Retraction Notice to: Activation of the PPAR/PGC-1α Pathway Prevents a Bioenergetic Deficit and Effectively Improves a Mitochondrial Myopathy Phenotype

Publication date: 13 December 2016
Source:Cell Metabolism, Volume 24, Issue 6
Author(s): Tina Wenz, Francisca Diaz, Bruce M. Spiegelman, Carlos T. Moraes




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Bacterial Colonization and Antibiotic Resistance in a Prospective Cohort of Newborn Infants During the First Year of Life.

Related Articles

Bacterial Colonization and Antibiotic Resistance in a Prospective Cohort of Newborn Infants During the First Year of Life.

Open Forum Infect Dis. 2016 Oct;3(4):ofw221

Authors: Meropol SB, Stange KC, Jacobs MR, Weiss JK, Bajaksouzian S, Bonomo RA

Abstract
BACKGROUND: Infants are virtually sterile at birth and frequently use antibiotics; our objective was to (1) characterize the longitudinal colonization with bacterial pathogens and associated antibiotic resistance in a cohort of community-dwelling infants in Northeast Ohio and (2) describe longitudinal concurrent antibiotic and daycare exposures.
METHODS: For 35 newborns, nasopharyngeal swabs were cultured for Streptococcus pneumoniae, anterior nasal for Staphylococcus aureus, and perirectal for extended-spectrum beta-lactamase (ESBL)-producing Gram-negative enteric bacteria, at 3-month intervals for 12 months. Infant and household antibiotics and daycare exposure were assessed longitudinally.
RESULTS: Thirteen infants received perinatal or nursery antibiotics. By 3 months, at least 22 were colonized with Gram-negative bacteria; 2 with S pneumoniae (type 19A, resistant; 15C, susceptible), 5 with methicillin-susceptible S aureus. By 12 months, at least 22 of 35 infants received antibiotics, 20 had household members with antibiotics, and 12 attended daycare; 7 more had household members with daycare exposure. The ESBL-producing organisms were not identified. At least 10 infants were colonized at some time with an antibiotic-resistant organism, 3 more with pathogens displaying intermediate resistance. Pathogen colonization and resistance were intermittent and inconsistent.
CONCLUSIONS: In a community-based cohort followed from birth, early antibiotic and daycare exposures are common, especially considering perinatal maternal exposures. Colonization patterns of Gram-negative bacteria, S pneumoniae, S aureus, and resistant pneumococci are strikingly dynamic. Further research can identify key areas for potential interventions to maximize clinical antibiotic outcomes while minimizing future resistance.

PMID: 27957505 [PubMed - in process]

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Oral shedding of human herpesviruses in patients undergoing radiotherapy/chemotherapy treatment for head and neck squamous cell carcinoma

Abstract

Objective

Opportunistic infections may affect the oral mucosa of patients undergoing radio/chemotherapy through exacerbation of oral mucositis. The aim of this study is to evaluate the oral shedding of all eight human herpesviruses and its possible association with oral mucositis.

Materials and methods

In this prospective cohort study, we analyzed oral rinse samples, collected weekly, from 20 patients during radiotherapy treatment. Serologic status to HSV1 and HSV2, EBV, CMV, and VZV in three different periods was performed by ELISA assay. PCR and enzymatic digestion was performed to detect HSV1, HSV2, EBV, CMV, VZV, HHV6, HHV7, and HHV8. Oral mucositis was evaluated according to the WHO criteria.

Results

Oral shedding of EBV, HHV6, and HHV7 was observed in all weeks of radiotherapy. Considering the episodes of shedding, the highest frequency was found in patients with EBV excretion (55.0%). No virus reactivation was observed by serological analysis. EBV oral shedding frequency was significantly higher than that of other viruses and showing a positive correlation with oral mucositis grade ≥2.

Conclusions

There was a positive correlation between EBV oral shedding and oral mucositis grade ≥2, particularly after 3 weeks of radiotherapy, a period in which the severity of mucositis was statistically higher. These findings allow us to infer that the local inflammatory environment in mucositis grade ≥2 is more favorable for EBV replication.

Clinical relevance

Mucositis is a frequent and important side effect of radio/chemotherapy treatment. Understanding the possible participation of viruses in the mechanism of this condition is important to develop strategies for treatment and prevention.

http://ift.tt/2hu0ZGT

Divergent Roles of Endothelial Nitric Oxide Synthases System in Maintaining Cardiovascular Homeostasis

Publication date: Available online 14 December 2016
Source:Free Radical Biology and Medicine
Author(s): Shigeo Godo, Hiroaki Shimokawa
Accumulating evidence has demonstrated the importance of reactive oxygen species (ROS) as an essential second messenger in health and disease. Endothelial dysfunction is the hallmark of atherosclerotic cardiovascular diseases, in which pathological levels of ROS are substantially involved. The endothelium plays a crucial role in modulating tone of underlying vascular smooth muscle by synthesizing and releasing nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) factors in a distinct vessel size-dependent manner through the diverse roles of the endothelial NO synthases (NOSs) system. Endothelium-derived hydrogen peroxide (H2O2) is a physiological signaling molecule serving as one of the major EDH factors especially in microcirculations and has gained increasing attention in view of its emerging relevance for cardiovascular homeostasis. In the clinical settings, it has been reported that antioxidant supplements are unexpectedly ineffective to prevent cardiovascular events. These lines of evidence indicate the potential importance of the physiological balance between NO and H2O2/EDH through the diverse functions of endothelial NOSs system in maintaining cardiovascular homeostasis. A better understanding of cardiovascular redox signaling is certainly needed to develop novel therapeutic strategies in cardiovascular medicine. In this review, we will briefly summarize the current knowledge on the emerging regulatory roles of redox signaling pathways in cardiovascular homeostasis, with particular focus on the two endothelial NOSs-derived mediators, NO and H2O2/EDH.



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Chemical Basis for the Disparate Neuroprotective Effects of the Anthocyanins, Callistephin and Kuromanin, Against Nitrosative Stress

Publication date: Available online 13 December 2016
Source:Free Radical Biology and Medicine
Author(s): Aimee N. Winter, Erika K. Ross, Sonia Khatter, Keith Miller, Daniel A. Linseman
Oxidative and nitrosative stress are major factors in neuronal cell death underlying neurodegenerative disease. Thus, supplementation of antioxidant defenses may be an effective therapeutic strategy for diseases such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. In this regard, treatment with nutraceutical antioxidants has garnered increasing attention; however, the differential neuroprotective effects of structurally similar nutraceuticals, which may affect their suitability as therapeutic agents, has not been directly examined. In this study we compare the ability of two anthocyanins, callistephin (pelargonidin-3-O-glucoside) and kuromanin (cyanidin-3-O-glucoside) to protect cerebellar granule neurons from damage induced by either oxidative or nitrosative stress. These anthocyanins differ by the presence of a single hydroxyl group on the B-ring of kuromanin, forming a catechol moiety. While both compounds protected neurons from oxidative stress induced by glutamate excitotoxicity, a stark contrast was observed under conditions of nitrosative stress. Only kuromanin displayed the capacity to defend neurons from nitric oxide (NO)-induced apoptosis. This protective effect was blocked by addition of Cu, Zn-superoxide dismutase, indicating that the neuroprotective mechanism is superoxide dependent. Based on these observations, we suggest a unique mechanism by which slight structural variances, specifically the absence or presence of a catechol moiety, lend kuromanin the unique ability to generate superoxide, which acts as a scavenger of NO. These findings indicate that kuromanin and compounds that share similar chemical characteristics may be more effective therapeutic agents for treating neurodegenerative diseases than callistephin and related (non-catechol) compounds.



