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).


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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.


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.


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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.


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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.


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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.


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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.


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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.


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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.


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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.


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.


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.


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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.


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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.


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.


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Novel topical agent containing superoxide dismutase 100 000 IU and 4% of plant extracts as a mono-therapy for atopic dermatitis

Abstract

Introduction

Corticosteroids are the mainstay of treatment for the acute phase of atopic dermatitis (AD), whereas topical emollients are mainly used for maintenance of remission. A topical agent that combines emollient and anti-inflammatory properties would achieve control of all phases of AD, without the need for chronic corticosteroid use.

Aim

To assess the efficacy of a novel topical agent containing superoxide dismutase (SOD) 100 000 IU and 4% of a combination of plant extracts (blackcurrant seed oil, sunflower oil concentrate, balloon vine extract).

Methods

Twenty patients (age range from 8 months to 72 years old) with mild-to-moderate atopic dermatitis were assessed. The product was used as mono-therapy, applied to the affected skin areas twice daily. Patients were evaluated before and after a 30-day course using the SCORAD and the Visual Analog Scale for assessment of pruritus intensity. Primary endpoint was improvement of AD according to SCORAD and clinical assessment. Secondary endpoint was patient satisfaction and improvement of pruritus.

Results

Mean SCORAD on day 0 was 32.61(range = 16.0-46.9) and decreased to 10.55 (range = 0-17.0) on day 30, reflecting a reduction of 67.6%. On day 30, all patients described significant improvement in pruritus and quality of sleep.

Conclusion

The application of the study product cream resulted in significant improvement of AD, as reflected by the objective SCORAD measurement, and the subjective assessment of pruritus and quality of life. This novel anti-inflammatory emollient product may emerge as a safe and effective therapeutic tool for all phases of AD without the adverse effects of chronic use of corticosteroids.

http://ift.tt/2z0A95g

Controversies and recommendations regarding sentinel lymph node biopsy in primary breast cancer: a comprehensive review of current data

Publication date: Available online 13 November 2017
Source:European Journal of Surgical Oncology
Author(s): Petros Charalampoudis, Christos Markopoulos, Tibor Kovacs
In primary breast cancer, sentinel lymph node biopsy has been established as the gold standard for regional axillary staging. A robust body of randomized data support its accuracy and safety in patients with early, clinically node negative disease. However, the role of SLNB remains debatable in various patient subgroups, and recent advances in histopathology, dedicated axillary ultrasound imaging and chemotherapy regimens, put its role under a new perspective. Herein, we review the current literature data on the indications for SLNB and discuss the challenges in management germane to special patient subgroups and patterns of disease. We also present emerging data on the optimal management of the SLN+ patient, in light of recent trials challenging the dogma of completion axillary dissection after a positive sentinel node biopsy.



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Management of benign papilloma without atypia diagnosed at ultrasound-guided core needle biopsy: Scoring system for predicting malignancy

Publication date: Available online 13 November 2017
Source:European Journal of Surgical Oncology
Author(s): Soo kyung Ahn, Wonshik Han, Hyeong-Gon Moon, Min Kyoon Kim, Dong-Young Noh, Bong-wha Jung, Sung-Won Kim, M.D. Eunyoung ko
BackgroundThe management of benign intraductal papilloma diagnosed on core needle biopsy (CNB) remains unclear. This study was designed to evaluate factors predicting malignancy in patients diagnosed with benign papilloma without atypia at ultrasound-guided CNB and to develop a scoring system predicting malignancy based on clinical, radiological and pathological factors on further excisional biopsy.MethodsThe study enrolled patients diagnosed with benign papillomas (including benign and atypical papillary lesions) at CNB. Multivariate analysis was used to identify relevant clinical, radiological and pathological factors that may predict malignancy.ResultsA total of 520 CNBs were diagnosed with benign or atypical papilloma. Of these, 452 were benign papilloma without atypia. Of the 250 lesions subsequently excised surgically from 234 women, 17 (6.8%) were diagnosed with malignancy. Multivariate analysis revealed that bloody nipple discharge, size on imaging ≥15 mm, BI-RADS≥4b, peripheral location and palpability were independent predictors of malignancy. A scoring system was developed based on logistic regression models and beta coefficients for each variable. The area under the ROC curve was 0.947 (95% CI: 0.913–0.981, p<0.001) and a negative predictive value was100%. In a validation set of 62 patients, an area under the ROC curve was 0.926 (95% CI: 0.857–0.995, p<0.001).ConclusionsA scoring system predicting malignancy in patients diagnosed by CNB with benign papilloma without atypia was developed.This system was able to identify a subset of patients with lesions likely to be benign, indicating that imaging follow-up rather than surgical excision may be appropriate.



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Exome sequencing of synchronously resected primary colorectal tumours and colorectal liver metastases to inform oncosurgical management

Publication date: Available online 13 November 2017
Source:European Journal of Surgical Oncology
Author(s): P.A. Sutton, P.V. Jithesh, R.P. Jones, J.P. Evans, D. Vimalachandran, H.Z. Malik, B.K. Park, C.E. Goldring, D.H. Palmer, N.R. Kitteringham
BackgroundNext generation sequencing technology has facilitated mapping of the colorectal cancer genotype and furthered our understanding of metastogenesis. The aim of this study was to investigate for conserved and different mutations in the exomes of synchronously resected primary colorectal tumour and liver metastases. This information could potentially be utilised to guide the treatment of advanced disease with the help of biological information from the primary tumour.MethodsWe performed exome sequencing of synchronously resected primary colorectal cancer and colorectal liver metastases as well as normal colonic mucosa and liver parenchyma, from four patients who had received neo-adjuvant chemotherapy, at a depth of 50X using the Ion Proton platform. Raw data was mapped to the reference genome prior to variant calling, annotation and downstream analysis.ResultsExome sequencing identified 585 non-synonymous missense single nucleotide variants (SNVs), of which 215 (36.8%) were unique to the primary tumour, 226 (38.6%) unique to the metastasis and 81 (13.8%) present in patient matched pairs. SNVs identified in the ErbB pathway appear to be concordant between primary and metastatic tumours.ConclusionOnly 13.8% of the metastatic exome can be predicted by the genotype of the primary tumour. We have demonstrated concordance of a number of SNVs in the ErbB pathway, which may inform selection of therapeutic agents in advanced colorectal cancer.



http://ift.tt/2jpAo38

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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Influence of post-stroke spasticity on EMG-force coupling and force steadiness in biceps brachii

Publication date: Available online 13 November 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Jennilee K. Carlyle, George Mochizuki
BackgroundIndividuals with spasticity after stroke experience a decrease in force steadiness which can impact function. Alterations in the strength of EMG-force coupling may contribute to the reduction in force steadiness observed in spasticity. The aim was to determine the extent to which force steadiness and EMG-force coupling is affected by post-stroke spasticity.MethodsThis cross-sectional study involved individuals with upper limb spasticity after stroke. Participants were required to generate and maintain isometric contractions of the elbow flexors at varying force levels. Coefficient of variation of force, absolute force, EMG-force cross-correlation function peak and peak latency was measured from both limbs with surface electromyography and isometric dynamometry.ResultsStatistically significant differences were observed between the affected and less affected limbs for all outcome measures. Significant main effects of force level were also observed. Force steadiness was not statistically significantly correlated with EMG-force coupling; however, both force steadiness and absolute force were associated with the level of impairment as measured by the Chedoke McMaster Stroke Assessment Scale.DiscussionSpasticity after stroke uncouples the relationship between EMG and force and is associated with reduced force steadiness during isometric contractions; however, these features of control are not associated in individuals with spasticity.



