated thrombosis and line-related infection. Thus, it has been postulated that prevention of catheter-related clot formation could minimize the risk of infection originating from the catheter. Recombinant tissue plasminogen activator (rtPA, AlteplaseTM), lyses clots by binding plasmin-bound fibrin in a clot and cleaving plasminogen to plasmin; moreover, it is widely utilized to clear occluded CVADs. Methods: Prophylactic rtPA lock therapy in children with SBS was evaluated as a single site pilot study to minimize line-associated-VTE, infection, need for line replacement and hospitalization at the Children's Hospital of Pittsburgh of UPMC. rtPA lock therapy was administered by parents/caregivers on a weekly basis over a 6-month time period in place of heparin lock therapy. Comparisons were made between line-associated complications in the cohort in the 6 months prior to study versus during the study period. Results: Six out of eight subjects completed the study over a one-year time period. As a group, subjects experienced a significant decrease in the number of line-associated bloodstream infections from a mean of 1.9 infections in the 6 months prior to the study to a mean of 0.5 infections (p = 0.025). There was no change in the need for line replacement amongst subjects while on study. The primary outcome of VTE was not found in the cohort, and it is unclear whether rtPA lock therapy contributed to the lack of thrombosis development. Given the success of rtPA in this pilot study in reducing bloodstream infections, further investigation or rtPA lock therapy in SBS patients is warranted. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
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Expediting Drug Development for Pediatric Inflammatory Bowel Disease: A Discussion with Stakeholders.
Objectives: Lack of scientific consensus on efficacy endpoints and outcome assessments presents a hurdle for global drug development in pediatric inflammatory bowel disease (IBD). Multiple stakeholders participated in a meeting November 2015, sponsored by The Pediatric IBD Foundation, which is a 501c3 organization formed by parents of children with IBD whose mission is to improve the lives of children with Crohn's disease and ulcerative colitis by supporting innovative research and educational programs ( www.pedsibd.org). Wth representatives of the Federal Drug Administration (FDA), European Medicines Agency (EMA), pediatric gastroenterologists, and representatives of the pharmaceutical industry, this meeting was organized to harmonize present thinking about various aspects of global drug development in pediatric IBD. The meeting was designed to be interactive, allowing participants from the pharmaceutical industry, regulatory agencies, academia and clinical practice an opportunity to collaborate in a public forum and to identify potential strategies to expedite drug evaluation in children. Methods: Prior to the meeting, a questionnaire focused on the hurdles hindering approval of medications used to treat children with IBD was sent to all participants as well as other pediatric gastroenterologists in North America and Europe with expertise in IBD. Responses were reviewed by the steering committee and results presented at the meeting. Following the presentation of the survey, participants were divided into small groups comprised of representatives from academia, industry, regulatory agencies, and members of the Pediatric IBD Foundation and assigned the task of working together to find solutions to the hurdles that had been identified. Results: Hurdles hindering approval included: (i) pediatric trials start later in the development process; (ii) lack of enrollment in pediatric trials; (iii) lack of monitoring safety registries that might expedite approval; (iv) different priorities among stakeholders. Conclusions: This one-day meeting discussed how to expedite pediatric drug development in IBD therapy. Hurdles for achieving approvals of pediatric indications for treatments of IBD were identified. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
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Avoiding Small Intestinal Biopsies for Diagnosis of Celiac Disease in Children: A Reliable Strategy for All Patients?.
Background: Current reports applying ESPGHAN exception criteria (EEC) to diagnose celiac disease (CD) without duodenal biopsies indicate that a high percentage of patients with CD may be identified when applied correctly in specialized settings. However, application of the EEC in "daily life conditions" at the different levels of medical services is not clear. Methods: EEC was applied to 130 pediatric patients evaluated for CD at five public hospitals in Santiago, Chile, during 2010-2015. Clinical presentation, serum anti-tissue transglutaminase 2 (TTG) and anti-endomysium antibodies (EMA), genotyping and small intestinal histology were obtained from clinical charts. Results: 78/130 patients reviewed had some of the data required for analysis, but EMA was determined in 54% and genotyping in 2.3% of patients, limiting the study. After offering free genotyping, only 12/78 (15%) had all data required for EEC application. In this small group, 10/12 (83.3%) patients could avoid duodenal biopsies and two (16.7%) with potential CD were misdiagnosed. Main reasons for not doing EMA and genotyping were that they are expensive, unavailable in the local health-care center and considered "not necessary" for diagnosis. Conclusion: Limited resources in clinical settings reduce availability of EMA and genotyping, making application of EEC criteria difficult and only possible only in 15% of our patients. Within this subgroup, biopsies could be avoided in 83.3%, and 16.7% of patients with potential CD were misdiagnosed. Insufficient studies and incorrect interpretation of EEC contributed to incomplete assessment in 52/130 (40%) patients. The Chilean public health system is likely representative of several others present in developing and developed countries. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
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Compliance With Fecal Calprotectin Testing in Pediatric Inflammatory Bowel Disease Patients.