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Editorial Board

Publication date: December 2016
Source:Free Radical Biology and Medicine, Volume 101





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Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Raya Ahmed, Laureline Roger, Pedro Costa del Amo, Kelly L. Miners, Rhiannon E. Jones, Lies Boelen, Tinhinane Fali, Marjet Elemans, Yan Zhang, Victor Appay, Duncan M. Baird, Becca Asquith, David A. Price, Derek C. Macallan, Kristin Ladell
Adaptive immunity requires the generation of memory T cells from naive precursors selected in the thymus. The key intermediaries in this process are stem cell-like memory T (TSCM) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the TSCM pool may be imprinted statically as a function of largely dormant cells and/or retained dynamically by more transitory subpopulations. To explore the origins of immunological memory, we measured the turnover of TSCM cells in vivo using stable isotope labeling with heavy water. The data indicate that TSCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, TSCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that TSCM cells exist in a state of perpetual flux throughout the human lifespan.

Graphical abstract

Teaser

Stem cell-like memory T (TSCM) cells are multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. Ahmed et al. find that human TSCM cells are maintained by ongoing proliferation and display limited telomere length erosion coupled with high expression levels of active telomerase and Ki67.


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A Combinatorial CRISPR-Cas9 Attack on HIV-1 DNA Extinguishes All Infectious Provirus in Infected T Cell Cultures

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Gang Wang, Na Zhao, Ben Berkhout, Atze T. Das
Current drug therapies effectively suppress HIV-1 replication but do not inactivate the provirus that persists in latent reservoirs. Recent studies have found that the guide RNA (gRNA)-directed CRISPR/Cas9 system can be used for sequence-specific attack on this proviral DNA. Although potent inhibition of virus replication was reported, HIV-1 can escape from a single antiviral gRNA by mutation of the target sequence. Here, we demonstrate that combinations of two antiviral gRNAs delay viral escape, and identify two gRNA combinations that durably block virus replication. When viral escape is prevented, repeated Cas9 cleavage leads to saturation of major mutations in the conserved target sequences that encode critical proteins. This hypermutation coincides with the loss of replication-competent virus as scored in sensitive co-cultures with unprotected cells, demonstrating complete virus inactivation. These results provide a proof-of-principle that HIV-1-infected cells can be functionally cured by dual-gRNA CRISPR/Cas9 treatment.

Graphical abstract

Teaser

Although antiviral drug therapy is a life-saving treatment for HIV-infected individuals, a cure is never reached because the virus persists. Using CRISPR-Cas9 gene editing, Wang et al. find that complete virus inactivation can be achieved in cultured T cells, suggesting an avenue toward a functional cure.


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The FA Core Complex Contains a Homo-dimeric Catalytic Module for the Symmetric Mono-ubiquitination of FANCI-FANCD2

Publication date: Available online 13 December 2016
Source:Cell Reports
Author(s): Paolo Swuec, Ludovic Renault, Aaron Borg, Fenil Shah, Vincent J. Murphy, Sylvie van Twest, Bram Snijders, Andrew J. Deans, Alessandro Costa
Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination of FANCI and FANCD2 by FANCL, the E3 ligase subunit of the Fanconi anemia core complex. FANCI and FANCD2 form a stable complex; however, the molecular basis of their ubiquitination is ill defined. FANCD2 mono-ubiquitination by FANCL is stimulated by the presence of the FANCB and FAAP100 core complex components, through an unknown mechanism. How FANCI mono-ubiquitination is achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. A transient interaction with FANCC-FANCE-FANCF alters the FANCI-FANCD2 configuration, stabilizing the dimerization interface. Our data provide a model to explain how equivalent mono-ubiquitination of FANCI and FANCD2 occurs.

Graphical abstract

Teaser

Mono-ubiquitination of FANCI-FANCD2 by the Fanconi anemia core complex activates a major DNA interstrand-crosslink repair pathway important for genome stability maintenance. Here, Swuec et al. reveal the structural basis of this reaction by showing that the core complex exists as a dimeric catalytic module for the symmetric mono-ubiquitination of FANCI-FANCD2.


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Clinical profiles of pediatric patients with GPP alone and with different IL36RN genotypes

Publication date: Available online 13 December 2016
Source:Journal of Dermatological Science
Author(s): Yirong Wang, Ruhong Cheng, Zhiyong Lu, Yifeng Guo, Ming Yan, Jianying Liang, Peichen Huang, Ming Li, Zhirong Yao
BackgroundIL36RN mutation has been identified as one pathogenesis of generalized pustular psoriasis, but the existence of GPP patients without mutation makes this controversial.ObjectiveOur study aimed at assessing the differences in clinical profiles of children with GPP, with and without IL36RN mutation.MethodsAn ambispective case series study involved review of the records of 66 childhood patients with pediatric-onset GPP and without previous psoriasis vulgaris.Resultsc.115+6T>C was the most common mutation in this Chinese population with GPP alone. The age at onset was nearly halved in the homozygotes/compound heterozygotes than in IL36RN-negative patients. Besides a more severe inflammatory progression, three minor signs could prioritize patients with GPP for IL36RN screening (confluent lakes of pus (P=0.002), perianal erosion (P=0.014), and flexural erosion (P=0.007)). More patients with the pathogenic mutation converted to ACH than those without mutation (χ2=4.773, P=0.029). Children with GPP with or without IL36RN mutation responded well to oral low-dose acitretin, but IL36RN-positive cases suffered a much higher half-year recurrence rate after withdrawl of acitretin treatment(χ2=10.370, P=0.001).ConclusionsSpecific clinical features can remind dermatologists of the necessity of sequencing diagnosis. The mild pustular phenotype of those without mutation may imply the possible role of the epigenetic changes of IL36RN, or other IL36-blockers in the pathogenesis. Pediatric patients with GPP alone, both with and without IL36RN mutation responded well to low-dose acitretin.



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Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Katharina S. Rauch, Miriam Hils, Ekaterina Lupar, Susana Minguet, Mikael Sigvardsson, Martin E. Rottenberg, Ana Izcue, Christian Schachtrup, Kristina Schachtrup
The transcription factor Foxp3 dominantly controls regulatory T (Treg) cell function, and only its continuous expression guarantees the maintenance of full Treg cell-suppressive capacity. However, transcriptional regulators maintaining Foxp3 transcription are incompletely described. Here, we report that high E47 transcription factor activity in Treg cells resulted in unstable Foxp3 expression. Under homeostatic conditions, Treg cells expressed high levels of the E47 antagonist Id3, thus restricting E47 activity and maintaining Foxp3 expression. In contrast, stimulation of Id3-deficient or E47-overexpressing Treg cells resulted in the loss of Foxp3 expression in a subset of Treg cells in vivo and in vitro. Mechanistic analysis indicated that E47 activated expression of the transcription factor Spi-B and the suppressor of cytokine signaling 3 (SOCS3), which both downregulated Foxp3 expression. These findings demonstrate that the balance of Id3 and E47 controls the maintenance of Foxp3 expression in Treg cells and, thus, contributes to Treg cell plasticity.

