Podcast Interviews

ATA Members give podcast interviews on Thyroid Topics at www.docthyroid.com

Información Importante Sobre los Nódulos Tiroideos con la Dra Regina Castro de la Clínica Mayo
Interviewed and produced by Philip James | May 4, 2017 | Endocrine, Pathology, Podcast

You Have a Thyroid Nodule, What Happens Next? with Dr. Regina Castro from The Mayo Clinic
Interviewed and produced by Philip James | Apr 2, 2017 | Pathology, Podcast, Surgery

 

The post Podcast Interviews appeared first on American Thyroid Association.

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Structural Basis for Regulation of ESCRT-III Complexes by Lgd

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Brian J. McMillan, Christine Tibbe, Andrew A. Drabek, Tom C.M. Seegar, Stephen C. Blacklow, Thomas Klein
The ESCRT-III complex induces outward membrane budding and fission through homotypic polymerization of its core component Shrub/CHMP4B. Shrub activity is regulated by its direct interaction with a protein called Lgd in flies, or CC2D1A or B in humans. Here, we report the structural basis for this interaction and propose a mechanism for regulation of polymer assembly. The isolated third DM14 repeat of Lgd binds Shrub, and an Lgd fragment containing only this DM14 repeat and its C-terminal C2 domain is sufficient for in vivo function. The DM14 domain forms a helical hairpin with a conserved, positively charged tip, that, in the structure of a DM14 domain-Shrub complex, occupies a negatively charged surface of Shrub that is otherwise used for homopolymerization. Lgd mutations at this interface disrupt its function in flies, confirming functional importance. Together, these data argue that Lgd regulates ESCRT activity by controlling access to the Shrub self-assembly surface.

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Shrub is a Drosophila ESCRT-III protein that self-associates to promote membrane budding and fission. Its activity is modulated by binding to Lgd, which suppresses self-association. McMillan et al. report the structural basis for masking of the Shrub self-association surface of Shrub by Lgd, which, together with functional studies in flies, suggests models for modulation of Shrub activity by Lgd.


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The Histone Variant MacroH2A1 Is a BRCA1 Ubiquitin Ligase Substrate

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Beom-Jun Kim, Doug W. Chan, Sung Yun Jung, Yue Chen, Jun Qin, Yi Wang
The breast- and ovarian-cancer-specific tumor suppressor BRCA1 and its heterodimeric partner BARD1 contain RING domains that implicate them as E3 ubiquitin ligases. Despite extensive efforts, the bona fide substrates of BRCA1/BARD1 remain elusive. Here, we used recombinant GST fused to four UBA domains to enrich ubiquitinated proteins followed by a Lys-ε-Gly-Gly (diGly) antibody to enrich ubiquitinated tryptic peptides. This tandem affinity purification method coupled with mass spectrometry identified 101 putative BRCA1/BARD1 E3 substrates. We identified the histone variant macroH2A1 from the screen and showed that BRCA1/BARD1 ubiquitinates macroH2A1 at lysine 123 in vitro and in vivo. Primary human fibroblasts stably expressing a ubiquitination-deficient macroH2A1 mutant were defective in cellular senescence compared to their wild-type counterpart. Our study demonstrates that BRCA1/BARD1 is a macroH2A1 E3 ligase and implicates a role for macroH2A1 K123 ubiquitination in cellular senescence.

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Using a tandem affinity purification method coupled with mass spectrometry, Kim et al. identified 101 putative substrates of the BRCA1/BARD1 E3 ubiquitin ligase. They report that, among these substrates, ubiquitination at Lys123 of macroH2A1 plays an important role in replicative senescence.


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Synaptic Remodeling Depends on Signaling between Serotonin Receptors and the Extracellular Matrix

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Monika Bijata, Josephine Labus, Daria Guseva, Michał Stawarski, Malte Butzlaff, Joanna Dzwonek, Jenny Schneeberg, Katrin Böhm, Piotr Michaluk, Dmitri A. Rusakov, Alexander Dityatev, Grzegorz Wilczyński, Jakub Wlodarczyk, Evgeni Ponimaskin
Rewiring of synaptic circuitry pertinent to memory formation has been associated with morphological changes in dendritic spines and with extracellular matrix (ECM) remodeling. Here, we mechanistically link these processes by uncovering a signaling pathway involving the serotonin 5-HT7 receptor (5-HT7R), matrix metalloproteinase 9 (MMP-9), the hyaluronan receptor CD44, and the small GTPase Cdc42. We highlight a physical interaction between 5-HT7R and CD44 (identified as an MMP-9 substrate in neurons) and find that 5-HT7R stimulation increases local MMP-9 activity, triggering dendritic spine remodeling, synaptic pruning, and impairment of long-term potentiation (LTP). The underlying molecular machinery involves 5-HT7R-mediated activation of MMP-9, which leads to CD44 cleavage followed by Cdc42 activation. One important physiological consequence of this interaction includes an increase in neuronal outgrowth and elongation of dendritic spines, which might have a positive effect on complex neuronal processes (e.g., reversal learning and neuronal regeneration).

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Bijata et al. examine a signaling module involving the 5-HT7 receptor (5-HT7R), matrix metalloproteinase 9 (MMP-9), the hyaluronan receptor CD44, and the small GTPase Cdc42. Stimulation of 5-HT7R results in MMP-9 activation, which, in turn, cleaves CD44. This results in local detachment from the ECM, thus facilitating spine elongation via 5-HT7R/Cdc42 signaling.


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A Glio-Protective Role of mir-263a by Tuning Sensitivity to Glutamate

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Sherry Shiying Aw, Isaac Kok Hwee Lim, Melissa Xue Mei Tang, Stephen Michael Cohen
Glutamate is a ubiquitous neurotransmitter, mediating information flow between neurons. Defects in the regulation of glutamatergic transmission can result in glutamate toxicity, which is associated with neurodegeneration. Interestingly, glutamate receptors are expressed in glia, but little is known about their function, and the effects of their misregulation, in these non-neuronal cells. Here, we report a glio-protective role for Drosophila mir-263a mediated by its regulation of glutamate receptor levels in glia. mir-263a mutants exhibit a pronounced movement defect due to aberrant overexpression of CG5621/Grik, Nmdar1, and Nmdar2. mir-263a mutants exhibit excitotoxic death of a subset of astrocyte-like and ensheathing glia in the CNS. Glial-specific normalization of glutamate receptor levels restores cell numbers and suppresses the movement defect. Therefore, microRNA-mediated regulation of glutamate receptor levels protects glia from excitotoxicity, ensuring CNS health. Chronic low-level glutamate receptor overexpression due to mutations affecting microRNA (miRNA) regulation might contribute to glial dysfunction and CNS impairment.

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Excessive glutamatergic signaling can cause neurodegeneration. Aw et al. report that Drosophila mir-263a limits glutamate receptor levels in a subset of glia, protecting them from excitotoxicity. mir-263a mutants exhibit severe movement defects. This study reveals a mechanism by which glia protect themselves from excess glutamate signaling to maintain CNS health.


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ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Diane DeZwaan-McCabe, Ryan D. Sheldon, Michelle C. Gorecki, Deng-Fu Guo, Erica R. Gansemer, Randal J. Kaufman, Kamal Rahmouni, Matthew P. Gillum, Eric B. Taylor, Lynn M. Teesch, D. Thomas Rutkowski
The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.

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The mechanisms by which the liver and kidney become steatotic when challenged by ER stress are not known. DeZwaan-McCabe et al. show that ER stress inhibits fatty acid oxidation in the liver and that unmitigated stress causes anorexia and promotes adipose lipolysis and further steatosis in the liver and kidney.


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Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Claire E. Hall, Zhi Yao, Minee Choi, Giulia E. Tyzack, Andrea Serio, Raphaelle Luisier, Jasmine Harley, Elisavet Preza, Charlie Arber, Sarah J. Crisp, P. Marc D. Watson, Dimitri M. Kullmann, Andrey Y. Abramov, Selina Wray, Russell Burley, Samantha H.Y. Loh, L. Miguel Martins, Molly M. Stevens, Nicholas M. Luscombe, Christopher R. Sibley, Andras Lakatos, Jernej Ule, Sonia Gandhi, Rickie Patani
Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS.

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Hall et al. use iPSCs to examine the sequence of events by which motor neurons degenerate in a genetic form of ALS. They find that astrocytes, a type of supportive cell, also degenerate under these conditions. The ALS-causing mutation disrupts the ability of astrocytes to promote survival of motor neurons.


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Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Kexin Zhao, Neale D. Ridgway
Lipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs) by Niemann-Pick C1 (NPC1). However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER) is poorly characterized. We report that oxysterol-binding protein-related protein 1L (ORP1L) is necessary for this stage of cholesterol export. CRISPR-mediated knockout of ORP1L in HeLa and HEK293 cells reduced esterification of cholesterol to the level in NPC1 knockout cells, and it increased the expression of sterol-regulated genes and de novo cholesterol synthesis, indicative of a block in cholesterol transport to the ER. In the absence of this transport pathway, cholesterol-enriched LELs accumulated in the Golgi/perinuclear region. Cholesterol delivery to the ER required the sterol-, phosphatidylinositol 4-phosphate-, and vesicle-associated membrane protein-associated protein (VAP)-binding activities of ORP1L, as well as NPC1 expression. These results suggest that ORP1L-dependent membrane contacts between LELs and the ER coordinate cholesterol transfer with the retrograde movement of endo-lysosomal vesicles.