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In Reply

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First Prospective Multicenter Italian Study on the Impact of the 21‐Gene Recurrence Score in Adjuvant Clinical Decisions for Patients with ER Positive/HER2 Negative Breast Cancer

AbstractBackground.The Breast DX Italy prospective study evaluated the impact of the 21‐gene recurrence score (RS) result on adjuvant treatment decisions for patients with early breast cancer.Materials and Methods.Nine centers (two Hub and seven Spoke centers of the Veneto Oncology Network) participated. Consecutive patients with estrogen receptor positive, human epidermal growth receptor negative, T1–T3, N0–N1 early breast cancer were prospectively registered; only those meeting protocol‐defined clinicopathological "intermediate risk" criteria were eligible for the RS test. Pre‐RS and post‐RS physicians' treatment recommendations and treatment actually received were collected.Results.A total of n = 124 N0 and n = 126 N1 patients underwent the RS assay. The majority had Grade 2 tumors (71%); median age was 55 years, median tumor size was 16 mm, and median Ki67 expression was 20%. Patients enrolled at Hub centers presented higher‐risk features. The distribution of RS results was <18 (60.8%), 18–30 (32.4%), and >30 (6.8%). The indication before RS was hormonal therapy (HT) alone in 52% of cases. An indication before RS of chemotherapy (CT)+HT was more frequent for patients with N1 versus N0 tumors (57% vs. 39%, p = .0035) and for patients enrolled at Hub versus Spoke centers (54% vs. 36%, p = .007).The overall rate of change in treatment decision was 16% (n = 40), mostly from CT+HT to HT (n = 30). According to nodal status, rate of change in treatment decision was 12% for the N0 cohort and 20% for the N1 cohort. The proportion of patients recommended to CT+HT was significantly reduced from before to after RS (48% to 40%, p < .0016), especially in the N1 cohort (57% to 45%, p = .0027) and at Hub centers (54% to 44%, p = .001).Conclusion.Despite frequent indication of HT before RS, the use of the RS assay further contributed to sparing CT, especially for patients with N1 tumors and at Hub centers.Implications for Practice.This study shows that, although a high proportion of patients were recommended to endocrine treatment alone before knowing the recurrence score (RS) assay, the RS test further contributed in sparing chemotherapy for some of these patients, especially in case of the N1 stage or for patients enrolled at referral centers. These data highlight the need for further work in collaboration with health authorities and companies in order to define strategies for the implementation of the use of RS testing in clinical practice in the Italian setting.

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Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma

AbstractLessons Learned. Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma.Treatment of recurrent glioblastoma remains challenging as this study and others attempt to improve progression‐free survival and overall survival with BEV‐containing regimens.Background.Recurrent glioblastoma (GBM; World Health Organization grade 4) continues to have a very poor prognosis. Bevacizumab (BEV) has been shown to improve progression‐free survival (PFS) in recurrent GBM and is approved by the U.S. Food and Drug Administration for the treatment of recurrent GBM. Combination regimens have been explored, and in this phase II nonrandomized trial, we evaluated the efficacy of BEV combined with histone deacetylase inhibitor vorinostat (VOR) in recurrent GBM.Materials and Methods.In this phase II, single‐center, nonrandomized study, subjects with recurrent GBM received BEV 10 mg/kg intravenously (IV) every 2 weeks combined with VOR 400 mg p.o. daily for 7 days on, 7 days off, in a 28‐day cycle. The primary endpoint was 6‐month PFS (PFS6).Results.Forty patients with recurrent GBM were enrolled and evaluated. PFS6 was 30.0% (95% confidence interval [CI] 16.8%–44.4%). Median overall survival (OS) was 10.4 months (95% CI 7.6–12.8 months). Overall radiographic response rate was 22.5% based on 9 partial responses. The most common grade 2 and above treatment‐related adverse events were lymphopenia (55%), leukopenia (45%), neutropenia (35%), and hypertension (33%). Grade 4 adverse events were leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and venous thromboembolism (3%). Two deaths occurred in this study, with one due to tumor progression and another possibly related as death not otherwise specified.Conclusion.Combination treatment of BEV and VOR was well tolerated. This combination therapy for this study population did not improve PFS6 or median OS when compared with BEV monotherapy.

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Clinical Trials in Oncology and Defining Benefit

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Quality of Randomized Controlled Trials Reporting in the Treatment of Adult Patients with High‐Grade Gliomas

AbstractBackground.The randomized controlled trial (RCT) is the gold standard to objectively assess the effect of treatments. To help improve the quality of RCTs, experts established a list of recommendations, the CONsolidated Standards of Reporting Trials (CONSORT) Statement. In this study, we evaluated the implementation of the CONSORT Statement in the field of high‐grade gliomas in adult patients and looked for criteria associated with higher quality of RCTs.Materials and Methods.We searched all high‐grade gliomas RCTs published in PubMed between January 1990 and December 2016. The quality of these RCTs was assessed by completing a modified CONSORT Score (CS).Results.Ninety‐six published RCTs were identified. The median CS was 19.5 on a scale of 0–33. Items were not equally reported. Items regarding the method of randomization or the blinding were reported in less than 25% of RCTs. However, the CS has constantly improved over the years. Before the implementation of the CONSORT Statement in 1996, the median CS was 13, whereas it was 17 for the period 1996–2004 and 22 after 2005. A higher CS was observed when RCTs were published in a journal with an impact factor above 10 (p < .001) or after 2010 (p = .001), when the primary outcome was clearly defined (p < .001) and for RCTs that enrolled more than 200 patients (p = .004).Conclusion.Although there has been a steady improvement in the CS over the years in the field of high‐grade gliomas, a major effort must be made in the reporting methods for randomization and blinding.Implications for Practice.This study showed that the quality of reporting of randomized control trials (RCTs) concerning the treatment of high‐grade gliomas is poor. Factors associated with a better quality of reports were identified and should be incorporated into the design of future RCTs. When clinicians read the results of RCTs, they should be aware of the possible inadequate reporting from these trials and take it into account for the management of their patients. This study identifies how RCTs can be improved in their reporting but also in their design, in order to advance care for patients with high‐grade gliomas in the future.

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“Rather one more chemo than one less…”: Oncologists and Oncology Nurses’ Reasons for Aggressive Treatment of Young Adults with Advanced Cancer

AbstractBackground.Empirical research demonstrates that there is a tendency to administer tumor‐directed therapy to patients with advanced cancer close to death, especially if they are young. The aim of this qualitative study was to understand oncologists' treatment decisions and oncology nurses' perception of these decisions in young adult patients and to investigate the extent to which young age was a factor in cancer treatment decisions.Materials and Methods.We conducted 29 face‐to‐face interviews with oncologists and oncology nurses at the Department of Hematology and Oncology at the University Hospital in Munich, Germany. The interviews were analyzed according to the grounded theory approach.Results.Oncologists and nurses reported that decisions about limiting cancer treatment with young adult patients are the most challenging and stressful in clinical practice. Apart from using young age as a proxy for patient's medical fitness, oncologists' decisions in favor of more aggressive treatment of younger patients were mainly guided by ethical reasons such as patient preferences and the perceptions of injustice associated with dying at a young age, as well as by psychological reasons, such as identification and emotional entanglement.Conclusion."Struggling" together with the patient against the injustice of dying young for a longer lifetime is an important factor driving aggressive treatment in young adult patients. However, oncologists might run a risk of neglecting other ethical aspects, such as a principle of nonmaleficence, that might even result in life‐shortening adverse events.Implications for Practice.We could identify two ethical and one psychological reason for patients' overtreatment. 1) patients' preference for further treatment; 2) oncologists' perception of un‐fairness of dying young; and 3) identification and emotional entanglement with patient. Our findings emphasize the need for oncologists' awareness of the reasons guiding their treatment decisions — a sole focus on patients' preferences and on the fighting against the unfairness of dying young might lead to neglecting obligations of non‐maleficence. Self‐reflection, the balance of empathy and professional distance as well as timely end of life discussions and involvement of psycho‐oncologists are needed to care of young cancer patients.