Graphical abstract

Teaser

Stable Foxp3 expression is instrumental for Treg cell function. Rauch et al. found that the transcriptional regulator Id3 maintains Foxp3 transcription in established Treg cells by restricting E47 transcription factor activity. They suggest that a dynamic modulation of the Id3-E47 balance could transiently alter Treg cell function during immune responses.


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Oral supplementation with bovine whey-derived Ig-rich fraction and lactoferrin improves SCORAD and DLQI in atopic dermatitis

Publication date: Available online 13 December 2016
Source:Journal of Dermatological Science
Author(s): Philip L. Tong, Nicholas P. West, Amanda J. Cox, Val J. Gebski, Annabelle M. Watts, Annabel Dodds, Barbara Fazekas de St Groth, Allan W. Cripps, Stephen Shumack




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Proline Catabolism Modulates Innate Immunity in Caenorhabditis elegans

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Haiqing Tang, Shanshan Pang
Metabolic pathways are regulated to fuel or instruct the immune responses to pathogen threats. However, the regulatory roles for amino acid metabolism in innate immune responses remains poorly understood. Here, we report that mitochondrial proline catabolism modulates innate immunity in Caenorhabditis elegans. Modulation of proline catabolic enzymes affects host susceptibility to bacterial pathogen Pseudomonas aeruginosa. Mechanistically, proline catabolism governs reactive oxygen species (ROS) homeostasis and subsequent activation of SKN-1, a critical transcription factor regulating xenobiotic stress response and pathogen defense. Intriguingly, proline catabolism-mediated activation of SKN-1 requires cell-membrane dual-oxidase Ce-Duox1/BLI-3, highlighting the importance of interaction between mitochondrial and cell-membrane components in host defense. Our findings reveal how animals utilize metabolism of a single amino acid to defend against a pathogen and identify proline catabolism as a component of innate immune signaling.

Graphical abstract

Teaser

Tang and Pang show that proline catabolism is a component of the innate immune system in C. elegans. In response to P. aeruginosa infection, proline catabolic enzymes modulate ROS homeostasis and subsequent SKN-1 activation, likely through metabolic intermediate P5C and dual-oxidase Ce-Duox1/BLI-3.


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Glucagon-like Peptide 1 Receptor Signaling in Acinar Cells Causes Growth-Dependent Release of Pancreatic Enzymes

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Nicolai J. Wewer Albrechtsen, Reidar Albrechtsen, Lasse Bremholm, Berit Svendsen, Rune E. Kuhre, Steen S. Poulsen, Charlotte B. Christiansen, Elisa P. Jensen, Charlotte Janus, Linda Hilsted, Carolyn F. Deacon, Bolette Hartmann, Jens J. Holst
Incretin-based therapies are widely used for type 2 diabetes and now also for obesity, but they are associated with elevated plasma levels of pancreatic enzymes and perhaps a modestly increased risk of acute pancreatitis. However, little is known about the effects of the incretin hormone glucagon-like peptide 1 (GLP-1) on the exocrine pancreas. Here, we identify GLP-1 receptors on pancreatic acini and analyze the impact of receptor activation in humans, rodents, isolated acini, and cell lines from the exocrine pancreas. GLP-1 did not directly stimulate amylase or lipase release. However, we saw that GLP-1 induces phosphorylation of the epidermal growth factor receptor and activation of Foxo1, resulting in cell growth with concomitant enzyme release. Our work uncovers GLP-1-induced signaling pathways in the exocrine pancreas and suggests that increases in amylase and lipase levels in subjects treated with GLP-1 receptor agonists reflect adaptive growth rather than early-stage pancreatitis.

Graphical abstract

Teaser

Glucagon-like peptide 1 (GLP-1)-based therapies are used to treat type 2 diabetes and obesity. Wewer Albrechtsen et al. detect GLP-1 receptor expression in pancreatic acinar cells and show that its activation leads to mild c-Src-dependent proliferation, increasing constitutive enzyme release. This enzyme increase during GLP-1 treatment does not reflect sub-clinical pancreatitis.


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The Left Hand Doesn’t Know What the Right Hand Is Doing—or Does It?

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Jody C. Culham
In this issue of Cell Reports, Ossmy and Mukamel (2016) show that virtual reality enhances learning of new motor sequences through practice with one hand and synchronous feedback of the other hand moving. The approach holds promise for motor rehabilitation.

Teaser

In this issue of Cell Reports, Ossmy and Mukamel (2016) show that virtual reality enhances learning of new motor sequences through practice with one hand and synchronous feedback of the other hand moving. The approach holds promise for motor rehabilitation.


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Early-Onset Hypertrophic Cardiomyopathy Mutations Significantly Increase the Velocity, Force, and Actin-Activated ATPase Activity of Human β-Cardiac Myosin

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Arjun S. Adhikari, Kristina B. Kooiker, Saswata S. Sarkar, Chao Liu, Daniel Bernstein, James A. Spudich, Kathleen M. Ruppel
Hypertrophic cardiomyopathy (HCM) is a heritable cardiovascular disorder that affects 1 in 500 people. A significant percentage of HCM is attributed to mutations in β-cardiac myosin, the motor protein that powers ventricular contraction. This study reports how two early-onset HCM mutations, D239N and H251N, affect the molecular biomechanics of human β-cardiac myosin. We observed significant increases (20%–90%) in actin gliding velocity, intrinsic force, and ATPase activity in comparison to wild-type myosin. Moreover, for H251N, we found significantly lower binding affinity between the S1 and S2 domains of myosin, suggesting that this mutation may further increase hyper-contractility by releasing active motors. Unlike previous HCM mutations studied at the molecular level using human β-cardiac myosin, early-onset HCM mutations lead to significantly larger changes in the fundamental biomechanical parameters and show clear hyper-contractility.

Graphical abstract

Teaser

Hypertrophic cardiomyopathy (HCM) can be attributed to mutations in β-cardiac myosin. Here, Adhikari et al. show that early-onset HCM mutations, H251N and D239N, significantly increase myosin biomechanical functions. In addition, H251N disrupts S1-S2 intramolecular myosin interactions, potentially releasing more active heads and further contributing to hyper-contractility.


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Functional Mutations Form at CTCF-Cohesin Binding Sites in Melanoma Due to Uneven Nucleotide Excision Repair across the Motif

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Rebecca C. Poulos, Julie A.I. Thoms, Yi Fang Guan, Ashwin Unnikrishnan, John E. Pimanda, Jason W.H. Wong
CTCF binding sites are frequently mutated in cancer, but how these mutations accumulate and whether they broadly perturb CTCF binding are not well understood. Here, we report that skin cancers exhibit a highly specific asymmetric mutation pattern within CTCF motifs attributable to ultraviolet irradiation and differential nucleotide excision repair (NER). CTCF binding site mutations form independently of replication timing and are enriched at sites of CTCF/cohesin complex binding, suggesting a role for cohesin in stabilizing CTCF-DNA binding and impairing NER. Performing CTCF ChIP-seq in a melanoma cell line, we show CTCF binding site mutations to be functional by demonstrating allele-specific reduction of CTCF binding to mutant alleles. While topologically associating domains with mutated CTCF anchors in melanoma contain differentially expressed cancer-associated genes, CTCF motif mutations appear generally under neutral selection. However, the frequency and potential functional impact of such mutations in melanoma highlights the need to consider their impact on cellular phenotype in individual genomes.