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Cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs) by Niemann-Pick C1 (NPC1), but how cholesterol is subsequently transported to organelles is poorly characterized. Zhao and Ridgway find that OSBP-related protein 1L (ORP1L) mediates cholesterol transfer from LELs to the endoplasmic reticulum (ER) at contacts between these organelles.


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Replication-Coupled Dilution of H4K20me2 Guides 53BP1 to Pre-replicative Chromatin

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Stefania Pellegrino, Jone Michelena, Federico Teloni, Ralph Imhof, Matthias Altmeyer
The bivalent histone modification reader 53BP1 accumulates around DNA double-strand breaks (DSBs), where it dictates repair pathway choice decisions by limiting DNA end resection. How this function is regulated locally and across the cell cycle to channel repair reactions toward non-homologous end joining (NHEJ) in G1 and promote homology-directed repair (HDR) in S/G2 is insufficiently understood. Here, we show that the ability of 53BP1 to accumulate around DSBs declines as cells progress through S phase and reveal that the inverse relationship between 53BP1 recruitment and replicated chromatin is linked to the replication-coupled dilution of 53BP1's target mark H4K20me2. Consistently, premature maturation of post-replicative chromatin restores H4K20me2 and rescues 53BP1 accumulation on replicated chromatin. The H4K20me2-mediated chromatin association of 53BP1 thus represents an inbuilt mechanism to distinguish DSBs in pre- versus post-replicative chromatin, allowing for localized repair pathway choice decisions based on the availability of replication-generated template strands for HDR.

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Pellegrino et al. report how replication-dependent differences in chromatin inform the DNA damage response machinery about the replication status of broken genomic loci. This chromatin-embedded information affects 53BP1 binding and directs the choice of repair pathway used to fix DNA double-strand breaks.


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Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Daniel Henry Marks, Rozario Thomas, Yvette Chin, Riddhi Shah, Christine Khoo, Robert Benezra
The mitotic checkpoint ensures proper segregation of chromosomes by delaying anaphase until all kinetochores are bound to microtubules. This inhibitory signal is composed of a complex containing Mad2, which inhibits anaphase progression. The complex can be disassembled by p31^comet and TRIP13; however, TRIP13 knockdown has been shown to cause only a mild mitotic delay. Overexpression of checkpoint genes, as well as TRIP13, is correlated with chromosomal instability (CIN) in cancer, but the initial effects of Mad2 overexpression are prolonged mitosis and decreased proliferation. Here, we show that TRIP13 overexpression significantly reduced, and TRIP13 reduction significantly exacerbated, the mitotic delay associated with Mad2 overexpression, but not that induced by microtubule depolymerization. The combination of Mad2 overexpression and TRIP13 loss reduced the ability of checkpoint complexes to disassemble and significantly inhibited the proliferation of cells in culture and tumor xenografts. These results identify an unexpected dependency on TRIP13 in cells overexpressing Mad2.

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TRIP13 is a putative mitotic checkpoint silencing protein. However, depletion of TRIP13 causes only mild mitotic exit phenotypes. Marks et al. find that TRIP13 becomes critical for mitotic exit in Mad2-overexpressing cells. Both proteins are co-overexpressed in cancer, and TRIP13 may be a therapeutic target in Mad2-overexpressing tumors.


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2-HG Inhibits Necroptosis by Stimulating DNMT1-Dependent Hypermethylation of the RIP3 Promoter

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Zhentao Yang, Bin Jiang, Yan Wang, Hengxiao Ni, Jia Zhang, Jinmei Xia, Minggang Shi, Li-Man Hung, Jingsong Ruan, Tak Wah Mak, Qinxi Li, Jiahuai Han
2-hydroxyglutarate-(2-HG)-mediated inhibition of TET2 activity influences DNA hypermethylation in cells harboring mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2). Here, we show that 2-HG also regulates DNA methylation mediated by DNA methyltransferase 1 (DNMT1). DNMT1-dependent hypermethylation of the RIP3 promoter occurred in both IDH1 R132Q knockin mutant mouse embryonic fibroblast (MEFs) and 2-HG-treated wild-type (WT) MEFs. We found that 2-HG bound to DNMT1 and stimulated its association with the RIP3 promoter, inducing hypermethylation that reduces RIP3 protein and consequently impaired RIP3-dependent necroptosis. In human glioma samples, RIP3 protein levels correlated negatively with IDH1 R132H levels. Furthermore, ectopic expression of RIP3 in transformed IDH1-mutated MEFs inhibited the growth of tumors derived from these cells following transplantation into nude mice. Thus, our research sheds light on a mechanism of 2-HG-induced DNA hypermethylation and suggests that impaired necroptosis contributes to the tumorigenesis driven by IDH1/2 mutations.

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Yang et al. report that oncometabolite 2-HG produced by tumor-associated IDH1 mutation physically binds to DNMT1 and stimulates its association with the RIP3 promoter, inducing hypermethylation that reduces RIP3 protein and consequently impaired RIP3-dependent necroptosis. Loss of RIP3-mediated necroptosis contributes to tumorigenesis driven by 2-HG.


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Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Andrea E. Calvert, Alexandra Chalastanis, Yongfei Wu, Lisa A. Hurley, Fotini M. Kouri, Yingtao Bi, Maureen Kachman, Jasmine L. May, Elizabeth Bartom, Youjia Hua, Rama K. Mishra, Gary E. Schiltz, Oleksii Dubrovskyi, Andrew P. Mazar, Marcus E. Peter, Hongwu Zheng, C. David James, Charles F. Burant, Navdeep S. Chandel, Ramana V. Davuluri, Craig Horbinski, Alexander H. Stegh
Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBMs. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs the survival of animal subjects bearing patient-derived xenografts (PDXs). On a molecular level, diminished IDH1 activity results in reduced α-ketoglutarate (αKG) and NADPH production, paralleled by deficient carbon flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common metabolic adaptation by GBMs to support macromolecular synthesis, aggressive growth, and therapy resistance.

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Calvert et al. demonstrate that wild-type IDH1 is overexpressed in glioblastoma and that genetic or pharmacological suppression of IDH1 activity reduces tumor cell growth through effect on lipid production, redox homeostasis, and the regulation of cellular differentiation.


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A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Yohei Takeda, Keisuke Kataoka, Junya Yamagishi, Seishi Ogawa, Tsukasa Seya, Misako Matsumoto
Cancer patients having anti-programmed cell death-1 (PD-1)/PD ligand 1 (L1)-unresponsive tumors may benefit from advanced immunotherapy. Double-stranded RNA triggers dendritic cell (DC) maturation to cross-prime antigen-specific cytotoxic T lymphocytes (CTLs) via Toll-like receptor 3 (TLR3). The TLR3-specific RNA agonist, ARNAX, can induce anti-tumor CTLs without systemic cytokine/interferon (IFN) production. Here, we have developed a safe vaccine adjuvant for cancer that effectively implements anti-PD-L1 therapy. Co-administration of ARNAX with a tumor-associated antigen facilitated tumor regression in mouse models, and in combination with anti-PD-L1 antibody, activated tumor-specific CTLs in lymphoid tissues, enhanced CTL infiltration, and overcame anti-PD-1 resistance without cytokinemia. The TLR3-TICAM-1-interferon regulatory factor (IRF)3-IFN-β axis in DCs exclusively participated in CD8⁺ T cell cross-priming. ARNAX therapy established Th1 immunity in the tumor microenvironment, upregulating genes involved in DC/T cell/natural killer (NK) cell recruitment and functionality. Human ex vivo studies disclosed that ARNAX+antigen induced antigen-specific CTL priming and proliferation in peripheral blood mononuclear cells (PBMCs), supporting the feasibility of ARNAX for potentiating anti-PD-1/PD-L1 therapy in human vaccine immunotherapy.

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PD-1 blockade benefits a small proportion of cancer patients with pre-existing anti-tumor CTLs. Takeda et al. show that the TLR3-specific ligand, ARNAX, and tumor-associated antigens (TAAs) induce anti-tumor CTLs, establish Th1-type anti-tumor immunity, and lead to tumor regression without inflammation. Combination therapy using ARNAX/TAA and anti-PD-L1 Ab overcomes PD-1 blockade-unresponsiveness.


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Genome-wide Analysis of STAT3-Mediated Transcription during Early Human Th17 Cell Differentiation

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Subhash K. Tripathi, Zhi Chen, Antti Larjo, Kartiek Kanduri, Kari Nousiainen, Tarmo Äijo, Isis Ricaño-Ponce, Barbara Hrdlickova, Soile Tuomela, Essi Laajala, Verna Salo, Vinod Kumar, Cisca Wijmenga, Harri Lähdesmäki, Riitta Lahesmaa
The development of therapeutic strategies to combat immune-associated diseases requires the molecular mechanisms of human Th17 cell differentiation to be fully identified and understood. To investigate transcriptional control of Th17 cell differentiation, we used primary human CD4⁺ T cells in small interfering RNA (siRNA)-mediated gene silencing and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) to identify both the early direct and indirect targets of STAT3. The integrated dataset presented in this study confirms that STAT3 is critical for transcriptional regulation of early human Th17 cell differentiation. Additionally, we found that a number of SNPs from loci associated with immune-mediated disorders were located at sites where STAT3 binds to induce Th17 cell specification. Importantly, introduction of such SNPs alters STAT3 binding in DNA affinity precipitation assays. Overall, our study provides important insights for modulating Th17-mediated pathogenic immune responses in humans.