Fecal calprotectin (FC) is a highly sensitive biomarker for inflammatory bowel diseases (IBDs). Utilization of this assay has been steadily increasing. However, adherence levels for FC have yet to be examined in the pediatric IBD setting. We analyzed 100 consecutive patients diagnosed with IBD between 2014 and 2015 at Texas Children's Hospital. Fifty-six percent of patients were male and median age at diagnosis was 13.7 years. Following diagnosis of IBD, 84 patients had a minimum of one FC requested, and 95.2% of these patients completed the test at least once. An average of two FCs per patient were ordered each year, and the overall compliance was 76.6%. Patients who completed the initial testing with a minimum of three consecutive tests were more likely to remain compliant than those who failed to perform the first lab (p
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Premature Infants have Lower Gastric Digestion Capacity for Human Milk Proteins than Term Infants.
Objectives: Whether premature infants have lower gastric protein digestive capacity than term infants and the extent to which human milk proteases contribute to overall gastric digestion are unknown and were investigated in this study. Methods: Human milk and infant gastric samples were collected from 16 preterm (24-32 wk gestational age (GA)) and 6 term (38-40 wk GA) mother-infant pairs within a range of 5-42 days postnatal age. For each pair, an aliquot of human milk was adjusted to pH 4.5 and incubated for 2 h at 37 [degrees]C to simulate the gastric conditions without pepsin (milkinc). Their gastric protein digestion capacity was measured as proteolysis (free N-terminals) and protease activities. Two-way ANOVA followed by Tukey's post hoc test were applied to compare measurements between preterm and term infants as well as among human milk, milkinc and gastric samples. Results: Measurements of gastric protein digestion were significantly lower in preterm infants than term infants. Overall milk protease activity did not differ between human milk samples from term- and preterm-delivering mothers. As protease activity did not increase with simulated gastric incubation, milk proteases likely contributed minimally to gastric digestion. Conclusions: Preterm infants have lower gastric protein digestion capacity than term infants, which could impair nutrient acquisition. Human milk proteases contribute minimally to overall gastric digestion. The limited activity of milk proteases suggests that these enzymes cannot compensate for the premature infant's overall lower gastric protein digestion. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
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The Changing Face of Pediatric Ulcerative Colitis: A Population-based Cohort Study.
Objectives: The aims of this retrospective study were to describe ulcerative colitis (UC) phenotype at diagnosis and follow-up and to identify possible predictors of severe disease course. Methods: This was a retrospective, single-center study. We reviewed the charts of patients with UC diagnosed between 2 and 18 years at our referral center from January 2007 to January 2016. Laboratory and clinical features at diagnosis, such as disease extent, atypical phenotypes, extraintestinal manifestations, and therapies, and pattern changes during the follow-up, including relapse rate, disease extension, and the cumulative risk for colectomy were collected. Results: One hundred eleven patients were identified. Atypical phenotypes were identified at diagnosis in 55 out of 111 patients (49.5%). Extraintestinal manifestations were detected in 16 out of 111 (14.4%) at the diagnosis. During the follow-up 60 out of 111 (54%) patients needed to start azathioprine, 9 out of 111 (8.1%) patients started biologic therapy and 10 out of 111 (patients underwent surgery, resulting in a cumulative risk of 8% at 5 years and 16% at 10 years. Steroid refractoriness (hazard ratio: 13.9) and starting of biologic therapy (hazard ratio: 25.3) represented the best predictors for surgery. The cumulative probability of first relapse was 47% at 6 months and 63% at 1 year. Disease extension was reported in 21 out of 70 patients (30%). Conclusion: Pediatric UC is associated with a severe phenotype and a high percentage of atypical features. Surgery rate seems to be decreased from early reports. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
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Shortened 8 Weeks Course of Dual Sofosbuvir/Daclatasvir Therapy in Adolescent Patients, with Chronic Hepatitis C Infection.