Graphical abstract

Teaser

Poulos et al. identify a specific mutation pattern within CTCF binding sites in skin cancers, which is attributable to differential nucleotide excision repair across the motif. Mutations on highly conserved bases cause allele-specific reduction of CTCF binding. Despite the frequency of these mutations, they are generally under neutral selection in melanoma.


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The Drosophila Clock Neuron Network Features Diverse Coupling Modes and Requires Network-wide Coherence for Robust Circadian Rhythms

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Zepeng Yao, Amelia J. Bennett, Jenna L. Clem, Orie T. Shafer
In animals, networks of clock neurons containing molecular clocks orchestrate daily rhythms in physiology and behavior. However, how various types of clock neurons communicate and coordinate with one another to produce coherent circadian rhythms is not well understood. Here, we investigate clock neuron coupling in the brain of Drosophila and demonstrate that the fly's various groups of clock neurons display unique and complex coupling relationships to core pacemaker neurons. Furthermore, we find that coordinated free-running rhythms require molecular clock synchrony not only within the well-characterized lateral clock neuron classes but also between lateral clock neurons and dorsal clock neurons. These results uncover unexpected patterns of coupling in the clock neuron network and reveal that robust free-running behavioral rhythms require a coherence of molecular oscillations across most of the fly's clock neuron network.

Graphical abstract

Teaser

Yao et al. show that molecular rhythms of the Drosophila morning and evening circadian oscillators are not tightly coupled. While these two sets of oscillators collaborate to determine the timing of daily activity bouts, additional oscillators, including dorsal clock neurons, are required for robust circadian rhythms under constant conditions.


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Serotonin 1B Receptors Regulate Prefrontal Function by Gating Callosal and Hippocampal Inputs

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Celia Kjaerby, Jegath Athilingam, Sarah E. Robinson, Jillian Iafrati, Vikaas S. Sohal
Both medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety; however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency mPFC activity (4–12 Hz), and reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function, including anxiety-related behaviors.

Graphical abstract

Teaser

Kjaerby et al. find that serotonin acts presynaptically to suppress callosal and ventral hippocampal inputs to layer V of prefrontal cortex through 5-HT1B receptors. Infusion of a 5-HT1B agonist suppresses prefrontal theta oscillations and anxiety-related avoidance behavior, suggesting that prefrontal serotonin can act as a gatekeeper to regulate such behavior.


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Neural Network Underlying Intermanual Skill Transfer in Humans

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Ori Ossmy, Roy Mukamel
Physical practice with one hand results in performance gains of the other (un-practiced) hand, yet the role of sensory feedback and underlying neurophysiology is unclear. Healthy subjects learned sequences of finger movements by physical training with their right hand while receiving real-time movement-based visual feedback via 3D virtual reality devices as if their immobile left hand was training. This manipulation resulted in significantly enhanced performance gain with the immobile hand, which was further increased when left-hand fingers were yoked to passively follow right-hand voluntary movements. Neuroimaging data show that, during training with manipulated visual feedback, activity in the left and right superior parietal lobule and their degree of coupling with motor and visual cortex, respectively, correlate with subsequent left-hand performance gain. These results point to a neural network subserving short-term motor skill learning and may have implications for developing new approaches for learning and rehabilitation in patients with unilateral motor deficits.

Graphical abstract

Teaser

Physical practice is important when learning a new motor skill. Ossmy and Mukamel demonstrate a training scheme in the absence of voluntary physical training and establish a link between neural activity during training and subsequent learning. Their results may have practical implications for rehabilitation of patients with upper-extremity hemiparesis.


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TRPV1 Nociceptor Activity Initiates USP5/T-type Channel-Mediated Plasticity

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Patrick Stemkowski, Agustin García-Caballero, Vinicius De Maria Gadotti, Said M'Dahoma, Shuo Huang, Stefanie Alice Gertrud Black, Lina Chen, Ivana Assis Souza, Zizhen Zhang, Gerald Werner Zamponi
Peripheral nerve injury and tissue inflammation result in upregulation of the deubiquitinase USP5, thus causing a dysregulation of T-type calcium channel activity and increased pain sensitivity. Here, we have explored the role of afferent fiber activity in this process. Conditioning stimulation of optogenetically targeted cutaneous TRPV1 expressing nociceptors, but not that of non-nociceptive fibers, resulted in enhanced expression of USP5 in mouse dorsal root ganglia and spinal dorsal horn, along with decreased withdrawal thresholds for thermal and mechanical stimuli that abated after 24 hr. This sensitization was drastically reduced by an interfering peptide that prevented USP5-Cav3.2 association. Sensitization was relieved by pharmacological block of TRPV1 afferents, but not of myelinated neurons. In spinal cord slice recordings, we could optogenetically trigger an activity-dependent potentiation of presynaptic neurotransmission in the spinal dorsal horn that relied on Cav3.2 channel activity. This neuronal-activity-induced USP5 upregulation may underlie a protective, transient sensitization of the pain pathway.

Graphical abstract

Teaser

Stemkowski et al. establish that sensory modality of nociceptors can be enhanced by neuronal activity in the absence of physical injury. This process is dependent on a T-type calcium channel-mediated enhancement of dorsal horn synaptic activity that derives from activity-induced upregulation of USP5 expression.


http://ift.tt/2gHKIRC

Distal Limb Patterning Requires Modulation of cis-Regulatory Activities by HOX13

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Rushikesh Sheth, Iros Barozzi, David Langlais, Marco Osterwalder, Stephen Nemec, Hanqian L. Carlson, H. Scott Stadler, Axel Visel, Jacques Drouin, Marie Kmita
The combinatorial expression of Hox genes along the body axes is a major determinant of cell fate and plays a pivotal role in generating the animal body plan. Loss of HOXA13 and HOXD13 transcription factors (HOX13) leads to digit agenesis in mice, but how HOX13 proteins regulate transcriptional outcomes and confer identity to the distal-most limb cells has remained elusive. Here, we report on the genome-wide profiling of HOXA13 and HOXD13 in vivo binding and changes of the transcriptome and chromatin state in the transition from the early to the late-distal limb developmental program, as well as in Hoxa13^−/−; Hoxd13^−/− limbs. Our results show that proper termination of the early limb transcriptional program and activation of the late-distal limb program are coordinated by the dual action of HOX13 on cis-regulatory modules.