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Tripathi et al. show that STAT3 is critical for transcriptional regulation of early human Th17 cell differentiation. A number of SNPs from loci associated with immune-mediated disorders occur at STAT3-binding sites. Introduction of such SNPs alters STAT3 binding in DNA affinity precipitation assays.


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Specification and Diversification of Pericytes and Smooth Muscle Cells from Mesenchymoangioblasts

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Akhilesh Kumar, Saritha Sandra D'Souza, Oleg V. Moskvin, Huishi Toh, Bowen Wang, Jue Zhang, Scott Swanson, Lian-Wang Guo, James A. Thomson, Igor I. Slukvin
Elucidating the pathways that lead to vasculogenic cells, and being able to identify their progenitors and lineage-restricted cells, is critical to the establishment of human pluripotent stem cell (hPSC) models for vascular diseases and development of vascular therapies. Here, we find that mesoderm-derived pericytes (PCs) and smooth muscle cells (SMCs) originate from a clonal mesenchymal progenitor mesenchymoangioblast (MB). In clonogenic cultures, MBs differentiate into primitive PDGFRβ⁺CD271⁺CD73⁻ mesenchymal progenitors, which give rise to proliferative PCs, SMCs, and mesenchymal stem/stromal cells. MB-derived PCs can be further specified to CD274⁺ capillary and DLK1⁺ arteriolar PCs with a proinflammatory and contractile phenotype, respectively. SMC maturation was induced using a MEK inhibitor. Establishing the vasculogenic lineage tree, along with identification of stage- and lineage-specific markers, provides a platform for interrogating the molecular mechanisms that regulate vasculogenic cell specification and diversification and manufacturing well-defined mural cell populations for vascular engineering and cellular therapies from hPSCs.

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Kumar et al. find that mesodermal pericytes and smooth muscle cells in human pluripotent stem cell cultures originate from a common endothelial and mesenchymal cell precursor, the mesenchymoangioblast. They show how different lineages of mural cells are specified from mesenchymoangioblasts and define stage- and lineage-specific markers for vasculogenic cells.


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Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Takako Saito, Marcel Bokhove, Romina Croci, Sara Zamora-Caballero, Ling Han, Michelle Letarte, Daniele de Sanctis, Luca Jovine
Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor β (TGF-β) superfamily, mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1) and involved in tumor angiogenesis and preeclampsia. Here, we present crystal structures of the ectodomain of human ENG and its complex with the ligand bone morphogenetic protein 9 (BMP9). BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of ENG, which adopts a new duplicated fold generated by circular permutation. The interface involves residues mutated in HHT1 and overlaps with the epitope of tumor-suppressing anti-ENG monoclonal TRC105. The structure of the C-terminal zona pellucida module suggests how two copies of ENG embrace homodimeric BMP9, whose binding is compatible with ligand recognition by type I but not type II receptors. These findings shed light on the molecular basis of the BMP signaling cascade, with implications for future therapeutic interventions in this fundamental pathway.

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Endoglin (ENG)/CD105, a key player in angiogenesis and vascular homeostasis, is mutated in the genetic disorder HHT1 and implicated in tumor angiogenesis and preeclampsia. Saito et al. determine structures of human ENG alone and in complex with the physiological ligand BMP9, shedding light onto the molecular basis of BMP signaling.


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Sequential Steps of CRAC Channel Activation

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Raz Palty, Zhu Fu, Ehud Y. Isacoff
Interaction between the endoplasmic reticulum protein STIM1 and the plasma membrane channel ORAI1 generates calcium signals that are central for diverse cellular functions. How STIM1 binds and activates ORAI1 remains poorly understood. Using electrophysiological, optical, and biochemical techniques, we examined the effects of mutations in the STIM1-ORAI1 activating region (SOAR) of STIM1. We find that SOAR mutants that are deficient in binding to resting ORAI1 channels are able to bind to and boost activation of partially activated ORAI1 channels. We further show that the STIM1 binding regions on ORAI1 undergo structural rearrangement during channel activation. The results suggest that activation of ORAI1 by SOAR occurs in multiple steps. In the first step, SOAR binds to ORAI1, partially activates the channel, and induces a rearrangement in the SOAR-binding site of ORAI1. That rearrangement of ORAI1 then permits sequential steps of SOAR binding, via distinct molecular interactions, to fully activate the channel.

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How the interaction between STIM1 and the ORAI1 CRAC channel activates ORAI1 is poorly understood. Palty et al. identify mutations in STIM1 that disrupt partial activation but support the transition from partial to full activation. The study reveals the existence of sequential modes of STIM1-ORAI1 interaction.


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Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Marc Parisien, Samar Khoury, Anne-Julie Chabot-Doré, Susana G. Sotocinal, Gary D. Slade, Shad B. Smith, Roger B. Fillingim, Richard Ohrbach, Joel D. Greenspan, William Maixner, Jeffrey S. Mogil, Inna Belfer, Luda Diatchenko
Dorsal root ganglia (DRG) relay sensory information to the brain, giving rise to the perception of pain, disorders of which are prevalent and burdensome. Here, we mapped expression quantitative trait loci (eQTLs) in a collection of human DRGs. DRG eQTLs were enriched within untranslated regions of coding genes of low abundance, with some overlapping with other brain regions and blood cell cis-eQTLs. We confirm functionality of identified eQTLs through their significant enrichment within open chromatin and highly deleterious SNPs, particularly at the exon level, suggesting substantial contribution of eQTLs to alternative splicing regulation. We illustrate pain-related genetic association results explained by DRG eQTLs, with the strongest evidence for contribution of the human leukocyte antigen (HLA) locus, confirmed using a mouse inflammatory pain model. Finally, we show that DRG eQTLs are found among hits in numerous genome-wide association studies, suggesting that this dataset will help address pain components of non-pain disorders.

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Parisien et al. present a database of expression quantitative trait loci in human dorsal root ganglia. The dataset represents a tool for interpreting human GWAS with sensory components. Its analysis demonstrates contributions of the HLA locus to pain phenotypes.


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Quantitative Cell Cycle Analysis Based on an Endogenous All-in-One Reporter for Cell Tracking and Classification

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Thomas Zerjatke, Igor A. Gak, Dilyana Kirova, Markus Fuhrmann, Katrin Daniel, Magdalena Gonciarz, Doris Müller, Ingmar Glauche, Jörg Mansfeld
Cell cycle kinetics are crucial to cell fate decisions. Although live imaging has provided extensive insights into this relationship at the single-cell level, the limited number of fluorescent markers that can be used in a single experiment has hindered efforts to link the dynamics of individual proteins responsible for decision making directly to cell cycle progression. Here, we present fluorescently tagged endogenous proliferating cell nuclear antigen (PCNA) as an all-in-one cell cycle reporter that allows simultaneous analysis of cell cycle progression, including the transition into quiescence, and the dynamics of individual fate determinants. We also provide an image analysis pipeline for automated segmentation, tracking, and classification of all cell cycle phases. Combining the all-in-one reporter with labeled endogenous cyclin D1 and p21 as prime examples of cell-cycle-regulated fate determinants, we show how cell cycle and quantitative protein dynamics can be simultaneously extracted to gain insights into G1 phase regulation and responses to perturbations.

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Zerjatke et al. present endogenously tagged PCNA as an all-in-one cell cycle reporter for living cells to classify all cell cycle phases and quiescence using a single fluorescent channel. Visualizing endogenous cyclin D1 in living cells, they show that cyclin D1 maintains G1 phase and prevents the transition into quiescence.


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Clinical Significance and Prognostic Value of Femoral Lymph Node Metastasis in FIGO Stage III Vulvar Carcinoma

Publication date: Available online 31 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Hua Tu, Peng Sun, Haifeng Gu, Xinke Zhang, He Huang, Ting Wan, Jihong Liu
ObjectivesTo determine the clinical significance and prognostic value of femoral lymph node metastasis (FLNM) in patients with International Federation of Gynecology and Obstetrics (FIGO) stage III vulvar carcinoma.MethodsThe medical records of patients with vulvar carcinoma who underwent inguinofemoral lymphadenectomy between 1990 and 2013 were retrospectively reviewed.ResultsOf 66 patients with stage III vulvar carcinoma, 42 had superficial lymph node metastasis (SLNM) only and 24 had FLNM. Significantly higher rates of extracapsular invasion (P=0.008), multiple nodal metastasis (P=0.042), and advanced FIGO substage (P=0.026) as well as a larger tumor diameter (≥4 cm, P=0.023) and greater depth of invasion (≥5 mm, P=0.020) were observed among patients with FLNM compared to those with SLNM only. After a median follow-up of 46 months (range, 6–172 months), 35 patients experienced relapse and 30 died from disease. The 5-year cancer-specific survival (CSS) rates were 70.1% and 30.8% for patients with SLNM only and FLNM, respectively (P=0.001). In multivariate analysis, only FLNM was found to be an independent risk factor for reduced recurrence-free survival (RFS) and CSS among patients with stage III vulvar cancer (hazard ratio [HR]=2.277, P=0.037 for RFS; HR=2.360, P=0.042 for CSS). When the FLNM cases were considered together as stage IIIC, significant differences emerged in the RFS (P=0.002) and CSS (P=0.004) among the re-divided FIGO substages.ConclusionsFLNM represented an unfavorable status of node metastasis with a worse prognosis compared to that of SLNM alone, and this should be considered in a future FIGO staging system for vulvar cancer.