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Rush hour at the Museum – Diversification patterns provide new clues for the success of figs (Ficus L., Moraceae)

Publication date: Available online 13 November 2017
Source:Acta Oecologica
Author(s): Sam Bruun-Lund, Brecht Verstraete, Finn Kjellberg, Nina Rønsted
Tropical rainforests harbour much of the earth's plant diversity but little is still known about how it evolved and why a small number of plant genera account for the majority. Whether this success is due to rapid turnover or constant evolution for these hyper-diverse plant genera is here tested for the species-rich genus Ficus L. (figs). The pan-tropical distribution of figs makes it an ideal study group to investigate rainforest hyper-diversification patterns. Using a recently published, dated and comprehensive phylogenetic hypothesis, we infer that figs are an old lineage that gradually accumulated species and exhibits very low extinction rates, which corresponds to the 'museum model' of evolution. Overall, no major significant shifts in evolutionary dynamics are detected, yet two shifts with lower probability are found. Hemi-epiphytism, monoecy, and active pollination are traits that possibly are associated with the hyper-diversity found in figs, making it possible for the plants to occupy new niches followed by extensive radiation over evolutionary time scales. Figs possess unique diversification patterns compared to other typical rainforest genera.



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N-Arylsulfonylsubstituted-1H indole derivatives as small molecule dual inhibitors of signal transducer and activator of transcription 3 (STAT3) and tubulin

Publication date: Available online 13 November 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Qiang Zhou, Jinjin Zhu, Jinglei Chen, Peng Ji, Chunhua Qiao
Signal transducer and activator of transcription (STAT3) is a proposed therapeutictarget for the development of anti-cancer agents. In this report, a series of N-arylsulfonylsubstituted-1H indole derivatives were designed and synthesized as STAT3 inhibitors, their anti-proliferative activities were evaluated against a number of tumor cells, some potent compounds exhibited IC50 values less than 10 μM. The most potent compound 4a was further confirmed to inhibit STAT3 phosphorylation at Tyr705. It was further revealed that 4a arrested the cell cycle at the G2/M phase and inhibited tubulin polymerization. This study describes a series of N-arylsulfonylsubstituted-1H indole derivatives as potent anti-cancer agents targeting both STAT3 and tubulin.

Graphical abstract

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Design and synthesis of highly selective pyruvate dehydrogenase complex E1 inhibitors as bactericides

Publication date: Available online 13 November 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yuan Zhou, Shasha Zhang, Hongwu He, Wen Jiang, Leifeng Hou, Dan Xie, Meng Cai, Hao Peng, Lingling Feng
In order to obtain PDHc-E1 inhibitors with high selectivity and efficacy, four series (7, 12, 15, and 19) of 35 novel 4-aminopyrimidine derivatives were rationally designed and synthesized based on the binding site of ThDP in E. coli PDHc-E1. 12, 15, and 19 were confirmed to be potent inhibitors against E. coli PDHc-E1. Selected compounds 12g, 12i, 15f, and 19a showed negligible inhibition against porcine PDHc-E1. To understand their selectivity, the interaction of inhibitor and E. coli PDHc-E1 or porcine PDHc-E1 was studied by molecular docking. The newly introduced acylhydrazone and N-phenylbenzamide moieties could form stronger interaction by hydrogen bond at the active site of E. coli PDHc-E1 compared with that of porcine PDHc-E1. A part of title compounds as potent PDHc-E1 inhibitors also exhibited notable antibacterial activity. In particular, 12e, 12f, 12g, 12o, and 19a exhibited 72-92% inhibition against Xanthomonas oryzae pv. Oryzae and Ralstonia solanacearum at 100 μg/mL, which was better than thiodiazole-copper (34 and 29%, respectively) and bismerthiazol (56 and 55%, respectively). The results proved that we could obtain effective bactericidal compounds as highly selective PDHc inhibitors by rational molecular design utilizing the binding model of active site of E. coli PDHc-E1.

Graphical abstract

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Analysis of the influence of collagen fibres in the dermis on skin optical reflectance by Monte Carlo simulation in a nine-layered skin model

Abstract

Background

Collagen fibres in the dermis play an important structural role in the skin. Age-related changes to these fibres cause wrinkles and slackness of facial skin. However, it is not clear how dermal collagen fibres affect skin colour. The purpose of this study was to clarify the influence of altered collagen fibres on skin colour, using both experimental measurement of fibre density and Monte Carlo simulations in an optical model of skin.

Methods

Reflection spectra were measured from the cheeks of 12 Japanese women (22-65 years old) by spectral colorimeter. Two-dimensional autocorrelation functions were calculated from second harmonics generation (SHG) images acquired from the same locations and used to calculate collagen density indices. Monte Carlo simulations of light reflectance by skin were performed using a nine-layered model that precisely imitates skin structure. The relationship between dermal collagen fibre density and skin reflection spectra was analysed.

Results

A positive correlation was found between collagen density and skin brightness, as measured by the colour value, L* (using the L*a*b* colour space). In addition, collagen density showed a strong inverse correlation with age and with the optical absorption of dermis. The Monte Carlo simulations showed that the reflection spectrum of skin changes when the scattering coefficient of the dermis is altered. These changes were the same for simulated and experimentally measured reflection spectra.

Conclusion

When collagen fibre density in the upper dermis is decreased with age, skin colour becomes less bright because light scattering in the skin is decreased.

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Is it better at home with my family? The effects of people and place on children's eating behavior

Publication date: 1 February 2018
Source:Appetite, Volume 121
Author(s): L. Suzanne Suggs, Sara Della Bella, Natalie Rangelov, Pedro Marques-Vidal
The people and places children eat with can influence food consumption. This study investigates the people and places Swiss school-aged children ate with over a 7-day period and analyses the effects of eating at home with family on food consumption. Children completed a 7-day food diary documenting the foods they consumed, the people with whom they ate, and the place where they ate. Analyses were conducted for all meals and included 9911 meal occasions. Most meals (80.5%) were consumed at home with family. Generalized estimating equations were used to model the effects of the home-family dyad on the child's chance of consuming a certain food while controlling for age, gender and BMI of the child, education, nationality and BMI of the parent. Compared to eating in other dyads (e.g. school-peers or restaurant-family), eating in the home-family dyad was associated with higher consumption of vegetables (+66% and +142% at weekday lunch and dinner and +180% and +67% at weekend lunch and dinner), lower consumption of sweets (−45% and −49% at weekday lunch and dinner; −43% and −49% at weekend lunch and dinner), and fewer soft drinks (−37% and −61% at weekday lunch and dinner; −66% and −78% at weekend lunch and dinner). This study shows the positive influence of eating at home with the family on food consumption in a sample of Swiss children. Interventions and policies that encourage children and parents to eat together at home could serve as effective prevention against a poor diet.



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Inflammation and Atherosclerosis: The End of a Controversy.

Author: Hansson, Goran K. MD, PhD

Page: 1875-1877

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Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above: Analyses From the WOSCOPS (West of Scotland Coronary Prevention Study) 5-Year Randomized Trial and 20-Year Observational Follow-Up.

Author: Vallejo-Vaz, Antonio J. MD, PhD; Robertson, Michele BSc; Catapano, Alberico L. PhD; Watts, Gerald F. DSc, MD, PhD; Kastelein, John J. MD, PhD; Packard, Chris J. DSc; Ford, Ian PhD; Ray, Kausik K. MD, MPhil

Page: 1878-1891

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Closing the Remaining Evidence Gap: Randomized Controlled Trial Data to Support Statin Therapy for Low-Density Lipoprotein >=190 mg/dL.

Author: Watson, Karol E. MD, PhD; Fonarow, Gregg C. MD

Page: 1892-1894

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Timing of Angiography and Outcomes in High-Risk Patients With Non-ST-Segment-Elevation Myocardial Infarction Managed Invasively: Insights From the TAO Trial (Treatment of Acute Coronary Syndrome With Otamixaban).