Graphical abstract

Teaser

HOX13 homeobox transcription factors determine digit cell fate during limb bud development. Sheth et al. identify HOX13-dependent regulation of gene expression and chromatin state that suggests HOX13 activity at cis regulatory modules allows for a coordinated transition from the early to the late-distal program in the developing limb bud.


http://ift.tt/2gHPPS0

Sustained Rhythmic Brain Activity Underlies Visual Motion Perception in Zebrafish

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Verónica Pérez-Schuster, Anirudh Kulkarni, Morgane Nouvian, Sebastián A. Romano, Konstantinos Lygdas, Adrien Jouary, Mario Dipoppa, Thomas Pietri, Mathieu Haudrechy, Virginie Candat, Jonathan Boulanger-Weill, Vincent Hakim, Germán Sumbre




http://ift.tt/2gHOs5T

DNA Replication Origins in Immunoglobulin Switch Regions Regulate Class Switch Recombination in an R-Loop-Dependent Manner

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Eva-Maria Wiedemann, Mihaela Peycheva, Rushad Pavri
Class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) locus generates antibody isotypes. CSR depends on double-strand breaks (DSBs) induced by activation-induced cytidine deaminase (AID). Although DSB formation and repair machineries are active in G1 phase, efficient CSR is dependent on cell proliferation and S phase entry; however, the underlying mechanisms are obscure. Here, we show that efficient CSR requires the replicative helicase, the Mcm complex. Mcm proteins are enriched at IgH switch regions during CSR, leading to assembly of facultative replication origins that require Mcm helicase function for productive CSR. Assembly of CSR-associated origins is facilitated by R loops and promotes the physical proximity (synapsis) of recombining switch regions, which is reduced by R loop inhibition or Mcm complex depletion. Thus, R loops contribute to replication origin specification that promotes DSB resolution in CSR. This suggests a mechanism for the dependence of CSR on S phase and cell division.

Graphical abstract

Teaser

Class switch recombination (CSR) depends on double-strand breaks (DSBs) induced by activation-induced cytidine deaminase (AID). Here, Wiedemann et al. show that CSR correlates with the firing of DNA replication origins, which in turn depends on transcription-dependent R loop formation. Origin activation is required for efficient synapsis of recombining switch regions.


http://ift.tt/2gZyQa1

Structural Dynamics of the YidC:Ribosome Complex during Membrane Protein Biogenesis

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Alexej Kedrov, Stephan Wickles, Alvaro H. Crevenna, Eli O. van der Sluis, Robert Buschauer, Otto Berninghausen, Don C. Lamb, Roland Beckmann
Members of the YidC/Oxa1/Alb3 family universally facilitate membrane protein biogenesis, via mechanisms that have thus far remained unclear. Here, we investigated two crucial functional aspects: the interaction of YidC with ribosome:nascent chain complexes (RNCs) and the structural dynamics of RNC-bound YidC in nanodiscs. We observed that a fully exposed nascent transmembrane domain (TMD) is required for high-affinity YidC:RNC interactions, while weaker binding may already occur at earlier stages of translation. YidC efficiently catalyzed the membrane insertion of nascent TMDs in both fluid and gel phase membranes. Cryo-electron microscopy and fluorescence analysis revealed a conformational change in YidC upon nascent chain insertion: the essential TMDs 2 and 3 of YidC were tilted, while the amphipathic helix EH1 relocated into the hydrophobic core of the membrane. We suggest that EH1 serves as a mechanical lever, facilitating a coordinated movement of YidC TMDs to trigger the release of nascent chains into the membrane.

Graphical abstract

Teaser

Kedrov et al. use a combination of biochemical, biophysical, and structural approaches to study the insertase YidC in its native lipid environment upon interaction with ribosomes. The results describe how YidC recognizes translating ribosomes and changes its conformation upon nascent chain insertion.


http://ift.tt/2gZyIak

TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Daniel B. Graham, Ariel Lefkovith, Patrick Deelen, Niek de Klein, Mukund Varma, Angela Boroughs, A. Nicole Desch, Aylwin C.Y. Ng, Gaelen Guzman, Monica Schenone, Christine P. Petersen, Atul K. Bhan, Manuel A. Rivas, Mark J. Daly, Steven A. Carr, Cisca Wijmenga, Ramnik J. Xavier
Significant insights into disease pathogenesis have been gleaned from population-level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5–61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation. Strikingly, Tmem258 haploinsufficient mice exhibit severe intestinal inflammation in a model of colitis. At the mechanistic level, we demonstrate that TMEM258 is a required component of the oligosaccharyltransferase complex and is essential for N-linked protein glycosylation. Consequently, homozygous deficiency of Tmem258 in colonic organoids results in unresolved endoplasmic reticulum (ER) stress culminating in apoptosis. Collectively, our results demonstrate that TMEM258 is a central mediator of ER quality control and intestinal homeostasis.

Graphical abstract

Teaser

Graham et al. functionally dissect a complex genetic locus associated with inflammatory bowel disease. They find that TMEM258 is required for efficient N-linked protein glycosylation and, as such, is a central mediator of ER homeostasis in the context of intestinal inflammation.


http://ift.tt/2gZxLif

Downregulation of a GPCR by β-Arrestin2-Mediated Switch from an Endosomal to a TGN Recycling Pathway

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Nazish Abdullah, Muheeb Beg, David Soares, Jeremy S. Dittman, Timothy E. McGraw
Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in nutrient homeostasis. GIP receptor (GIPR) is constitutively internalized and returned to the plasma membrane, atypical behavior for a G-protein-coupled receptor (GPCR). GIP promotes GIPR downregulation from the plasma membrane by inhibiting recycling without affecting internalization. This transient desensitization is achieved by altered intracellular trafficking of activated GIPR. GIP stimulation induces a switch in GIPR recycling from a rapid endosomal to a slow trans-Golgi network (TGN) pathway. GPCR kinases and β-arrestin2 are required for this switch in recycling. A coding sequence variant of GIPR, which has been associated with metabolic alterations, has altered post-activation trafficking characterized by enhanced downregulation and prolonged desensitization. Downregulation of the variant requires β-arrestin2 targeting to the TGN but is independent of GPCR kinases. The single amino acid substitution in the variant biases the receptor to promote GIP-stimulated β-arrestin2 recruitment without receptor phosphorylation, thereby enhancing downregulation.

Graphical abstract

Teaser

Constitutive GIPR recycling is reduced upon GIP stimulation, leading to downregulation of the receptor. Abdullah et al. find that β-arrestin2-mediated trafficking of GIPR to the TGN underlies this slow recycling. Dysregulation of phosphorylation-dependent β-arrestin2 recruitment in a natural coding variant leads to enhanced downregulation.


http://ift.tt/2gZAA30

Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells

Publication date: 13 December 2016
Source:Cell Reports, Volume 17, Issue 11
Author(s): Xiaolin Luo, Rui Liao, Kaisa L. Hanley, Helen He Zhu, Kirsten N. Malo, Carolyn Hernandez, Xufu Wei, Nissi M. Varki, Nazilla Alderson, Catherine Chu, Shuangwei Li, Jia Fan, Rohit Loomba, Shuang-Jian Qiu, Gen-Sheng Feng
The complexity of liver tumorigenesis is underscored by the recently observed anti-oncogenic effects of oncoproteins, although the mechanisms are unclear. Shp2/Ptpn11 is a proto-oncogene in hematopoietic cells and antagonizes the effect of tumor suppressor Pten in leukemogenesis. In contrast, we show here cooperative functions of Shp2 and Pten in suppressing hepatocarcinogenesis. Ablating both Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH) and promoted genesis of liver tumor-initiating cells likely due to augmented cJun expression/activation and elevated ROS and inflammation in the hepatic microenvironment. Inhibiting cJun partially suppressed NASH-driven liver tumorigenesis without improving NASH. SHP2 and PTEN deficiencies were detected in liver cancer patients with poor prognosis. These data depict a mechanism of hepato-oncogenesis and suggest a potential therapeutic strategy.