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Kr-POK (ZBTB7c) regulates cancer cell proliferation through glutamine metabolism

Publication date: Available online 30 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Man-Wook Hur, Jae-Hyeon Yoon, Min-Young Kim, Hyeonseok Ko, Bu-Nam Jeon
Kr-POK (ZBTB7c) is a kidney cancer-related POK transcription factor that not only represses transcription of CDKN1A but also increases expression of FASN. However, precisely how Kr-POK affects cell metabolism by controlling gene expression in response to an energy source in rapidly proliferating cells remains unknown. In this study, we characterized the molecular and functional features of Kr-POK in the context of tumor growth and glutamine metabolism. We found that cells expressing Kr-POK shRNA exhibited more severe cell death than control cells in glucose-deprived medium, and that knockdown of Kr-POK decreased glutamine uptake. Glutamine is critical for tumor cell proliferation. Glutaminase (GLS1), which is activated by p-STAT1, catalyzes the initial reaction in the pathway of glutaminolysis. Kr-POK interacts with PIAS1 to disrupt the interaction between PIAS1 and p-STAT1, and free p-STAT1 can activate GLS1 transcription through an interaction with p300. Kr-POK can be also sumoylated by PIAS1, facilitating Kr-POK degradation by the ubiquitin-mediated proteasomal pathway. Finally, we showed that repression of Kr-POK inhibited tumor growth in vivo in a xenograft model by repressing GLS1 expression. Taken together, our data reveal that Kr-POK activates GLS1 transcription and increases glutamine uptake to support rapid cancer cell proliferation.



http://ift.tt/2rSA7rY

Acetylation of MKL1 by PCAF regulates pro-inflammatory transcription

Publication date: Available online 30 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Liming Yu, Zilong Li, Mingming Fang, Yong Xu
Inflammation is considered a fundamental host defense mechanism and, when aberrantly activated, contributes to a host of human diseases. Previously we have reported that the transcriptional regulator megakaryocytic leukemia 1 (MKL1) plays a role programming cellular inflammatory response by modulating NF-κB activity. Here we report that MKL1 was acetylated in vivo and pro-inflammatory stimuli (TNF-α and LPS) augmented MKL1 acetylation accompanying increased MKL1 binding to NF-κB target promoters. Further analysis revealed that the lysine acetyltransferase PCAF mediated MKL1 acetylation: TNF-α and LPS promoted the interaction between MKL1 and PCAF while depletion of PCAF abrogated the induction of MKL1 acetylation by TNF-α and LPS. Acetylation of MKL1 was necessary for MKL1 to activate the transcription of pro-inflammatory genes because mutation of four conserved lysine residues in MKL1 attenuated its capacity as a trans-activator of NF-κB target genes. Mechanistically, MKL1 acetylation served to promote MKL1 nuclear enrichment, to enhance the MKL1-NF-κB interaction, and to stabilize the binding of MKL1 on target promoters. In conclusion, our data unveil an important pathway that contributes to the transcriptional regulation of inflammatory response.



http://ift.tt/2rTgqAq

Miscalculations can lead to misinterpretation of the results

Publication date: Available online 30 May 2017
Source:Cancer Epidemiology
Author(s): Leena Derwish




http://ift.tt/2skuHm2

Incidence and survival of childhood cancer in the French islands of Reunion and Mayotte (2005–2011)

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): J. Ramiandrisoa, M. Jehanne, F. Sauvat, Y. Reguerre, A. Chamouine, E. Chirpaz
The aim of this study is to describe childhood cancer incidence and survival in the French islands of Reunion and Mayotte for the period 2005–2011. Data were taken from the population-based Cancer Registry of Reunion Island. All incident cases of malignant tumours and benign tumours of the Central Nervous System diagnosed between 2005 and 2011 in children under the age of 15 and living in Reunion or Mayotte were included. A total of 236 cases were registered (176 in Reunion, 60 in Mayotte). Age-standardised incidence rates (ASRs, world standard) for all cancers were 125.0 and 101.8 per million for Reunion and Mayotte, respectively. ASRs for the main cancer groups were lower than those described in mainland France for the same period. The 5-year overall survival rate for all patients was 78.5% (95%CI 71.9- 83.7), slightly lower than that reported in mainland France.



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Integration Pattern of Human Papillomavirus Is a Strong Prognostic Factor for Disease-Free Survival After Radiation Therapy in Cervical Cancer Patients

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Jungnam Joo, Hye-Jin Shin, Boram Park, Seog-Yun Park, Chong-Woo Yoo, Kyong-Ah Yoon, Sun-Young Kong, Youn-Jae Kim, Sang Soo Kim, Joo-Young Kim
PurposeThe standard chemoradiation therapy currently used for locally advanced cervical cancer (LACC) patients does not reflect the biological heterogeneity of this disease, and there is an increasing need for the development of biomarkers that can help guide the individualized treatment regimens. The purpose of this study was to investigate the prognostic value of the integration pattern of human papillomavirus (HPV) in LACC patients.Methods and MaterialsThe HPV integration pattern was determined by in situ hybridization and polymerase chain reaction, and the tumors were classified as the episomal pattern (group A), as the single-copy integrated or multicopy tandem repetition–integrated pattern (group B), or as undetectable HPV (group C). Ninety-eight LACC patients were included in a development dataset and 106 independent patients in a validation dataset. The multivariate Cox model was used to examine the effect of the HPV integration pattern on disease-free survival (DFS). The model was validated internally by the leave-one-out cross-validation method and externally by an independent dataset.ResultsAfter adjustment for significant prognostic factors (stage, histologic grade, histologic type, and tumor size), the HPV integration pattern was significantly associated with DFS in the development (P=.032) and validation (P=.023) datasets. Survival was worst in group C and best in group A. The multivariate model with HPV integration pattern as an explanatory variable showed good discrimination ability and could separate patients with different risk profiles.ConclusionsThis study identified the HPV integration pattern, as determined by in situ hybridization and polymerase chain reaction, as a strong prognostic biomarker for DFS in LACC patients treated by chemoradiation therapy. This finding may open the possibility of personalized treatment of these patients.



http://ift.tt/2skzJ23

Radiobiology and the Renewed Potential for Nanoparticles

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Brian Marples, Shanta Dhar




http://ift.tt/2r9v6Kf

Prostate Cancer With Isolated Bony Metastasis: Sternal Struggle

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Mark T. Corkum




http://ift.tt/2qEgbo1

Treatment-Related Toxicity in Patients With Early-Stage Non-Small Cell Lung Cancer and Coexisting Interstitial Lung Disease: A Systematic Review

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Hanbo Chen, Suresh Senan, Esther J. Nossent, R. Gabriel Boldt, Andrew Warner, David A. Palma, Alexander V. Louie
PurposeDefinitive treatment for patients with early-stage non-small cell lung cancer (ES-NSCLC) is usually well tolerated. Patients with ES-NSCLC and coexisting interstitial lung disease (ILD) are at increased risk of severe treatment-related toxicity after definitive therapy. The main objective of this systematic review is to provide a pooled estimation of treatment-related mortality and ILD-specific toxicity in this population of patients and to identify trends for further study.Methods and MaterialsThe MEDLINE and Embase databases were queried from respective dates of inception to January 2016. Studies that included patients who underwent definitive treatment for ES-NSCLC not combined with other treatments were included. Patients with oligometastases who were treated with aggressive palliation were included if it did not constitute the majority of patients in a specific study. The results were summarized with weighted proportions according to the sample size of individual studies.ResultsOverall, 3056 records were reviewed and 50 journal articles were included in the abstraction. The weighted proportion of treatment-related mortality (and ILD-specific toxicity) in primarily medically inoperable patients was as follows: stereotactic ablative radiation therapy (SABR) 15.6% (25%), particle beam therapy 4.3% (18.2%) and radiofrequency ablation (RFA) 8.7% (25%). The data for medically operable patients who underwent surgery were extracted for reference. Treatment-related mortality and ILD-specific toxicity were 2.2% and 12%, respectively, in the surgical population. On analysis of reported SABR dose parameters, V20 ≤ 6.5% and mean lung dose ≤4.5 Gy were found to be metrics associated with reduced mortality.ConclusionA consistently high level of treatment-related mortality and ILD-specific toxicity was observed in primarily medically inoperable patients treated with SABR, particle beam therapy, and RFA. For these patients, curative treatment should be considered in the context of the high toxicity rates and overall poor prognosis. Stringent radiation dosimetric parameters may result in reduced toxicity.