Author: Deharo, Pierre MD; Ducrocq, Gregory MD, PhD; Bode, Christoph MD; Cohen, Marc MD; Cuisset, Thomas MD, PhD; Mehta, Shamir R. MD; Pollack, Charles Jr MA, MD; Wiviott, Stephen D. MD; Elbez, Yedid MS; Sabatine, Marc S. MD, MPH; Steg, Philippe Gabriel MD

Page: 1895-1907

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Acute Myocardial Infarction: Changes in Patient Characteristics, Management, and 6-Month Outcomes Over a Period of 20 Years in the FAST-MI Program (French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction) 1995 to 2015.

Author: Puymirat, Etienne MD, PhD; Simon, Tabassome MD, PhD; Cayla, Guillaume MD, PhD; Cottin, Yves MD, PhD; Elbaz, Meyer MD, PhD; Coste, Pierre MD, PhD; Lemesle, Gilles MD, PhD; Motreff, Pascal MD, PhD; Popovic, Batric MD, PhD; Khalife, Khalife MD; Labeque, Jean-Noel MD; Perret, Thibaut MD; Le Ray, Christophe MD; Orion, Laurent MD; Jouve, Bernard MD; Blanchard, Didier MD; Peycher, Patrick; Silvain, Johanne MD, PhD; Steg, Philippe Gabriel MD; Goldstein, Patrick MD; Gueret, Pascal MD, PhD; Belle, Loic MD; Aissaoui, Nadia MD, PhD; Ferrieres, Jean MD, PhD; Schiele, Francois MD, PhD; Danchin, Nicolas MD, PhD; for the USIK, USIC 2000, and FAST-MI investigators

Page: 1908-1919

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Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension.

Author: Saito, Toshie MD; Miyagawa, Kazuya MD, PhD; Chen, Shih-Yu MD, PhD; Tamosiuniene, Rasa MD, PhD; Wang, Lingli MD; Sharpe, Orr MSc; Samayoa, Erik BS, CLS; Harada, Daisuke PhD; Moonen, Jan-Renier A.J. MD, PhD; Cao, Aiqin PhD; Chen, Pin-I PhD; Hennigs, Jan K. MD; Gu, Mingxia MD, PhD; Li, Caiyun G. PhD; Leib, Ryan D. PhD; Li, Dan PhD; Adams, Christopher M. PhD; del Rosario, Patricia A. BSN, RN, PHN; Bill, Matthew BS; Haddad, Francois MD; Montoya, Jose G. MD; Robinson, William H. MD, PhD; Fantl, Wendy J. PhD; Nolan, Garry P. PhD; Zamanian, Roham T. MD; Nicolls, Mark R. MD; Chiu, Charles Y. MD, PhD; Ariza, Maria E. PhD; Rabinovitch, Marlene MD

Page: 1920-1935

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Human Endogenous Retrovirus K and Pulmonary Arterial Hypertension: A New Take on a Retro Idea.

Author: Culley, Miranda K. BA; Chan, Stephen Y. MD, PhD

Page: 1936-1938

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Enhanced Therapeutic and Long-Term Dynamic Vascularization Effects of Human Pluripotent Stem Cell-Derived Endothelial Cells Encapsulated in a Nanomatrix Gel.

Author: Lee, Shin-Jeong PhD; Sohn, Young-Doug PhD; Andukuri, Adinarayana PhD; Kim, Sangsung MS; Byun, Jaemin MS; Han, Ji Woong PhD; Park, In-Hyun PhD; Jun, Ho-Wook PhD; Yoon, Young-sup MD, PhD

Page: 1939-1954

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International Expert Consensus on Switching Platelet P2Y12 Receptor-Inhibiting Therapies.

Author: Angiolillo, Dominick J. MD, PhD; Rollini, Fabiana MD; Storey, Robert F. MD; Bhatt, Deepak L. MD, MPH; James, Stefan MD, PhD; Schneider, David J. MD; Sibbing, Dirk MD; So, Derek Y.F. MD; Trenk, Dietmar PhD; Alexopoulos, Dimitrios MD; Gurbel, Paul A. MD; Hochholzer, Willibald MD; De Luca, Leonardo MD; Bonello, Laurent MD; Aradi, Daniel MD, PhD; Cuisset, Thomas MD, PhD; Tantry, Udaya S. PhD; Wang, Tracy Y. MD, MHS, MSc; Valgimigli, Marco MD, PhD; Waksman, Ron MD; Mehran, Roxana MD; Montalescot, Gilles MD; Franchi, Francesco MD; Price, Matthew J. MD

Page: 1955-1975

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Unusual ST-Segment Elevation in the Anterolateral Precordial Leads: Ischemia, Brugada Phenocopy, Brugada Syndrome, All, or None?.

Author: Perez-Riera, Andres Ricardo MD, PhD; Barbosa-Barros, Raimundo MD; Daminello-Raimundo, Rodrigo PhD; de Abreu, Luiz Carlos PhD; Baranchuk, Adrian MD

Page: 1976-1978

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Early Outcomes of Repair of Left Ventricular Apical Aneurysms in Patients With Hypertrophic Cardiomyopathy.

Author: Nguyen, Anita MBBS; Schaff, Hartzell V. MD; Nishimura, Rick A. MD; Dearani, Joseph A. MD; Ommen, Steve R. MD

Page: 1979-1981

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Letter by Natale et al Regarding Article, "Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study)".

Author: Natale, Francesco MD, PhD; Di Maio, Marco MD; Calabro, Paolo MD, PhD

Page: 1982-1983

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Response by Perez de Isla et al to Letter Regarding Article, "Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study)".

Author: Perez de Isla, Leopoldo MD, PhD; Saltijeral Cerezo, Adriana MD, PhD; Mata, Pedro MD, PhD

Page: 1984

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Letter by Jin-shan and Xue-bin Regarding Article, "Impact of the Clinical Frailty Scale on Outcomes After Transcatheter Aortic Valve Replacement".

Author: Jin-shan, He MD; Xue-bin, Li MD

Page: 1985-1986

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Response by Yamamoto et al to Letter Regarding Article, "Impact of the Clinical Frailty Scale on Outcomes After Transcatheter Aortic Valve Replacement".

Author: Yamamoto, Masanori MD; Shimura, Tetsuro MD; Hayashida, Kentaro MD

Page: 1987-1988

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Diagnosis and Management of Noncardiac Complications in Adults With Congenital Heart Disease: A Scientific Statement From the American Heart Association.

Author: Lui, George K. MD, Chair; Saidi, Arwa MB BCh, Vice Chair; Bhatt, Ami B. MD; Burchill, Luke J. MD; Deen, Jason F. MD; Earing, Michael G. MD; Gewitz, Michael MD, FAHA; Ginns, Jonathan MD; Kay, Joseph D. MD; Kim, Yuli Y. MD; Kovacs, Adrienne H. PhD; Krieger, Eric V. MD; Wu, Fred M. MD; Yoo, Shi-Joon MD, PhD; On behalf of the American Heart Association Adult Congenital Heart Disease Committee of the Council on Clinical Cardiology and Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; and Council on Quality of Care and Outcomes Research

Page: e348-e392

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Biomaterials for Articular Cartilage Tissue Engineering: Learning from Biology.

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): A.R. Armiento, M.J. Stoddart, M. Alini, D. Eglin
Articular cartilage is commonly described as a tissue made of up to 80% water, devoid of blood vessels, nerves and lymphatics, and populated by only one cell type: at first glance, an easy tissue for clinicians to repair and for scientists to reproduce in a laboratory. Yet, chondral and osteochondral defects currently remain an open challenge in orthopedics and tissue engineering of the musculoskeletal system, without considering osteoarthritis. Why do we fail in repairing and regenerating articular cartilage? Behind its simple and homogenous appearance articular cartilage hides a heterogeneous composition, a high level of organisation and specific biomechanical properties that taken together make articular cartilage a unique material that we are not able yet to repair or reproduce with high fidelity. The present review highlights the available therapies for cartilage repair and retraces the research on different biomaterials developed for tissue engineering strategies. Their potential to recreate the structure, including composition and organisation, as well as the function, intended as cell microenvironment and mechanical competent replacement, of articular cartilage is described. A perspective of the limitations of the current research is given in the light of the emerging technologies supporting tissue engineering of articular cartilage.Statement of significanceThe mechanical properties of articular tissue reflect its functionally organised composition and recreating its structure challenges the success of in vitro and in vivo reproduction of the native cartilage. Tissue engineering and biomaterials science have revolutionised the way scientists approach the challenge of articular cartilage repair and regeneration by introducing the concept of the interdisciplinary approach. The clinical translation of the current approaches are not yet fully successful, but promising results are expected from the emerging and developing new generation technologies.