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Teaser

Shp2 antagonizes Pten in leukemogenesis. Luo et al. now find that Shp2 and Pten synergistically suppress carcinogenesis in the liver. Ablating Shp2 and Pten in hepatocytes induced early-onset non-alcoholic steatohepatitis (NASH) and promoted genesis of tumor-initiating cells. These findings suggest a mechanism underlying disease as well as a therapeutic strategy.


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Imaging appearance of benign multicystic peritoneal mesothelioma: a case report and review of the literature

Publication date: March–April 2017
Source:Clinical Imaging, Volume 42
Author(s): Varun Mehta, Varun Chowdhary, Richa Sharma, Jennifer S Golia Pernicka
Benign multicystic peritoneal mesothelioma (BMPM) is a rare entity with fewer than 150 reported cases in the literature. Here we discuss a case of BMPM in a 22-year old female as presented to our urban community hospital, review epidemiology and clinical presentations of this entity, and perform a comprehensive literature review of various CT, US, and MR imaging features of BMPM.



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Radical Cystectomy Compared to Combined Modality Treatment for Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-Analysis of over 12,000 patients

Publication date: Available online 13 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Vishal Vashistha, Hanzhang Wang, Andrew Mazzone, Michael A. Liss, Robert S. Svatek, Mary Schleicher, Dharam Kaushik
PurposeRadical cystectomy (RC) has been the mainstay treatment for muscle-invasive bladder cancer (MIBC) while combined modality treatment (CMT-radiation therapy, concurrent chemotherapy and maximal transurethral resection of bladder tumor) is preserved for patients with substantial comorbidities. We performed a comprehensive assessment of overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), and treatment-related complications between RC and CMT.MethodsWe searched seven databases (PubMed, Scopus, EMBASE, Proquest, CINAHL, and the clinical trials.gov) for randomized-controlled trials (RCTs) and prospective and retrospective studies directly comparing RC with CMT from database inception to March 2016. We conducted meta-analyses evaluating OS, DSS, and PFS with hazard ratios (HR) and 95% confidence intervals (CI).ResultsNineteen studies evaluating 12,380 subjects were selected. For the 8 studies encompassing 9554 subjects eligible for meta-analyses, we found no difference in OS at 5 years (HR: 0.96, favoring CMT, CI [0.72–1.29; p = 0.778]) or 10 years (HR: 1.02, favoring cystectomy, CI [0.73–1.42; p = 0.905]). No difference was observed in DSS at 5 years (HR: 0.83, favoring radiation, CI [0.54–1.28; p = 0.390]) or 10 years (HR: 1.17, favoring cystectomy, CI [0.89–1.55; p = 0.264]), or PFS at 10 years (HR: 0.85, favoring CMT, CI [0.43–1.67; p = 0.639]). The cystectomy arms had higher rates of early major complications while rates of minor complications were similar between the two treatments.ConclusionCurrent meta-analysis reveals no differences in OS, DSS, or PFS between RC and CMT. Further RCTs are necessary to identify the optimal treatment for specific patients.

Teaser

Historically, radical cystectomy has been the mainstay treatment for muscle-invasive bladder cancer while combined modality treatment (radiation therapy, chemotherapy, and maximal resection of bladder tumor) has been preserved for poor surgical candidates. Our systematic review with quantitative syntheses of randomized trials and prospective and retrospective studies suggests cystectomy offers no benefit in survival or disease progression compared to radiation-based management for invasive bladder cancer.


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Influence of the extent and dose of radiation on complications after neoadjuvant chemoradiation and subsequent esophagectomy with gastric tube reconstruction with a cervical anastomosis

Publication date: Available online 14 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): M. Koëter, N. Kathiravetpillai, J.A. Gooszen, M.I. van Berge Henegouwen, S.S. Gisbertz, M.J.C. van der Sangen, M.D.P. Luyer, G.A.P. Nieuwenhuijzen, M.C.C.M. Hulshof
BackgroundThe influence of the extent and dose of radiation on complications was investigated in patients with esophageal cancer treated with neoadjuvant chemoradiation and subsequent esophagectomy with gastric tube reconstruction with a cervical anastomosis.MethodsBetween 2005 and 2012, 364 consecutive patients with esophageal cancer treated with neoadjuvant chemoradiation (41.4 Gy combined with chemotherapy) followed by esophagectomy were included. The future anastomotic region in the fundus was determined and the mean dose, V20-V40, upper planning target volume (PTV) border in relation to mediastinal length expressed as the mediastinal ratio were calculated.ResultsAnastomotic leakage (AL) occurred in 22% and anastomotic stenosis (AS) in 41%. Logistic regression analysis revealed no influence of age, comorbidity, mean fundus dose, V20-V40, or the mediastinal ratio on the incidence of AL or AS. In 28% of the patients severe complications (Clavien-Dindo score of ≥ IIIB) occurred. The presence of multiple co-morbidities (HR 2.4 [CI 1.3-4.5], p=0.006) and a mediastinal ratio of 0.5-1.0 (HR 1.9 [CI 1.0-3.5], p=0.036) were both independent predictors of severe complications.DiscussionWith a mean radiation dose of 24.2 Gy to the future anastomotic region of the gastric fundus, the radiation dose was not associated with the incidence of anastomotic leakage or anastomotic stenosis. The incidence of severe complications was associated with a high superior mediastinal PTV border.



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The Practice of Radiation Oncology in Canada

Publication date: Available online 14 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Nafisha Lalani, Bernard Cummings, Ross Halperin, Eileen Rakovitch, Michael Brundage, Eric Vigneault, Michael Milosevic




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Robust estimation of electron density from anatomical MR imaging of the brain using a unifying multi-atlas approach

Publication date: Available online 14 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Shangjie Ren, Wendy Hara, Lei Wang, Mark Buyyounouski, Quynh-Thu Le, Lei Xing, Ruijiang Li
Purpose/Objective(s)MRI has important advantages over CT as a primary image modality for radiation treatment planning. However, MRI lacks electron density information required for accurate radiation dose calculation. The purpose of this work is to develop a reliable method to estimate electron density based on anatomical MR imaging of the brain.Materials/MethodsWe proposed a unifying multi-atlas approach for electron density estimation based on standard T1 and T2-weighted MRI. First, a composite atlas was constructed through a voxel-wise matching process using multiple atlases, with the goal of mitigating effects of inherent anatomical variations between patients. Next, we computed for each voxel two kinds of conditional probabilities: (1) electron density given its image intensity on T1 and T2-weighted MR images, and (2) electron density given its spatial location in a reference anatomy, obtained by deformable image registration. These were combined into a unifying posterior probability density function using the Bayesian formalism, which provided the optimal estimates for electron density. We evaluated the method on 10 patients using leave-one-patient-out cross validation. ROC analyses for detecting different tissue types were performed.ResultsThe proposed method significantly reduced the errors in electron density estimation, with a mean absolute Hounsfield unit (HU) error of 119, compared with 140 and 144 (p < 0.0001) using conventional T1-weighted intensity and geometry-based approaches. For detection of bony anatomy, the proposed method achieved an 89% AUC, 86% sensitivity, 88% specificity, and 90% accuracy, which improved upon intensity and geometry-based approaches (AUC: 79% and 80%, respectively).ConclusionThe proposed multi-atlas approach provides robust electron density estimation and bone detection based on anatomical MRI. If validated on a larger population, our work could enable the use of MRI as a primary modality for radiation treatment planning.