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Treat All Known Disease

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Peter J. Hoskin




http://ift.tt/2r9uDIa

Prostate-Specific Membrane Antigen PET Before Aggressive Local Therapy to the Sternum

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Shankar Siva




http://ift.tt/2qEx7e1

Intriguing, but Not the Right Setting

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Kevin L. Stephans, Rupesh Kotecha




http://ift.tt/2r9r0BU

Issue Highlights

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3





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Sternum First, Perhaps Pelvis Later

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Brian J. Davis, Sean S. Park




http://ift.tt/2qEkBeA

Long-Term Survival Analysis of Stereotactic Ablative Radiotherapy Versus Liver Resection for Small Hepatocellular Carcinoma

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Ting-Shi Su, Ping Liang, Jian Liang, Huan-Zhen Lu, Hua-Yan Jiang, Tao Cheng, Yong Huang, Yang Tang, Xin Deng
PurposeTo compare the efficacy of stereotactic ablative radiation therapy (SABR) versus liver resection for small hepatocellular carcinoma (HCC) ≤5 cm with Child-Pugh A cirrhosis.Methods and MaterialsThis retrospective study included 117 patients with small HCCs with 1 or 2 nodules. Eighty-two patients received SABR (SABR group), and 35 patients underwent liver resection (resection group). Overall survival (OS) and progression-free survival (PFS) were analyzed. One-to-one matched pairs between the 2 groups were created using propensity score matching to reduce the potential confounding effect of treatment and selection bias.ResultsThere was no between-group difference in OS and PFS. Before propensity score matching, the 1-, 3-, and 5-year OS was 96.3%, 81.8%, and 70.0% in the SABR group and 93.9%, 83.1%, and 64.4% in the resection group, respectively (P=.558). The 1-, 3- and 5-year PFS was 81.4%, 50.2%, and 40.7% in the SABR group and 68.0%, 58.3%, and 40.3% in the resection group, respectively (P=.932). After propensity score matching, 33 paired patients were selected from the SABR and resection groups. The 1-, 3-, and 5-year OS was 100%, 91.8%, and 74.3% in the SABR group and 96.7%, 89.3%, and 69.2% in the resection group, respectively (P=.405). The 1-, 3-, and 5-year PFS was 84.4%, 59.2%, and 43.9% in the SABR group and 69.0%, 62.4%, and 35.9% in the resection group, respectively (P=.945). There was a similarity of hepatotoxicity between the 2 groups. The SABR group showed fewer complications, such as hepatic hemorrhage, hepatic pain, and weight loss. Acute nausea was significantly more frequent in the SABR group than in the resection group.ConclusionFor patients with small primary HCC with 1 or 2 nodules and Child-Pugh A cirrhosis, SABR has local effects that are similar to those with liver resection. Stereotactic ablative radiation therapy has an advantage over resection in being less invasive.



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Advancing Our Practice Through the Advanced Practice Radiation Therapist Model: Catching Up With Canada

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Neha Vapiwala, Meredith Giuliani, Nicole Harnett




http://ift.tt/2r9y3uy

Conservative Treatments of Ocular Melanomas: Technology Used Wisely

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Juliette Thariat, Joel Herault, Frederic Mouriaux




http://ift.tt/2qEvDQR

In Reply to Peñagarícano

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Oliver Micke, M. Heinrich Seegenschmiedt, Irenaeus A. Adamietz, Guenter Kundt, Khashayar Fakhrian, Ulrich Schaefer, Ralph Muecke




http://ift.tt/2skAwQF

Radiation Therapy in Palestine: Not Only Money, But Also Real Accessibility

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Maurizio Portaluri, Niveen Abu-Rmeileh, Emilio Gianicolo




http://ift.tt/2r9oKKU

Is It Time for New Target Volumes in Radiation Oncology?

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): David Palma




http://ift.tt/2r9JLFp

Plasma Levels of IL-8 and TGF-β1 Predict Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer: A Validation Study

Publication date: 1 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics, Volume 98, Issue 3
Author(s): Shulian Wang, Jeff Campbell, Matthew H. Stenmark, Jing Zhao, Paul Stanton, Martha M. Matuszak, Randall K. Ten Haken, Feng-Ming (Spring) Kong
Purpose and ObjectivesWe previously reported that the combination of mean lung dose (MLD) and inflammatory cytokines interleukin-8 (IL-8) and transforming growth factor-β1 (TGF-β1) may provide a more accurate model for radiation-induced lung toxicity (RILT) prediction in 58 patients with non-small cell lung cancer (NSCLC). This study is to validate the previous findings with new patients and to explore new models with more cytokines.Methods and MaterialsOne hundred forty-two patients with stage I-III NSCLC treated with definitive radiation therapy (RT) from prospective studies were included. Sixty-five new patients were used to validate previous findings, and all 142 patients were used to explore new models. Thirty inflammatory cytokines were measured in plasma samples before RT and 2 weeks and 4 weeks during RT (pre, 2w, 4w). Grade ≥2 RILT was defined as grade 2, and higher radiation pneumonitis or symptomatic pulmonary fibrosis was the primary endpoint. Logistic regression was performed to evaluate the risk factors of RILT. The area under the curve (AUC) for the receiver operating characteristic curves was used for model assessment.ResultsSixteen of 65 patients (24.6%) experienced RILT2. Lower pre IL-8 and higher TGF-β1 2w/pre ratio were associated with higher risk of RILT2. The AUC increased to 0.73 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.61 by MLD alone to predict RILT. In all 142 patients, 29 patients (20.4%) experienced grade ≥2 RILT. Among the 30 cytokines measured, only IL-8 and TGF-β1 were significantly associated with the risk of RILT2. MLD, pre IL-8 level, and TGF-β1 2w/pre ratio were included in the final predictive model. The AUC increased to 0.76 by combining MLD, pre IL-8, and TGF-β1 2w/pre ratio compared with 0.62 by MLD alone.ConclusionsWe validated that a combination of mean lung dose, pre IL-8 level, and TGF-β1 2w/pre ratio provided a more accurate model to predict the risk of RILT2 compared with MLD alone.



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Angiotensin Receptor Blockers Reduce Cardiovascular Events, Including the Risk of Myocardial Infarction.

Author: Messerli, Franz H. MD; Bangalore, Sripal MD, MHA

Page: 2085-2087

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Angiotensin Receptor Blockers Do Not Reduce Risk of Myocardial Infarction, Cardiovascular Death, or Total Mortality: Further Evidence for the ARB-MI Paradox.

Author: Strauss, Martin H. MD, BSc; Hall, Alistair S. MB ChB, PhD

Page: 2088-2090

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Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting.

Author: Natarajan, Pradeep MD, MMSc *; Young, Robin PhD *; Stitziel, Nathan O. MD, PhD; Padmanabhan, Sandosh MD, PhD; Baber, Usman MD; Mehran, Roxana MD; Sartori, Samantha PhD; Fuster, Valentin MD, PhD; Reilly, Dermot F. PhD; Butterworth, Adam PhD; Rader, Daniel J. MD; Ford, Ian PhD +; Sattar, Naveed MD, PhD +; Kathiresan, Sekar MD +

Page: 2091-2101

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Common Variants for Cardiovascular Disease: Clinical Utility Confirmed.

Author: Humphries, Steve E. PhD

Page: 2102-2105

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Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients With Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction.

Author: Halliday, Brian P. MBChB; Gulati, Ankur MD; Ali, Aamir MBChB; Guha, Kaushik MD; Newsome, Simon MSc; Arzanauskaite, Monika MD; Vassiliou, Vassilios S. MBBS; Lota, Amrit BMBCh; Izgi, Cemil MD; Tayal, Upasana BMBCh; Khalique, Zohya MBBS; Stirrat, Colin MBChB; Auger, Dominique MD; Pareek, Nilesh MD; Ismail, Tevfik F. PhD; Rosen, Stuart D. MD; Vazir, Ali PhD; Alpendurada, Francisco PhD; Gregson, John PhD; Frenneaux, Michael P. PhD; Cowie, Martin R. MD; Cleland, John G. F. PhD; Cook, Stuart A. PhD; Pennell, Dudley J. MD; Prasad, Sanjay K. MD

Page: 2106-2115

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Risk Stratification for Sudden Cardiac Death: Is It Too Late to Establish a Role for Cardiac MRI?.

Author: Markman, Timothy M. MD; Nazarian, Saman MD, PhD

Page: 2116-2118

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Multimodality Strategy for Cardiovascular Risk Assessment: Performance in 2 Population-Based Cohorts.

Author: de Lemos, James A. MD; Ayers, Colby R. MS; Levine, Benjamin MD; deFilippi, Christopher R. MD; Wang, Thomas J. MD; Hundley, W. Gregory MD; Berry, Jarett D. MD, MS; Seliger, Stephen L. MD; McGuire, Darren K. MD, MHSc; Ouyang, Pamela MBBS; Drazner, Mark H. MD, MSc; Budoff, Matthew MD; Greenland, Philip MD; Ballantyne, Christie M. MD; Khera, Amit MD, MSc

Page: 2119-2132

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Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study).

Author: Perez de Isla, Leopoldo MD, PhD; Alonso, Rodrigo MD, PhD; Mata, Nelva MD, PhD; Fernandez-Perez, Cristina MD, PhD; Muniz, Ovidio MD, PhD; Diaz-Diaz, Jose Luis MD, PhD; Saltijeral, Adriana MD, PhD; Fuentes-Jimenez, Francisco MD, PhD; de Andres, Raimundo MD, PhD; Zambon, Daniel MD, PhD; Piedecausa, Mar MD; Cepeda, Jose Maria MD; Mauri, Marta MD; Galiana, Jesus MD, PhD; Brea, Angel MD, PhD; Sanchez Munoz-Torrero, Juan Francisco MD, PhD; Padro, Teresa PhD; Argueso, Rosa MD; Miramontes-Gonzalez, Jose Pablo MD, PhD; Badimon, Lina PhD; Santos, Raul D. MD, PhD; Watts, Gerald F. MD, DSc; Mata, Pedro MD, PhD

Page: 2133-2144

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Temporal Trends in Adverse Events After Everolimus-Eluting Bioresorbable Vascular Scaffold Versus Everolimus-Eluting Metallic Stent Implantation: A Meta-Analysis of Randomized Controlled Trials.