Graphical abstract

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A model for hydrolytic degradation and erosion of biodegradable polymers

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): Kevser Sevim, Jingzhe Pan
For aliphatic polyesters such as PLAs and PGAs, there is a strong interplay between the hydrolytic degradation and erosion – degradation leads to a critically low molecular weight at which erosion starts. This paper considers the underlying physical and chemical processes of hydrolytic degradation and erosion. Several kinetic mechanisms are incorporated into a mathematical model in an attempt to explain different behaviours of mass loss observed in experiments. In the combined model, autocatalytic hydrolysis, oligomer production and their diffusion are considered together with surface and interior erosion using a set of differential equations and Monte Carlo technique. Oligomer and drug diffusion are modeled using Fick's law with the diffusion coefficients dependent on porosity. The porosity is due to the formation of cavities which are a result of polymer erosion. The model can follow mass loss and drug release up to 100%, which cannot be explained using a simple reaction-diffusion. The model is applied to two case studies from the literature to demonstrate its validity. The case studies show that a critical molecular weight for the onset of polymer erosion and an incubation period for the polymer dissolution are two critical factors that need to be considered when predicting mass loss and drug release.Statement of SignificanceIn order to design bioresorbable implants, it is important to have a mathematical model to predict polymer degradation and corresponding drug release. However, very different behaviours of polymer degradation have been observed and there is no single model that can capture all these behaviours. For the first time, the model presented in this paper is capable of capture all these observed behaviours by switching on and off different underlying mechanisms. Unlike the existing reaction-diffusion models, the model presented here can follow the degradation and drug release all the way to the full disappearance of an implant.

Graphical abstract

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Electrospun thermosensitive hydrogel scaffold for enhanced chondrogenesis of human mesenchymal stem cells

Publication date: Available online 8 November 2017
Source:Acta Biomaterialia
Author(s): Alexander R Brunelle, Christopher B Horner, Karen Low, Gerardo Ico, Jin Nam
Hydrogels have shown great potential for cartilage tissue engineering applications due to their capability to encapsulate cells within biomimetic, 3-dimensional (3D) microenvironments. However, the multi-step fabrication process that is necessary to produce cell/scaffold constructs with defined dimensions, limits their off-the-shelf translational usage. In this study, we have developed a hybrid scaffolding system which combines a thermosensitive hydrogel, poly(ethylene glycol)-poly(N-isopropylacrylamide) (PEG-PNIPAAm), with a biodegradable polymer, poly(ε-caprolactone) (PCL), into a composite, electrospun microfibrous structure. A judicious optimization of material composition and electrospinning process produced a structurally self-supporting hybrid scaffold. The reverse thermosensitivity of PEG-PNIPAAm allowed its dissolution/hydration upon cell seeding within a network of PCL microfibers while maintaining the overall scaffold shape at room temperature. A subsequent temperature elevation to 37 °C induced the hydrogel's phase transition to a gel state, effectively encapsulating cells in a 3D hydrogel without the use of a mold. We demonstrated that the hybrid scaffold enhanced chondrogenic differentiation of human mesenchymal stem cells (hMSCs) based on chondrocytic gene and protein expression, which resulted in superior viscoelastic properties of the cell/scaffold constructs. The hybrid scaffold enables a facile, single-step cell seeding process to inoculate cells within a 3D hydrogel with the potential for cartilage tissue engineering.Statement of SignificanceHydrogels have demonstrated the excellent ability to enhance chondrogenesis of stem cells due to their hydrated fibrous nanostructure providing a cellular environment similar to native cartilage. However, the necessity for multi-step processes including mixing of hydrogel precursor with cells and subsequent gelation in a mold to form a defined shape, limits their off-the-shelf usage. In this study, we developed a hybrid scaffold by combining a thermosensitive hydrogel with a mechanically stable polymer, which provides a facile means to inoculate cells in a 3D hydrogel with a mold-less, single step cell seeding process. We further showed that the hybrid scaffold enhanced chondrogenesis of mesenchymal stem cells, demonstrating its potential for cartilage tissue engineering.

Graphical abstract

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A robust multi-objective bargaining methodology for inter-basin water resource allocation: a case study

Abstract

In this study, a new methodology is proposed to balance environmental and economic issues in water allocation under uncertainty. Two objective functions, including maximizing economic income (EI) and minimizing environmental pollution (EP), were considered as two groups of players to construct a deterministic multi-objective bargaining methodology (DMOBM). In the next step, it is enhanced to a robust multi-objective bargaining methodology (RMOBM), which is capable of incorporating the main uncertainties exist in the problem. A large-scale inter-basin water transfer case study was utilized to investigate the applicability of the developed model. The outputs of the models showed that Nash equilibrium provide a rather narrow range of solutions. According to the results, the required rounds to reach Nash equilibrium raised as the uncertainty level increased. In addition, higher levels of uncertainty lead to higher reduction in water allocating of receiving basin. Sensitivity analysis showed that economic income values are less sensitive to changes of uncertain parameters than the environmental objective function. The developed methodology could provide a framework to incorporate the behavior of different stakeholders. Furthermore, the proposed method can be reliable under the condition of facing water allocation uncertainties.

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First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid

Publication date: Available online 13 November 2017
Source:Alexandria Journal of Medicine
Author(s): O.M. Ighodaro, O.A. Akinloye
The body encloses a complex antioxidant defence grid that relies on endogenous enzymatic and non-enzymatic antioxidants. These molecules collectively act against free radicals to resist their damaging effects to vital biomolecules and ultimately body tissues. Based on their response to general free radical invasion, they can be categorized into first, second, third and even fourth line defense antioxidants. The role and effectiveness of the first line defense antioxidants which basically include superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) is important and indispensable in the entire defense strategy of antioxidants, especially in reference to super oxide anion radical (^*O2) which is perpetually generated in normal body metabolism, particularly through the mitochondrial energy production pathway (MEPP). A lot has been published concerning antioxidants and their significance in preventing oxidative stress and the attendant cellular damage, howbeit with paucity of awareness on the fundamental role of SOD, CAT and GPX. The present review tends to articulate important information on SOD, CAT and GPX as first line defense antioxidant enzymes.



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The effects of local microinjection of selective dopamine D1 and D2 receptor agonists and antagonists into the dorsal raphe nucleus on sleep and wakefulness in the rat

Publication date: 26 February 2018
Source:Behavioural Brain Research, Volume 339
Author(s): Jaime M. Monti, Héctor Jantos
The effects of the dopamine (DA) D1 and D2 receptor agonists SKF38393, bromocriptine and quinpirole, respectively, on spontaneous sleep were analyzed in adult rats prepared for chronic sleep recordings. Local administration of the DAergic agonists into the dorsal raphe nucleus (DRN) during the light phase of the light-dark cycle induced a significant reduction of rapid-eye movement sleep (REMS) and the number of REM periods. Additionally, bromocriptine and quinpirole significantly increased wakefulness (W). Opposite, the microinjection into the DRN of the DA D1 and D2 receptor antagonists SCH23390 and sulpiride, respectively, significantly augmented REMS and the number of REM periods. Pretreatment with SCH23390 and sulpiride prevented the effects of SKF38393 and bromocriptine, respectively, on sleep variables. Our results tend to indicate that DAergic neurons located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) contribute to the regulation of predominantly W and REMS by DRN serotonergic neurons.