Teaser

Summary: We developed a unifying multi-atlas approach for electron density mapping based on standard-of-care T1 and T2-weighted MRI. The proposed method achieved robust electron density estimation and bone detection in 10 patients. Our work could provide the enabling tools for using MRI as a primary modality for radiation treatment planning.


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Joint estimation of cardiac toxicity and recurrence risks after comprehensive nodal photon vs. proton therapy for breast cancer

Publication date: Available online 13 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Line B. Stick, Jen Yu, Maja V. Maraldo, Marianne C. Aznar, Anders N. Pedersen, Søren M. Bentzen, Ivan R. Vogelius
PurposeTo perform joint estimation of the risk of recurrence caused by inadequate radiation dose coverage of lymph node targets and the risk of cardiac toxicity caused by radiation exposure to the heart. Delivered photons plans are compared to realistic proton plans thereby providing evidence-based estimates of the heterogeneity of treatment effects in consecutive cases for the two radiation modalities.Methods and MaterialsForty-one patients referred for post-lumpectomy comprehensive nodal photon irradiation for left-sided breast cancer were included. Comparative proton plans were optimized using spot scanning technique with single field optimization from two enface beams. Cardiotoxicity risk was estimated using the model by Darby et al and risk of recurrence following a compromise of lymph node coverage was estimated by a linear dose-response model fitted to the recurrence data from the recently published EORTC 22922/10925 and NCIC-CTG MA.20 randomized controlled trials.ResultsExcess absolute risk (EAR) of cardiac morbidity was small with photon therapy at an attained age of 80 years with a median (range) of 1.0% (0.2%-2.9%) /0.5% (0.03%-1.0%) with/without cardiac risk factors (CRFs), but even lower with proton therapy (0.13% (0.02%-0.5%)/0.06% (0.004%-0.3%)), respectively. The median estimated EAR of breast cancer recurrence after 10 years was 0.10% (range: 0.0%-0.9%) with photons and 0.02% (range 0.0%-0.07%) with protons. The association between age of the patient and benefit from proton therapy was weak, almost non-existing (Spearman's rank correlation: -0.15/−0.30 with/without CRFs).ConclusionsModern photon therapy yields limited risk of cardiac toxicity in most patients, but proton therapy can reduce the predicted risk of cardiac toxicity by up to 2.9% and the risk of breast cancer recurrence by 0.9% in individual patients. Predicted benefit correlates weakly with age. Combined assessment of the risk from cardiac exposure and inadequate target coverage is desirable for rational consideration of competing photon and proton therapy plans.

Teaser

Evidence-based bioeffect models are used to provide patient level risk estimates for clinically delivered photon therapy plans compared with proton therapy plans in 41 consecutive patients with left-sided breast cancer referred for comprehensive nodal irradiation. The joint estimation of risk of recurrence caused by target dose compromises and risk of cardiac morbidity differs markedly between patients and radiation modalities.


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Evaluation of anaphylactoid constituents in vitro and in vivo

Publication date: February 2017
Source:International Immunopharmacology, Volume 43
Author(s): Yubin Xu, Chunyan Liu, Deqiang Dou, Qiuhong Wang
Natural medicine injections have been widely used in clinics, while adverse reaction reports also have increased rapidly in recent years. To examine the anaphylactoid constituents of natural medicine injections, RBL-2H3 cell degranulation and human serum complement activation models were used to screen the anaphylactoid constituents, and the BN rat model was used to explore the anaphylactoid mechanism of these constituents. The result of an in vitro study showed that the individual compounds of natural medicine injections (chlorogenic acid, hyodeoxycholic acid, cholalic acid, ginkgolic acid, phillyrin, schisandrin B, schisandrin A, puerarin, and tanshinone IIA) and polysaccharide could not induce RBL-2H3 to release histamine and β-hexosaminidase, while proteins Tween-80 and tannic acid were the main anaphylactoid constituents in the natural medicine injections. The in vivo study also indicated that >10kDa molecules (proteins) activated classical complement pathways through direct stimulation to cause an anaphylactoid reaction. Tween-80 activated direct stimulation and coagulation pathways through classical and alternative pathways; tannic acid induced anaphylactoid reaction through co-activation of the kallikrein-kinin system, coagulation, integrated, classical and alternative complement pathways. This is the first study to evaluate the anaphylactoid constituents systematically through in vitro and in vivo study. And tannic acid, >10kDa molecules (proteins), and injection additives such as Tween-80 are the main anaphylactoid constituents of natural medicine injections.



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Mangiferin inhibits mastitis induced by LPS via suppressing NF-ĸB and NLRP3 signaling pathways

Publication date: February 2017
Source:International Immunopharmacology, Volume 43
Author(s): Shihui Qu, Wenqing Wang, Depeng Li, Shumin Li, Like Zhang, Yunhe Fu, Naisheng Zhang
During the past era, small molecules derived from various plants have attracted extensive attention for their versatile medicinal benefits. Among these, one organic molecule called mangiferin from certain plant species including mangoes and honey bush tea is widely used in treating inflammation. In this study, a LPS-induced mastitis model in mouse is established to investigate the anti-inflammatory effects and mechanism of mangiferin. The result shows that mangiferin significantly alleviates LPS-induced histopathology, meanwhile, also decreases LPS-induced MPO activity. Furthermore, mangiferin treatment remarkably impeded the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. In addition, mangiferin was found to inhibit LPS-induced NF-ĸB and NLRP3 inflammasome activation. In conclusion, these results suggested that LPS-induced mastitis can be abated by mangiferin through inhibiting NF-ĸB and NLRP3 signaling pathways.



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Verruconis gallopava cardiac and endovascular infection with dissemination after renal transplantation: case report and lessons learned

Publication date: Available online 13 December 2016
Source:Medical Mycology Case Reports
Author(s): Zoe Jennings, Kathy Kable, Catriona L. Halliday, Brian J. Nankivell, Jen Kok, Germaine Wong, Sharon C-A. Chen
Verruconis gallopava is an uncommon cause of phaeohyphomycosis. We describe an unusual case of disseminated V. gallopava infection in a renal transplant recipient involving the endocardium but without endocarditis, associated with fungaemia and infection in the skin, oral cavity, brain and lung. The isolate was first detected from blood cultures which is rare. Surgical resection of cardiac fungal mass was not possible. The patient died despite resolution of fungaemia and combination antifungal therapy.