Author: Montone, Rocco A. MD; Niccoli, Giampaolo MD, PhD; De Marco, Federico MD, PhD; Minelli, Silvia MD; D'Ascenzo, Fabrizio MD; Testa, Luca MD, PhD; Bedogni, Francesco MD; Crea, Filippo MD, PhD

Page: 2145-2154

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[gamma][delta] T Cells Mediate Angiotensin II-Induced Hypertension and Vascular Injury.

Author: Caillon, Antoine PhD; Mian, Muhammad Oneeb Rehman PhD; Fraulob-Aquino, Julio C. PhD; Huo, Ku-Geng BSc; Barhoumi, Tlili PhD; Ouerd, Sofiane MSc; Sinnaeve, Peter R. MD, PhD; Paradis, Pierre PhD; Schiffrin, Ernesto L. MD, PhD

Page: 2155-2162

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Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure.

Author: Sag, Can Martin MD *; Schnelle, Moritz MD, PhD *; Zhang, Juqian MD; Murdoch, Colin E. PhD; Kossmann, Sabine PhD; Protti, Andrea PhD; Santos, Celio X.C. PhD; Sawyer, Greta PhD; Zhang, Xiaohong MD; Mongue-Din, Heloise PhD; Richards, Daniel A. PhD; Brewer, Alison C. PhD; Prysyazhna, Oleksandra PhD; Maier, Lars S. MD; Wenzel, Philip MD; Eaton, Philip J. PhD; Shah, Ajay M. MD

Page: 2163-2177

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Magnetic Resonance Imaging of Cardiovascular Function and the Brain: Is Dementia a Cardiovascular-Driven Disease?.

Author: de Roos, Albert MD; van der Grond, Jeroen PhD; Mitchell, Gary MD; Westenberg, Jos PhD

Page: 2178-2195

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Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure: A Scientific Statement From the American Heart Association.

Author: Chow, Sheryl L. PharmD, FAHA, Chair; Maisel, Alan S. MD, Vice Chair; Anand, Inder MD, DPhil, FAHA; Bozkurt, Biykem MD, PhD, FAHA; de Boer, Rudolf A. MD, PhD, FAHA; Felker, G. Michael MD, MHS, FAHA; Fonarow, Gregg C. MD, FAHA; Greenberg, Barry MD, FAHA; Januzzi, James L. Jr MD; Kiernan, Michael S. MD; Liu, Peter P. MD, FAHA; Wang, Thomas J. MD, FAHA; Yancy, Clyde W. MD, MSc, FAHA; Zile, Michael R. MD, FAHA; On behalf of the American Heart Association Clinical Pharmacology Committee of the Council on Clinical Cardiology; Council on Basic Cardiovascular Sciences; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Epidemiology and Prevention; Council on Functional Genomics and Translational Biology; and Council on Quality of Care and Outcomes Research

Page: e1054-e1091

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Highlights From the Circulation Family of Journals.

Author:

Page: 2196-2201

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3D Printers Provide a Window into the Heart.

Author: Kuehn, Bridget M.

Page: 2202-2203

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Access to Nonstatin Lipid-Lowering Therapies in Patients at High Risk of Atherosclerotic Cardiovascular Disease.

Author: Knowles, Joshua W. MD, PhD; Howard, William B. PhD; Karayan, Lala MPH; Baum, Seth J. MD; Wilemon, Katherine A. BS; Ballantyne, Christie M. MD; Myers, Kelly D. BS

Page: 2204-2206

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The Revised Framingham Stroke Risk Profile in a Primary Prevention Population: The Rotterdam Study.

Author: Bos, Daniel MD, PhD; Ikram, M. Arfan MD, PhD; Leening, Maarten J. G. MD, PhD; Ikram, M. Kamran MD, PhD

Page: 2207-2209

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Letter by Saritas Regarding Article, "Total Anomalous Pulmonary Venous Connection: The Current Management Strategies in a Pediatric Cohort of 768 Patients".

Author: Saritas, Bulent MD

Page: e1092

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Letter by Ghimire Regarding Article, "Total Anomalous Pulmonary Venous Connection: The Current Management Strategies in a Pediatric Cohort of 768 Patients".

Author: Ghimire, Laxmi V. MD

Page: e1093-e1094

http://ift.tt/2sknsKQ

Response by Chen to Letters Regarding Article, "Total Anomalous Pulmonary Venous Connection: The Current Management Strategies in a Pediatric Cohort of 768 Patients".

Author: Chen, Huiwen MD, PhD

Page: e1095-e1096

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Predictors of Disruptions in Breast Cancer Care for Individuals with Schizophrenia

Background.

Patients with schizophrenia experience markedly increased breast cancer mortality, yet reasons for this disparity are poorly understood. We sought to characterize disruptions in breast cancer care for patients with schizophrenia and identify modifiable predictors of those disruptions.

Materials and Methods.

We performed a medical record review of 95 patients with schizophrenia and breast cancer treated at an academic cancer center between 1993 and 2015. We defined cancer care disruptions as processes that interfere with guideline-concordant cancer care, including delays to diagnosis or treatment, deviations from stage-appropriate treatment, and interruptions in treatment. We hypothesized that lack of psychiatric treatment at cancer diagnosis would be associated with care disruptions.

Results.

Half of patients with schizophrenia experienced at least one breast cancer care disruption. Deviations in stage-appropriate treatment were associated with breast cancer recurrence at 5 years (p = .045). Patients without a documented psychiatrist experienced more delays (p = .016), without documented antipsychotic medication experienced more deviations (p = .007), and with psychiatric hospitalizations after cancer diagnosis experienced more interruptions (p < .0001). Independent of stage, age, and documented primary care physician, lack of documented antipsychotic medication (odds ratio [OR] = 4.97, 95% confidence interval [CI] = 1.90, 12.98) and psychiatric care (OR = 4.56, 95% CI = 1.37, 15.15) predicted cancer care disruptions.

Conclusion.

Disruptions in breast cancer care are common for patients with schizophrenia and are associated with adverse outcomes, including cancer recurrence. Access to psychiatric treatment at cancer diagnosis may protect against critical disruptions in cancer care for this underserved population. The Oncologist 2017;22:1–9

Implications for Practice.

Disruptions in breast cancer care are common for patients with schizophrenia, yet access to mental health treatment is rarely integrated into cancer care. When oncologists documented a treating psychiatrist and antipsychotic medication, patients had fewer disruptions in breast cancer care after adjusting for age, cancer stage, and access to primary care. Addressing psychiatric comorbidity at breast cancer diagnosis may increase the likelihood that patients with schizophrenia receive timely, stage-appropriate cancer treatment. Comanagement of schizophrenia and breast cancer at cancer diagnosis may be one key strategy to decrease inequities in cancer treatment and improve cancer survival in this underserved population.

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Targeting the Molecular Subtypes of Triple Negative Breast Cancer: Understanding the Diversity to Progress the Field

Triple negative breast cancers (TNBCs) represent 10%–20% of primary breast cancers, and despite having greater initial sensitivity to cytotoxic chemotherapy, patients with TNBCs have higher rates of distant metastasis and a poorer prognosis compared with patients with hormone receptor positive and/or human epidermal growth factor receptor 2 positive disease. TNBC has historically been treated as a single disease entity in targeted therapy trials, but advances in gene expression profiling and other molecular diagnostic techniques over the last decade have revealed considerable biologic heterogeneity within TNBCs, including subgroups with distinct, targetable aberrations. Such molecular heterogeneity explains, in part, the disappointing performance of targeted therapeutics in unselected TNBC. Here we discuss the history of gene expression profiling in breast cancer and its application in partitioning TNBCs into subtypes that may lead to more consistent therapeutic successes in this heterogeneous disease. The Oncologist 2017;22:1–8

Implications For Practice.

Triple negative breast cancers (TNBCs) have historically been regarded as a single entity in clinical trial design. Over the last decade, molecular characterization has revealed much heterogeneity in TNBCs, explaining in part the lackluster performance of targeted therapeutics in TNBCs as a group. In this article, we review the history of the molecular classification of breast cancer based on gene expression profiling and discuss its role in TNBCs.

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Attitudes Toward Cancer and Cancer Patients in an Urban Iranian Population

Background.

Because of the significant incidence and mortality of cancer in Iran, a Comprehensive National Cancer Control Program for the prevention and early detection of cancer was launched in 2007. However, cancer awareness and screening rates in Iran did not improve. This study aimed to evaluate public attitudes toward cancer and cancer patients in Iran.

Materials and Methods.

We conducted a cross-sectional survey among 953 non-institutionalized individuals in Isfahan, Iran, from November 2014 to February 2015. We collected data on attitudes toward cancer in three domains (impossibility of recovery, cancer stereotypes, and discrimination), as well as questions on willingness to disclose a cancer diagnosis.

Results.

Among all participants, 33.9% agreed that it is very difficult to regain one's health after a cancer diagnosis, 17.4% felt uncomfortable with a cancer patient, and 26.9% said that they would avoid marrying people whose family members had cancer. While 88.9% of study participants said that cancer patients deserve to be protected in society, 53.3% and 48.4% of participants agreed that they would not disclose a cancer diagnosis to neighbors and coworkers, respectively.

Conclusion.