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Amyloid toxicity is enhanced after pharmacological or genetic invalidation of the σ1 receptor

Publication date: 26 February 2018
Source:Behavioural Brain Research, Volume 339
Author(s): Tangui Maurice, Manon Strehaiano, Fanny Duhr, Nathalie Chevallier
The sigma-1 receptor (S1R) is a molecular chaperone which activity modulates several intracellular signals including calcium mobilization at mitochondria-associated endoplasmic reticulum membranes. S1R agonists are potent neuroprotectants against neurodegenerative insults and particularly in rodent models of Alzheimer's disease (AD). We here analyzed whether S1R inactivation modifies vulnerability to amyloid toxicity in AD models. Two strategies were used: (1) amyloid β[25-35] (Aβ25-35) peptide (1, 3, 9nmol) was injected intracerebroventricularly in mice treated repeatedly with the S1R antagonist NE-100 or in S1RKO mice, and (2) WT, APPSweInd, S1RKO, and APPSweInd/S1RKO mice were created and female littermates analyzed at 8 months of age. Learning deficits, oxidative stress, Bax level and BDNF content in the hippocampus were analyzed. Aβ25-35 induced learning impairment, oxidative stress, Bax induction and BDNF alteration at lower dose in NE-100-treated mice or S1RKO mice as compared to WT animals. The extent of learning deficits and biochemical alterations were also higher in APPSweInd/S1RKO mice as compared to WT, APPSweInd, and S1RKO animals. S1R inactivation or altered S1R expression augmented the pathological status in pharmacologic and genetic AD mouse models. These observations, in relation with the well-known protective effects of S1R agonists, are coherent with a role of signal amplifier in neurodegeneration and neuroprotection proposed for S1R in AD and related neurodegenerative disorders.



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Progressive practice promotes motor learning and repeated transient increases in corticospinal excitability across multiple days

Publication date: Available online 13 November 2017
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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Intravenous immunoglobulin improves glucose control and β-cell function in human IAPP transgenic mice by attenuating islet inflammation and reducing IAPP oligomers

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Yue Zhang, Xiao-lin Yu, Jie Zhu, Shu-ying Liu, Xiang-meng Liu, Quan-xiu Dong, Jia-qian Chai, Rui-tian Liu
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by β-cell loss, insulin resistance, islet inflammation and amyloid deposits derived from islet amyloid polypeptide (IAPP). Reducing toxic IAPP oligomers and inhibiting islet inflammation may provide therapeutic benefit in treating T2DM. Intravenous immunoglobulin (IVIg) is an efficient anti-inflammatory and immunomodulatory agent for the treatment of several autoimmune or inflammatory neurological diseases. However, whether IVIg has therapeutic potential on T2DM remains unclear. In present study, we showed that IVIg treatment significantly improved glucose control and insulin sensitivity, and prevented β-cell apoptosis by lowering toxic IAPP oligomer levels, attenuating islet inflammation and activating autophagy in human IAPP transgenic mouse model. These results suggest that IVIg is a promising therapeutic potential for T2DM treatment.



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Enantioselective degradation of Myclobutanil and Famoxadone in grape

Abstract

The enantioselective degradation of myclobutanil and famoxadone enantiomers in grape under open field was investigated in this study. The absolute configuration of myclobutanil and famoxadone enantiomers was determined by the combination of experimental electronic circular dichroism (ECD) and calculated ECD spectra. The enantiomers residues of myclobutanil and famoxadone in grape were measured by sensitive high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS). The linearity, precision, accuracy, matrix effect, and stability were assessed. And the limit of quantification (LOQ) for each enantiomer of myclobutanil and famoxadone in grape was evaluated to be 1.5 and 2 μg kg⁻¹. The myclobutanil and famoxadone showed the enantioselective degradation in grape, and the enantioselectivity of degradation for myclobutanil was more pronounced than that for famoxadone. The half-lives were 13.1 days and 25.7 days for S-(+)-myclobutanil and R-(−)-myclobutanil in grape, separately. The half-life of S-(+)-famoxadone was 31.5 days slightly shorter than that of R-(−)-famoxadone with half-life being 38.5 days in grape. The probable reasons for the enantioselective degradation behavior of these two fungicides were also discussed. The results in the article might provide a reference to better assess the risks of myclobutanil and famoxadone enantiomers in grapes to human and environment.

Graphical abstract

The enantioselective analysis of myclobutanil and famoxadone in grape

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Masthead

Publication date: November–December 2017
Source:Practical Radiation Oncology, Volume 7, Issue 6





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Editorial Board

Publication date: November–December 2017
Source:Practical Radiation Oncology, Volume 7, Issue 6





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Table of Contents

Publication date: November–December 2017
Source:Practical Radiation Oncology, Volume 7, Issue 6





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Editorial Advisory Board

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12





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Contents

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12





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Potential of Contrast-Enhanced Ultrasound as a Bedside Monitoring Technique in Cerebral Perfusion: a Systematic Review

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Elisabeth J. Vinke, Anna J. Kortenbout, Jens Eyding, Cornelis H. Slump, Johannes G. van der Hoeven, Chris L. de Korte, Cornelia W.E. Hoedemaekers
Contrast-enhanced ultrasound (CEUS) has been suggested as a new method to measure cerebral perfusion in patients with acute brain injury. In this systematic review, the tolerability, repeatability, reproducibility and accuracy of different CEUS techniques for the quantification of cerebral perfusion were assessed. We selected studies published between January 1994 and March 2017 using CEUS to measure cerebral perfusion. We included 43 studies (bolus kinetics n = 31, refill kinetics n = 6, depletion kinetics n = 6) with a total of 861 patients. Tolerability was reported in 28 studies describing 12 patients with mild and transient side effects. Repeatability was assessed in 3 studies, reproducibility in 2 studies and accuracy in 19 studies. Repeatability was high for experienced sonographers and significantly lower for less experienced sonographers. Reproducibility of CEUS was not clear. The sensitivity and specificity of CEUS for the detection of cerebral ischemia ranged from 75% to 96% and from 60% to 100%. Limited data on repeatability, reproducibility and accuracy may suggest that this technique could be feasible for use in acute brain injury patients.



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Repeatability of Bolus Kinetics Ultrasound Perfusion Imaging for the Quantification of Cerebral Blood Flow

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Elisabeth J. Vinke, Jens Eyding, Chris L. de Korte, Cornelis H. Slump, Johannes G. van der Hoeven, Cornelia W.E. Hoedemaekers
Ultrasound perfusion imaging (UPI) can be used for the quantification of cerebral perfusion. In a neuro-intensive care setting, repeated measurements are required to evaluate changes in cerebral perfusion and monitor therapy. The aim of this study was to determine the repeatability of UPI in quantification of cerebral perfusion. UPI measurement of cerebral perfusion was performed three times in healthy patients. The coefficients of variation of the three bolus injections were calculated for both time- and volume-derived perfusion parameters in the macro- and microcirculation. The UPI time-dependent parameters had overall the lowest CVs in both the macro- and microcirculation. The volume-related parameters had poorer repeatability, especially in the microcirculation. Both intra-observer variability and inter-observer variability were low. Although UPI is a promising tool for the bedside measurement of cerebral perfusion, improvement of the technique is required before implementation in routine clinical practice.