Recently, sofosbuvir and the fixed dose combination of sofosbuvir/ ledipasvir were approved for the treatment of chronic hepatitis C virus infection (HCV) in adolescents, 12 years old and above or weighing at least 35 kilograms. Here we present the results of a pilot single cohort of 10 consecutive adolescent patients with chronic HCV and treated with dual sofosbuvir/daclatasvir (SOF/DCV) therapy for a response-tailored duration of 8 weeks for those who achieved very rapid virologic response (vRVR) and 12 weeks for those who did not. All patients achieved vRVR at week 2 and completed the shortened 8 weeks course. All patients (10/10 (100% (CI: 72.25-100%)) achieved sustained virologic response at week 12 post-treatment (SVR12) with good tolerability and no serious adverse events. This data could provide support to our suggested response-tailored protocol of dual therapy with SOF/DCV in adolescents particularly for shortened duration in those who achieved vRVR. Further larger randomized controlled studies are recommended. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
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A Pilot Study Measuring The Novel Satiety Hormone, Pro-Uroguanylin, In Adolescents With And Without Obesity.
Objective: Disruption of satiety signaling may lead to increased caloric intake and obesity. Uroguanylin, the intestinal hormone, travels as a precursor to the central nervous system where it activates guanylyl cyclase C (GUCY2C) and stimulates pro-satiety neurons. Rodent studies have demonstrated that (1) GUCY2C-knockout mice over-eat and have increased weight gain vs. wild-type mice; and (2) hyper-caloric obesity diminishes uroguanylin expression. We measured circulating plasma pro-uroguanylin, along with other gastrointestinal peptides and inflammatory markers, in human adolescents with and without obesity, as a pilot study. We hypothesized that adolescents with obesity would have less circulating pro-uroguanylin than adolescents without obesity have. Methods: We recruited 24 adolescents (age 14-17) with and without obesity (BMI >95% or BMI
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Early motor function after local treatment of brain metastases in the motor cortex region with stereotactic radiotherapy/radiosurgery or microsurgical resection: a retrospective study of two consecutive cohorts
We compared the functional outcome and influential factors of two standard treatment modalities for central cerebral metastases: electrophysiological-controlled microsurgical resection (MSR) and stereotactic r...
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Classification of sleep and wake using a novel minimal-contact single-channel device
Abstract
Background
Polysomnography (PSG) is the gold standard for sleep analysis and the diagnosis of sleep-disordered breathing (SDB). As PSG is time-consuming and labor-intensive, it is the last step in a stepwise diagnostic workup. An early preliminary diagnosis can be obtained by a novel single-channel minimal-contact device which is placed under the patient's mattress topper.
Objectives
This study assessed the diagnostic accuracy of the novel minimal-contact device VitaLog (SWG Sportwerk GmbH & Co. KG, Dortmund, Germany) for sleep–wake classification and measurement of heart rate (HR). The results were compared to PSG.
Materials and methods
VitaLog is a minimal-contact sensor that does not restrict sleep. The diagnostic accuracy of VitaLog was studied in 49 patients referred to our sleep research unit due to suspected SBD. Results obtained by VitaLog were compared to those of a simultaneous PSG to assess the diagnostic accuracy of VitaLog for sleep–wake classification and measurement of HR.
Results
Compared to PSG, the accuracy of HR determined by VitaLog was excellent (r = 0.99) with a bias of 0.15 beats per min (bpm). Regarding total sleep time (TST), we found a good correlation of r = 0.8 and a bias of 14 min. For sleep efficiency (SE) estimated by VitaLog, the correlation was moderate with r = 0.6 with a bias of 4.0%. Sleep latency (SL) and wake after sleep onset (WASO) were underestimated by 1 and 12 min, respectively.
Conclusions
VitaLog is a promising approach for the estimation of the sleep-related parameters TST, SE, SL, and WASO based on a minimal-contact sensor. In addition, it measures HR with excellent accuracy. However, algorithm modifications are desired to provide appropriate diagnostic accuracy in all sleep disorder cohorts.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yXR3Sh
Exemplar Variability Facilitates Retention of Word Learning by Children With Specific Language Impairment
Purpose
Variability in the input plays an important role in language learning. The current study examined the role of object variability for new word learning by preschoolers with specific language impairment (SLI). Method
Eighteen 4- and 5-year-old children with SLI were taught 8 new words in 3 short activities over the course of 3 sessions. Half of the children saw 3 identical objects corresponding to each new word during training (No Variability group); the other half of the children saw 3 different objects corresponding to each new word during training (High Variability group). Children completed vocabulary learning tests for objects seen during training and for new within-category objects that were never seen during training as a test of category generalization. Learning was assessed the day after each training activity, and retention was assessed 3 weeks after the last training session. Results
There were no group differences on trained or generalization items immediately following training sessions. However, children in the High Variability group demonstrated significantly better retention 3 weeks after experimental training. Conclusion
These findings demonstrate that object variability facilitates retention of new word learning by children with SLI. Supplemental Material
http://ift.tt/2hwPDGPfrom #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://article/doi/10.1044/2017_LSHSS-17-0031/2663823/Exemplar-Variability-Facilitates-Retention-of-Word
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