Negative attitudes with respect to impossibility of recovery and discrimination toward cancer and cancer patients were common among urban Iranians. Most people would not disclose a cancer diagnosis to others in spite of advancements in cancer diagnosis and treatment, reflecting unfavorable attitudes toward cancer and cancer patients in society. Successful implementation of cancer awareness and prevention programs in Iran may require social changes based on adequate information on cancer and cancer patients. The Oncologist 2017;22:1–7

Implications for Practice.

Public attitudes toward cancer and cancer patients are an important factor affecting cancer control programs as well as quality of life and recovery of cancer patients. The issue has not been studied in Iran and the surrounding countries in the Middle East. This is the first report presented on the subject. These findings can be used by health policy makers, health managers, and clinicians for better practice.

http://ift.tt/2qEfQ4w

Complete Responses to Mitotane in Metastatic Adrenocortical Carcinoma--A New Look at an Old Drug

Purpose.

Based largely on reports that predate modern reporting standards, mitotane has been considered a systemic treatment option for both hormone control and antitumor control of metastatic adrenocortical cancer (ACC), although the therapeutic window is narrow.

Methods.

We searched electronic medical records to identify patients with metastatic ACC treated and prescribed single agent mitotane at Memorial Sloan Kettering Cancer Center from March 15, 1989–September 18, 2015. Reference radiologists reviewed all imaging and determined efficacy according to Response Evaluation Criteria in Solid Tumors 1.1. Patient demographics, toxicities, and treatment outcomes were reviewed. Next generation sequencing was performed in selected cases.

Results.

Thirty-six patients were identified. The mean age was 54 and 50% had functional tumors. Grade 3 or greater toxicities were documented in 16 out of 36 patients (44%) and 17% had documented long term adrenal insufficiency. Progression of the disease as the best response occurred in 30 out of 36 patients (83%) and one patient (3%) experienced clinical progression. Three patients achieved a complete response (CR) (8%), one patient achieved a partial response (3%), and one patient (3%) had stable disease after slow disease progression prior to initiation of therapy (durable for 6 months). All responders had nonfunctional tumors. Next generation sequencing in two of the three CR patients was performed and failed to identify any novel alterations.

Conclusion.

In this retrospective series, mitotane had a low response rate and low tumor control rate; however, a disproportionately high complete response rate suggested it should be used in selected individuals. Adrenal insufficiency is common with mitotane use and aggressive treatment with steroid supplementation should be considered when appropriate to avoid excess toxicities. Biomarkers are desperately needed to further define this disease. The Oncologist 2017;22:1–5

Implications for Practice.

This is the first objective report of single agent mitotane using modern objective criteria. Although the vast majority of patients did not respond (and toxicity was high), we identified a remarkable 8% complete response rate (i.e. cure) in biopsy proven stage IV adrenocortical cancer patients. Biomarkers are desperately needed for this rare disease.

http://ift.tt/2r9r84o

Case Report: Encephalitis, with Brainstem Involvement, Following Checkpoint Inhibitor Therapy in Metastatic Melanoma

Checkpoint inhibitors are increasingly being used in the treatment of malignant melanoma and other cancers. With the use of such therapies, autoimmune-mediated adverse events in the central and peripheral nervous system are likely to occur more frequently. We report a unique case of brainstem encephalitis with a sudden lethal outcome following ipilimumab and pembrolizumab therapy in a patient with malignant melanoma. The autopsy showed a diffuse nodular activation of microglia in the whole encephalon with prominent intraparenchymal and perivascular lymphocytic infiltration of the brainstem. Non-infectious brainstem encephalitis is a well-recognized subset of paraneoplastic encephalitis. Brainstem involvement is usually accompanied by a wide spectrum of signs and symptoms, which were not observed in this case. The timing of the clinical symptoms as well as the histopathological findings suggest an autoimmune-adverse event of ipilimumab and pembrolizumab administration rather than a paraneoplastic disorder. In the presence of neurological symptoms, immediate cessation of the immunotherapy and immunosuppressive therapy may lead to successful therapeutic intervention, as described in previous reports. Therefore, it is crucial that physicians are aware of the possible side effects of immunotherapies on the nervous system. The Oncologist 2017;22:1–5

Implications for Practice.

Metastatic melanoma patients treated with the anti-CTLA-4 inhibitor ipilimumab have a high utilization of various types of health care services, such as inpatient hospital stays or doctor visits. There are differences across countries regarding patterns of health care utilization and economic burden of the disease. Health care services are used more frequently after patients experience progression of their disease. The study highlights that better therapies leading to durable response in patients with metastatic melanoma have the potential to decrease health care costs and patient burden in terms of hospitalizations and other health care services.

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Association of Pre-Chemotherapy Peripheral Blood Pro-Inflammatory and Coagulation Factors with Physical Function in Women with Breast Cancer

Background.

Pro-inflammatory and coagulation factors serve as biomarkers of aging and functional reserve. The purpose of this study was to determine if pro-inflammatory (interleukin-6 [IL-6], C-reactive protein [CRP]), and coagulation (D-dimer) factors were associated with pre-chemotherapy functional status in women with stage I–III breast cancer.

Patients and Methods.

Prior to chemotherapy initiation in patients with stage I–III breast cancer, the following was captured: IL-6, CRP, D-dimer blood levels, and physical function measures including activities of daily living (ADL, subscale of Medical Outcomes Study Physical Health); instrumental activities of daily living (IADL, subscale of the Older Americans Resources and Services Program); Timed Up and Go (TUG); physician-rated Karnofsky Performance Status (KPS); and self-rated KPS. The association of these biomarkers with physical function measures was evaluated.

Results.

One hundred sixty patients (mean age 58.3 years, range 30–81 years) with stage I–III breast cancer (stages I [n = 34; 21.5%], II [n = 88; 55.7%], III [n = 36; 22.8%]) were enrolled. The group with poorest physical function (defined by ADL <70, IADL <14, and TUG ≥10 seconds) had higher levels of IL-6 (p = .05), D-dimer (p = .0004), and CRP (p = .05). There was no significant association between these biomarkers and KPS. Patients with at least two biomarkers in the highest quartile were more likely to have poorer physical function (odds ration [OR] 18.75, p < .001). In multivariate analysis adjusting for age, stage, number of comorbidities, and body mass index, the association remained (OR 14.6, p = .002).

Conclusion.

Pre-chemotherapy biomarkers of aging are associated with poorer physical function among patients with breast cancer across the aging spectrum. The Oncologist 2017;22:1–7

Implications for Practice.

Commonly used physical function assessment tools may not reflect the diverse nature of physical function and risk for chemotherapy toxicity, particularly in older adults. No laboratory test reflects functional reserve. Pro-inflammatory and coagulation factors, such as IL-6, CRP, and D-dimer, can serve as biomarkers of aging and physical function; however, few studies have evaluated their utility in patients with cancer. This study was designed to understand the association between pre-chemotherapy biomarkers and physical function in women with early stage breast cancer undergoing adjuvant chemotherapy. Results indicate that elevated pre-chemotherapy levels in two of the three peripheral biomarkers are associated with the poorest physical function among patients with breast cancer across the aging spectrum.

http://ift.tt/2qE2UMk

Social Network Structures of Breast Cancer Patients and the Contributing Role of Patient Navigators

Background.

Minority women in the U.S. continue to experience inferior breast cancer outcomes compared with white women, in part due to delays in care delivery. Emerging cancer care delivery models like patient navigation focus on social barriers, but evidence demonstrating how these models increase social capital is lacking. This pilot study describes the social networks of newly diagnosed breast cancer patients and explores the contributing role of patient navigators.

Materials and Methods.

Twenty-five women completed a one hour interview about their social networks related to cancer care support. Network metrics identified important structural attributes and influential individuals. Bivariate associations between network metrics, type of network, and whether the network included a navigator were measured. Secondary analyses explored associations between network structures and clinical outcomes.

Results.

We identified three types of networks: kin-based, role and/or affect-based, or heterogeneous. Network metrics did not vary significantly by network type. There was a low prevalence of navigators included in the support networks (25%). Network density scores were significantly higher in those networks without a navigator. Network metrics were not predictive of clinical outcomes in multivariate models.

Conclusion.

Patient navigators were not frequently included in support networks, but provided distinctive types of support. If navigators can identify patients with poorly integrated (less dense) social networks, or who have unmet tangible support needs, the intensity of navigation services could be tailored. Services and systems that address gaps and variations in patient social networks should be explored for their potential to reduce cancer health disparities. The Oncologist 2017;22:1–7

Implications for Practice.

This study used a new method to identify the breadth and strength of social support following a diagnosis of breast cancer, especially examining the role of patient navigators in providing support. While navigators were only included in one quarter of patient support networks, they did provide essential supports to some individuals. Health care providers and systems need to better understand the contributions of social supports both within and outside of health care to design and tailor interventions that seek to reduce health care disparities and improve cancer outcomes.

http://ift.tt/2r9D9qz

Ceftriaxone reverses deficits of behavior and neurogenesis in an MPTP-induced rat model of Parkinson’s disease dementia

Publication date: Available online 30 May 2017
Source:Brain Research Bulletin
Author(s): Ming-Hong Hsieh, Wan-Yun Meng, Wen-Chieh Liao, Jun-Cheng Weng, Hsin-Hua Li, Hong-Lin Su, Chih-Li Lin, Ching-Sui Hung, Ying-Jui Ho
Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinson's disease (PD) so that glutamatergic modulation maybe a potential therapeutic target for PD. Ceftriaxone (CEF) has been reported to increase glutamate uptake by increasing glutamate transporter expression and has been demonstrated neuroprotective effects in animal study. The aim of this study was to determine the effects of CEF on behavior and neurogenesis in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. MPTP was stereotaxically injected into the substantia nigra pars compacta (SNc) of male Wistar rats. Starting on the same day after MPTP lesioning (day 0), the rats were injected daily with either CEF or saline for 14days and underwent a T-maze test on days 8-10 and an object recognition test on days 12-14, then the brain was taken for histological evaluation on day 15. The results showed that MPTP lesioning resulted in decreased motor function, working memory, and object recognition and reduced neurogenesis in the substantial nigra and dentate gyrus of the hippocampus. These behavioral and neuronal changes were prevented by CEF treatment. To our knowledge, this is the first study showing that CEF prevents loss of neurogenesis in the brain of PD rats. CEF may therefore have clinical potential in the treatment of PD.