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Masthead

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12





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Intra-Individual Comparison between 2-D Shear Wave Elastography (GE System) and Virtual Touch Tissue Quantification (Siemens System) in Grading Liver Fibrosis

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Rosa M.S. Sigrist, Ahmed El Kaffas, R. Brooke Jeffrey, Jarrett Rosenberg, Jürgen K. Willmann
Ultrasound-based shear wave elastography (SWE) has recently gained substantial attention for non-invasive assessment of liver fibrosis. The purpose of this study was to perform an intra-individual comparison between 2-D shear wave elastography (2-D-SWE with a GE system) and Virtual Touch Tissue Quantification (VTTQ with a Siemens system) to assess whether these can be used interchangeably to grade fibrosis. Ninety-three patients (51 men, 42 women; mean age, 54 y) with liver disease of various etiologies (hepatitis B virus = 47, hepatitis C virus = 22; alcohol = 6, non-alcoholic steatohepatitis = 5, other = 13) were included. Using published system-specific shear wave speed cutoff values, liver fibrosis was classified into clinically non-significant (F0/F1) and significant (≥F2) fibrosis. Results indicated that intra-modality repeatability was excellent for both techniques (GE 2-D-SWE: intra-class correlation coefficient = 0.89 [0.84–0.93]; VTTQ: intra-class correlation coefficient = 0.90 [0.86–0.93]). Intra-modality classification agreement for fibrosis grading was good to excellent (GE 2-D-SWE: κ = 0.65, VTTQ: κ = 0.82). However, inter-modality agreement for fibrosis grading was only fair (κ = 0.31) using published system-specific shear wave speed cutoff values of fibrosis. In conclusion, although both GE 2-D-SWE and Siemens VTTQ exhibit good to excellent intra-modality repeatability, inter-modality agreement is only fair, suggesting that these should not be used interchangeably.



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2017 Subject Index for Volume 43, 2017

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12





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Prospective Comparison of the Diagnostic Performance of Magnetic Resonance Elastography with Acoustic Radiation Force Impulse Elastography for Pre-operative Staging of Hepatic Fibrosis in Patients with Hepatocellular Carcinoma

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Chen-Te Chou, Ran-Chou Chen, Wen-Pei Wu, Ping-Yi Lin, Yao-Li Chen
The purpose of this study was to compare the diagnostic accuracy of magnetic resonance (MR) elastography with that of acoustic radiation force impulse (ARFI) elastography for pre-operative staging of hepatic fibrosis in patients with hepatocellular carcinoma. We prospectively enrolled 77 patients who were scheduled to undergo hepatectomy for hepatocellular carcinoma. Pre-operative MRE and ARFI elastography examinations were performed on the same day, and liver stiffness/velocity values were determined. Fibrosis stage and necro-inflammatory activity of resected specimens were determined histopathologically using the METAVIR scoring system. Correlations between MRE and ARFI elastography findings and histologic findings were determined by receiver operating characteristic (ROC) analysis. Correlation of MRE was excellent and correlation of ARFI elastography was good with fibrosis stage. MRE had better diagnostic performance than ARFI elastography in estimating substantial fibrosis (F2), severe fibrosis (F3) and cirrhosis (F4). The optimal cutoff value and the area under the ROC curve (AUROC) were determined using ROC curve analysis. The highest Youden index was used as a criterion for selecting the optimal cutoff value. ROC analysis revealed that MRE discriminated advanced stages of fibrosis (F ≥ 2) well in patients with hepatocellular carcinoma at a cutoff value of 3.0 kPa with an AUROC value of 0.93, and ARFI elastography did so at a cutoff value of 1.77 m/s with an AUROC value of 0.81 for predicting advanced stages of fibrosis (F ≥ 2). In conclusion, MRE is a more accurate imaging modality than ARFI elastography in estimating advanced stages of fibrosis and cirrhosis.



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Tracking Dynamic Tongue Motion in Ultrasound Images for Obstructive Sleep Apnea

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Chih-Yen Chien, Jeng-Wen Chen, Chun-Hsiang Chang, Chih-Chung Huang
Obstructive sleep apnea (OSA), a breathing disorder characterized by repetitive collapse of the pharyngeal airway during sleep, can cause intermittent hypoxemia and frequent arousal. The evaluation of dynamic tongue motion not only provides the biomechanics and pathophysiology for OSA diagnosis, but also helps doctors to determine treatment strategies for these patients with OSA. The purpose of this study was to develop and verify a dedicated tracking algorithm, called the modified optical flow (OF)-based method, for monitoring the dynamic motion of the tongue base in ultrasound image sequences derived from controls and patients with OSA. The performance of the proposed method was verified by phantom and synthetic data. A common tracking method, the normalized cross-correlation method, was included for comparison. The efficacy of the algorithms was evaluated by calculating the estimated displacement error. All results indicated that the modified OF-based method exhibited higher accuracy in verification experiments. In the human subject experiment, all participants performed the Müller maneuver (MM) to simulate the contour changes of the tongue base with a negative pharyngeal airway pressure in sleep apnea. Ultrasound image sequences of the tongue were obtained during 10 s of a transition from normal breathing to the MM, and these were measured using the modified OF-based method. The results indicated that the displacement of the tongue base during the MM was larger in the controls than in the patients with OSA (p < 0.05); the calculated areas of the tongue in the controls and patients with OSA were 24.9 ± 3.0 and 27.6 ± 3.3 cm², respectively, during normal breathing (p < 0.05), and 24.7 ± 3.6 and 27.3 ± 3.8 cm², respectively, at the end of the MM. The percentage changes in the tongue area were 2.2% and 1.3% in the controls and patients with OSA, respectively. We found that quantitative assessment of tongue motion by ultrasound imaging is suitable for evaluating pharyngeal airway behavior in OSA patients with minimal invasiveness and easy accessibility.



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Ankle Evaluation in Active Rheumatoid Arthritis by Ultrasound: A Cross-Sectional Study

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Ahmed M. Elsaman, Ehab Saad Mostafa, Ahmed R. Radwan
Ankle joint evaluation is underestimated in many clinical and sonographic scores used for evaluation and follow-up of rheumatoid arthritis (RA) patients. Agreement on examination parameters is poor among sonographic scores that include the ankle joint. More effort is needed to detect the value of ankle joint examination in RA and assessment of ultrasonographic signs according to frequency, disease duration and activity. The objective of this study was to use ultrasound (US) to detect ankle involvement in active RA and to compare findings with disease duration, disease activity and assessment of ankle bone erosion. A total of 63 RA patients with active disease and 20 controls were included in the study. The tibiotalar and talonavicular joints were examined by US for synovitis and/or effusion in gray-scale and power Doppler modes. The anterior, lateral and posterior ankle tendons were examined for tenosynovitis and tendinosis. Mean age was 35.1 ± 8.3 y, mean disease duration was 22.7 ± 9.6 mo and the mean 28-joint Disease Activity Score–erythrocyte sedimentation rate was 3.05 ± 0.66. Ankle involvement was seen in 28 patients (44.4%). The most frequent pathologies detected were tenosynovitis (30.2%), followed by synovitis (18.3%), erosion (8.7%) and tendinosis (4%). The earliest sonographic signs were tenosynovitis, followed by synovitis, erosion and tendinosis. The right ankle exhibited greater involvement than the left ankle, which was significant with respect to erosions (p = 0.009). The most common tendon affected by tenosynovitis was the tibialis anterior (22.2%), followed by the tibialis posterior (20.6%). Tenosynovitis, especially of the tibialis anterior and posterior, tibiotalar synovitis and erosions should be considered in future US ankle scores for the assessment of RA.



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Quantitative 3-D Ultrasound of the Medial Gastrocnemius Muscle in Children with Unilateral Spastic Cerebral Palsy

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Steven J. Obst, Roslyn Boyd, Felicity Read, Lee Barber
Three-dimensional ultrasound (3-DUS) was used to examine the size and appearance of the medial gastrocnemius (MG) muscle in children with unilateral cerebral palsy (CP). Twenty-six children with CP and 10 typically developing (TD) children participated. Three-dimensional US images of both limbs in children with CP and the right limb in TD children were analysed using quantitative methods to determine muscle volume, global echo intensity, global echo pattern and regional echo intensity. Significant differences in MG volume and all echo parameters were found between TD and CP children. The more involved limb was smaller and had higher echo intensity and a more heterogenous echo pattern compared with the TD group. Compared with that of the more involved limb, the MG of the less involved limb was larger but had a similar echo appearance. The MG of both limbs in children with unilateral spastic CP is smaller and, based on quantitative ultrasound, structurally different from that of TD children.