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Rotator cuff tendinopathy alters the muscle activity onset and kinematics of scapula

Publication date: Available online 30 May 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Hio Teng Leong, Gabriel Yin-fat Ng, Shing Chung Chan, Siu Ngor Fu
Athletes with rotator cuff (RC) tendinopathy demonstrate an aberrant pattern of scapular motion which might relate to deficits in the scapular muscles. This study aimed to determine whether alteration in scapular kinematics is associated with deficits in the activity onset of scapular muscles. Forty-three male volleyball players (17 asymptomatic and 26 with RC tendinopathy) joined the study. Three-dimensional scapular kinematics was quantified using an acromial marker cluster method. The activity onset of the upper (UT), middle (MT), and lower trapezius (LT), and serratus anterior (SA) during arm abduction was assessed with electromyography. Athletes with RC tendinopathy demonstrated less scapular upward rotation (6.6 ± 2.3° vs. 8.2 ± 1.1°, p = 0.021) in the early phase of shoulder abduction from 0° to 30° when compared to asymptomatic athletes. The tendinopathy group had delayed activity onset of LT (14.1 ± 31.4 ms vs. 74.4 ± 45.1 ms, p < 0.001) and SA (-44.9 ± 26.0 ms vs. 23.0 ± 25.2 ms, p < 0.001) relative to UT when compared to the asymptomatic group. In asymptomatic athletes, earlier activity onset of MT and LT relative to UT was associated with more scapular upward rotation during 0° to 30° of abduction (r = 0.665, p = 0.021) and 30° to 60° of abduction (r = 0.680, p = 0.015), respectively. Our findings showed the control of the scapular upward rotation is related to the activity onset of the scapular muscles in athletes.



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Ankle and knee biomechanics during normal walking following ankle plantarflexor fatigue

Publication date: Available online 30 May 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Michael A. Hunt, Gillian L. Hatfield
The purpose of this study was to investigate the immediate effects of unilateral ankle plantarflexor fatigue on bilateral knee and ankle biomechanics during gait. Lower leg kinematics, kinetics, and muscle activation were assessed before and after an ankle plantarflexor fatiguing protocol in 31 healthy individuals. Fatigue (defined as > 10% reduction in maximal isometric ankle plantarflexor torque production and a downward shift in the median power frequency of both heads of the gastrocnemius muscle of the fatigued limb) was achieved in 18 individuals, and only their data were used for analysis purposes. Compared to pre-fatigue walking trials, medial gastrocnemius activity was significantly reduced in the study (fatigued) limb. Other main changes following fatigue included significantly more knee flexion during loading, and an associated larger external knee flexion moment in the study limb. At the ankle joint, participants exhibited significantly less peak plantarflexion (occurring at toe-off) with fatigue. No significant differences were observed in the contralateral (non-fatigued) limb. Findings from this study indicate that fatigue of the ankle plantarflexor muscle does not produce widespread changes in gait biomechanics, suggesting that small to moderate changes in maximal ankle plantarflexor force production capacity (either an increase or decrease) will not have a substantial impact on normal lower limb functioning during gait.



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Long term beneficial effect of neurotrophic factors-secreting mesenchymal stem cells transplantation in the BTBR mouse model of autism

Publication date: 28 July 2017
Source:Behavioural Brain Research, Volume 331
Author(s): Nisim Perets, Hadar Segal-Gavish, Yael Gothelf, Ran Barzilay, Yael Barhum, Natalie Abramov, Stav Hertz, Darya Morozov, Michael London, Daniel Offen
Autism spectrum disorders (ASD) are neurodevelopmental disabilities characterized by severe impairment in social communication skills and restricted, repetitive behaviors. We have previously shown that a single transplantation of mesenchymal stem cells (MSC) into the cerebral lateral ventricles of BTBR autistic-like mice resulted in an improvement across all diagnostic criteria of ASD. We suggested that brain-derived neurotrophic factor (BDNF), a protein which supports the survival and regeneration of neurons secreted by MSC, largely contributed to the beneficial behavioral effect. In this study, we investigated the behavioral effects of transplanted MSC induced to secrete higher amounts of neurotrophic factors (NurOwn^®), on various ASD-related behavioral domains using the BTBR mouse model of ASD. We demonstrate that NurOwn^® transplantation had significant advantages over MSC transplantation in terms of improving communication skills, one and six months following treatment, as compared to sham-treated BTBR mice. Furthermore, NurOwn^® transplantation resulted in reduced stereotypic behavior for as long as six months post treatment, compared to the one month improvement observed in the MSC treated mice. Notably, NurOwn^® treatment resulted in improved cognitive flexibility, an improvement that was not observed by MSC treatment. Both MSC and NurOwn^® transplantation induced an improvement in social behavior that lasted for six months. In conclusion, the present study demonstrates that a single transplantation of MSC or NurOwn^® have long-lasting benefits, while NurOwn^® may be superior to MSC treatment.



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Reduced Vesicular Acetylcholine Transporter favors antidepressant behaviors and modulates serotonin and dopamine in female mouse brain

Publication date: 14 July 2017
Source:Behavioural Brain Research, Volume 330
Author(s): Marina Pádua-Reis, Nayara S. Aquino, Vinícius E.M. Oliveira, Raphael E. Szawka, Marco A.M. Prado, Vânia F. Prado, Grace S. Pereira
Depression is extremely harmful to modern society. Despite its complex spectrum of symptoms, previous studies have mostly focused on the monaminergic system in search of pharmacological targets. However, other neurotransmitter systems have also been linked to the pathophysiology of depression. In this study, we provide evidence for a role of the cholinergic system in depressive-like behavior of female mice. We evaluated mice knockdown for the vesicular acetylcholine transporter (VAChT KD mice), which have been previously shown to exhibit reduced cholinergic transmission. Animals were subjected to the tail suspension and marble burying tests, classical paradigms to assess depressive-like behaviors and to screen for novel antidepressant drugs. In addition, brain levels of serotonin and dopamine were measured by high performance liquid chromatography. We found that female homozygous VAChT KD mice spent less time immobile during tail suspension and buried less marbles, indicating a less depressive phenotype. These differences in behavior were reverted by central, but not peripheral, acetylcholinesterase inhibition. Moreover, female homozygous VAChT KD mice exhibited higher levels of dopamine and serotonin in the striatum, and increased dopamine in the hippocampus. Our study thus shows a connection between depressive-like behaviors and the cholinergic system, and that the latter interacts with the monoaminergic system.



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Time and Speed of Vascular Pedicle Dissection in Deep Inferior Epigastric Artery Perforator Flap Elevation

J reconstr Microsurg
DOI: 10.1055/s-0037-1603351

Introduction Breast reconstruction using deep inferior epigastric artery perforator (DIEP) free flap is widely used because of the advantages of minimizing donor-site morbidity, but it requires technical competency in vascular dissection. This study evaluated the influence of patient factors and vascular status on the time and speed of dissection of the vascular pedicle. Methods DIEP free flap procedures were performed in 49 patients assigned to immediate or delayed reconstruction groups. Factors that significantly influenced the time required and the speed of dissection were evaluated. Results The average total dissection time was 55.9 minutes (34.5 minutes for the intramuscular dissection and 21.4 minutes for the submuscular dissection). The dissection speed for the total vascular pedicle was 2.65 cm/10 minutes (1.71 cm/10 minutes for the intramuscular dissection and 4.30 cm/10 minutes for the submuscular dissection). The presence of a Pfannenstiel scar, length of the vascular pedicle in the intramuscular area, and the number of microclips used significantly correlated with the total dissection time. Conclusion The length of the intramuscular pedicle, number of microclips used, and presence of a Pfannenstiel scar significantly correlated with the total dissection time of the vascular pedicle. An assessment prior to the surgery can reduce the time of operation and make it easier to elevate the flap.
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Scholar : These new articles for Amyloid are available online

The online platform for Taylor & Francis Online content New for Amyloid and online now on Taylor & Francis Online: Original Article Diagnostic score for the detection of cardiac amyloidosis in patients with left ventricular hypertrophy and impact on prognosis Eve Cariou, Youssef Bennani Smires, Gérard Victor, Guillaume Robin, David Ribes, Pierre Pascal, Antoine Petermann, Pauline Fournier, Stanislas Faguer, Jérôme Roncalli, Hervé Rousseau, Dominique Chauveau, Didier Carrié, Isabelle Berry, Michel Galinier & Olivier Lairez; On behalf of the Toulouse Amyloidosis Research Network collaborators Pages: 1-9 | DOI: 10.1080/13506129.2017.1333956 Free access World Diabetes Day research collection – Eyes on Diabetes. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

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