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Comparison of Electrical and Ultrasound Neurostimulation in Rat Motor Cortex

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Daniel W. Gulick, Tao Li, Jeffrey A. Kleim, Bruce C. Towe
Ultrasound (US) is known to non-invasively stimulate and modulate brain function; however, the mechanism of action is poorly understood. This study tested US stimulation of rat motor cortex (100 W/cm², 200 kHz) in combination with epidural cortical stimulation. US directly evoked hindlimb movement. This response occurred even with short US bursts (3 ms) and had short latency (10 ms) and long refractory (3 s) periods. Unexpectedly, the epidural cortical stimulation hindlimb response was not altered during the 3-s refractory period of the US hindlimb response. This finding suggests that the US refractory period is not a general suppression of motor cortex, but rather the recovery time of a US-specific mechanism.



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Non-invasive, Rapid Ablation of Tissue Volume Using Histotripsy

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Jonathan E. Lundt, Steven P. Allen, Jiaqi Shi, Timothy L. Hall, Charles A. Cain, Zhen Xu
Histotripsy is a non-invasive, non-thermal ablation technique that uses high-amplitude, focused ultrasound pulses to fractionate tissue via acoustic cavitation. The goal of this study was to illustrate the potential of histotripsy with electronic focal steering to achieve rapid ablation of a tissue volume at a rate matching or exceeding those of current clinical techniques (∼1–2 mL/min). Treatment parameters were established in tissue-mimicking phantoms and applied to ex vivo tissue. Six-microsecond pulses were delivered by a 250-kHz array. The focus was electrically steered to 1000 locations at a pulse repetition frequency of 200 Hz (0.12% duty cycle). Magnetic resonance imaging and histology of the treated tissue revealed a distinct region of necrosis in all samples. Mean lesion volume was 35.6 ± 4.3 mL, generated at 0.9–3.3 mL/min, a speed faster than that of any current ablation method for a large volume. These results suggest that histotripsy has the potential to achieve non-invasive, rapid, homogeneous ablation of a tissue volume.



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Numerical and Experimental Study of Mechanisms Involved in Boiling Histotripsy

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Ki Joo Pahk, Pierre Gélat, David Sinden, Dipok Kumar Dhar, Nader Saffari
The aim of boiling histotripsy is to mechanically fractionate tissue as an alternative to thermal ablation for therapeutic applications. In general, the shape of a lesion produced by boiling histotripsy is tadpole like, consisting of a head and a tail. Although many studies have demonstrated the efficacy of boiling histotripsy for fractionating solid tumors, the exact mechanisms underpinning this phenomenon are not yet well understood, particularly the interaction of a boiling vapor bubble with incoming incident shockwaves. To investigate the mechanisms involved in boiling histotripsy, a high-speed camera with a passive cavitation detection system was used to observe the dynamics of bubbles produced in optically transparent tissue-mimicking gel phantoms exposed to the field of a 2.0-MHz high-intensity focused ultrasound (HIFU) transducer. We observed that boiling bubbles were generated in a localized heated region and cavitation clouds were subsequently induced ahead of the expanding bubble. This process was repeated with HIFU pulses and eventually resulted in a tadpole-shaped lesion. A simplified numerical model describing the scattering of the incident ultrasound wave by a vapor bubble was developed to help interpret the experimental observations. Together with the numerical results, these observations suggest that the overall size of a lesion induced by boiling histotripsy is dependent on the sizes of (i) the heated region at the HIFU focus and (ii) the backscattered acoustic field by the original vapor bubble.



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Calendar

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12





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Protocol for Robust In Vivo Measurements of Erythrocyte Aggregation Using Ultrasound Spectroscopy

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Julian Garcia-Duitama, Boris Chayer, Damien Garcia, Yves Goussard, Guy Cloutier
Erythrocyte aggregation is a non-specific marker of acute and chronic inflammation. Although it is usual to evaluate this phenomenon from blood samples analyzed in laboratory instruments, in vivo real-time assessment of aggregation is possible with spectral ultrasound techniques. However, variable blood flow can affect the interpretation of acoustic measures. Therefore, flow standardization is required. Two techniques of flow standardization were evaluated with porcine and equine blood samples in Couette flow. These techniques consisted in either stopping the flow or reducing it. Then, the sensibility and repeatability of the retained method were evaluated in 11 human volunteers. We observed that stopping the flow compromised interpretation and repeatability. Conversely, maintaining a low flow provided repeatable measures and could distinguish between normal and high extents of erythrocyte aggregation. Agreement was observed between in vivo and ex vivo measures of the phenomenon (R² = 82.7%, p value < 0.0001). These results support the feasibility of assessing in vivo erythrocyte aggregation in humans by quantitative ultrasound means.



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In Vivo High-Frequency Ultrasound for the Characterization of Thrombi Associated with Aortic Aneurysms in an Experimental Mouse Model

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Christian H.P. Jansen, Julia Brangsch, Carolin Reimann, Lisa Adams, Bernd Hamm, Rene M. Botnar, Marcus R. Makowski
The development of abdominal aortic aneurysm (AAA) associated thrombi plays an important role during the onset and progression of AAAs. The aim of this study was to evaluate the potential of high-frequency ultrasound for characterization of AAA associated thrombi in an apolipoprotein-E-deficient mouse-model. Ultrasound measurements were performed using a high-resolution ultrasound system (Vevo770, FUJIFILM VisualSonics, Inc., Toronto, ON, Canada) with a 30 MHz linear-array transducer (RMV707 B). Magnetic resonance imaging with a 3 Tesla scanner (Achieva MR system, Philips Healthcare, Best, The Netherlands) and a single-loop microscopy coil was performed as a reference standard. All stages of aneurysm development were evaluated by histologic analyses. The "signal-thrombus-matrix" to "signal-blood" ratio on high-frequency ultrasound measurements showed a strong correlation (R² = 0.81, p < 0.05) with the state of extracellular matrix remodeling. Furthermore, size measurements derived from the high-frequency ultrasound correlated well with magnetic resonance imaging and histology. This study demonstrated that high-frequency ultrasound enables the reliable in vivo quantification of extracellular matrix remodeling at various stages of thrombus development, based on the thrombus echogenicity.



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Elastographic Assessment of Xenograft Pancreatic Tumors

Publication date: December 2017
Source:Ultrasound in Medicine & Biology, Volume 43, Issue 12
Author(s): Hexuan Wang, Michael D. Nieskoski, Kayla Marra, Jason R. Gunn, Stuart B. Trembly, Brian W. Pogue, Marvin M. Doyley
High tissue pressures prevent chemotherapeutics from reaching the parenchyma of pancreatic ductal adenocarcinoma, which makes it difficult to treat this aggressive disease. Researchers currently use invasive probes to monitor the effectiveness of pressure-reducing therapies, but this practice introduces additional complications. Here, we hypothesize that Young's modulus is a good surrogate for tissue pressure because collagen density and hyaluoronic acid, the key features of the tumor microenvironment responsible for high tissue pressures, also affect modulus elastograms. To corroborate this hypothesis, we used model-based quasi-static elastography to assess how the Young's modulus of naturally occurring AsPc-1 pancreatic tumors varies with collagen density and hyaluoronic acid concentration. We observed that Young's moduli of orthotopically grown xenograft tumors were 6 kPa (p < 0.05) higher than that of their subcutaneously grown counterparts. We also observed a strong correlation between Young's modulus and regions within the tumors with high collagen (R² ≈ 0.8) and hyaluoronic acid (R² ≈ 0.6) densities. These preliminary results indicate that hyaluronic acid and collagen density, features of the pancreatic ductal adenocarcinoma tumor microenvironment responsible for high tissue pressure, influence Young's modulus.



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