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Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs

Publication date: January 2017
Source:European Journal of Cancer, Volume 71
Author(s): Dirk Schadendorf, Céleste Lebbé, Axel zur Hausen, Marie-Françoise Avril, Subramanian Hariharan, Murtuza Bharmal, Jürgen C. Becker
Merkel cell carcinoma (MCC) is a rare skin cancer that is associated with Merkel cell polyomavirus infection in most cases. Incidence rates of MCC have increased in past decades. Risk factors for MCC include ultraviolet light exposure, immunosuppression and advanced age. MCC is an aggressive malignancy with frequent recurrences and a high mortality rate, although patient outcomes are generally more favourable if the patient is referred for treatment at an early stage. Although advances have been made recently in the MCC field, large gaps remain with regard to definitive biomarkers and prognostic indicators. Although MCC is chemosensitive, responses in advanced stages are mostly of short duration, and the associated clinical benefit on overall survival is unclear. Recent nonrandomised phase 2 clinical trials with anti–PD-L1/PD-1 antibodies have demonstrated safety and efficacy; however, there are still no approved treatments for patients with metastatic MCC. Patients with advanced disease are encouraged to participate in clinical trials for treatment, indicating the largely unmet need for durable, safe treatment within this population.



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Use of complementary and alternative medicine: A multicenter cross-sectional study in 1089 melanoma patients

Publication date: January 2017
Source:European Journal of Cancer, Volume 71
Author(s): Carmen Loquai, Dagmar Dechent, Marlene Garzarolli, Martin Kaatz, Katharina C. Kaehler, Peter Kurschat, Frank Meiss, Oliver Micke, Ralph Muecke, Karsten Muenstedt, Annette Stein, Dorothée Nashan, Christoph Stoll, Irene Schmidtmann, Jutta Huebner
BackgroundAbout half of patients with cancer use complementary and alternative medicine (CAM). So far, data on melanoma patients are missing.ObjectiveThe aim of our study was to evaluate the prevalence and predictors for the use of CAM in this patient group.MethodsAll patients with melanoma being attended at one of 7 skin cancer centres in Germany between March 2012 and March 2013 were invited to take part in a survey using a structured questionnaire on CAM. The physicians filled in a second part on the diagnosis, state and former and current therapy.ResultsNearly half of the 1089 participants (41.0%) used CAM and half of those using CAM (56.8%) marked that this made them feel better. Biological-based CAMs which consists of substances taken were used by 25.9% of all patients (63.1% of those using CAM). Predictors of CAM use were education, psychological support, interest in CAM and previous CAM use. CAM users show higher physical activity, more often use psychosocial help and have contact with a self-help group. Family and friends (41.0%) as well as print media (41.7%) are the main sources of information. Most important reasons to use CAM are to strengthen one's own forces (57.7%) or the immune system (63.4%) and to be able to do something for oneself (53.7%).ConclusionCommunication on CAM should become a regular topic in counselling melanoma patients. To increase safety, patients and physicians must have access to evidence-based information on these methods and their interactions with modern cancer treatments.



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Improving quality of life in patients with advanced cancer: Targeting metastatic bone pain

Publication date: January 2017
Source:European Journal of Cancer, Volume 71
Author(s): Roger von Moos, Luis Costa, Carla Ida Ripamonti, Daniela Niepel, Daniele Santini
Metastatic bone disease in patients with advanced cancer is frequently associated with skeletal complications. These can be debilitating, causing pain, impaired functioning and decreased quality of life, as well as reduced survival. This review considers how the management of metastatic bone pain might be optimised, to limit the considerable burden it can impose on affected patients. Cancer-related pain is notoriously under-reported and under-treated, despite the availability of many therapeutic options. Non-opioid and opioid analgesics can be used; the latter are typically administered with radiotherapy, which forms the current standard of care for patients with metastatic bone pain. Surgery is appropriate for certain complicated cases of metastatic bone disease, and other options such as radiopharmaceuticals may provide additional relief. Treatments collectively referred to as bone-targeted agents (BTAs; bisphosphonates and denosumab) can offer further pain reduction. Initiation of therapy with BTAs is recommended for all patients with metastatic bone disease because these agents delay not only the onset of skeletal-related events but also the onset of bone pain. With evidence also emerging for pain control properties of new anticancer agents, the potential to individualise care for these patients is increased further. Optimisation of care depends on physicians' thorough appreciation of the complementary benefits that might be achieved with the various agents, as well as their limitations. Appropriate anti-tumour treatment combined with early initiation of BTAs and adequate analgesia plays a key role in the holistic approach to cancer pain management and may minimise the debilitating effects of metastatic bone pain.



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Efficacy of FOLFOXIRI plus bevacizumab in liver-limited metastatic colorectal cancer: A pooled analysis of clinical studies by Gruppo Oncologico del Nord Ovest

Publication date: Available online 13 December 2016
Source:European Journal of Cancer
Author(s): Chiara Cremolini, Mariaelena Casagrande, Fotios Loupakis, Giuseppe Aprile, Francesca Bergamo, Gianluca Masi, Roberto Moretto R, Filippo Pietrantonio, Federica Marmorino, Gemma Zucchelli, Gianluca Tomasello, Giuseppe Tonini, Giacomo Allegrini, Cristina Granetto, Laura Ferrari, Lucio Urbani, Umberto Cillo, Pierluigi Pilati, Elisa Sensi, Alessio Pellegrinelli, Massimo Milione, Gabriella Fontanini, Alfredo Falcone
Secondary resection is a chance of cure for a subgroup of metastatic colorectal cancer (mCRC) patients with unresectable liver-limited disease. Medical treatment has a dual goal: to induce tumour shrinkage and to prevent disease relapse. The aims of the present analysis were to assess the efficacy of FOLFOXIRI plus bevacizumab in this setting, and to investigate whether this regimen could revert the poor prognosis of high-risk patients defined by clinical and molecular factors. We performed a pooled analysis of patients with unresectable and liver-limited mCRC, treated with first-line FOLFOXIRI plus bevacizumab in three prospective clinical trials by Gruppo Oncologico del Nord Ovest. 205 (37.9%) patients with liver-limited disease were selected, out of 541 treated patients. Liver metastases were synchronous, ≥4 and bilobar in 90%, 61%, and 79% of cases, respectively. The largest diameter was >5 cm in 42% of cases, and ≥6 segments were involved in 25%. Seventy-four patients (36.1%) underwent R0 or R1 resection of metastases. R2 resections were performed in 17 cases (8.3%). Having <6 involved segments (p < 0.001) and achieving RECIST response (p = 0.019) were associated with higher chances of resection. R0/R1 resected patients had significantly longer median progression-free survival (PFS) (18.1 versus 10.7 months, HR: 0.48 [0.35–0.66], p < 0.001) and overall survival (OS) (44.3 versus 24.4 months, HR: 0.32 [0.22–0.48], p < 0.001) compared with other patients, both in the univariate and multivariate analyses (PFS p = 0.025; OS p < 0.001). The 5-year PFS and OS rate in R0 resected patients were 12% and 43%, respectively. Neither negative baseline characteristics nor high clinical risk scores or RAS/BRAF mutations were associated with poor post-resection outcomes. In conclusion, FOLFOXIRI plus bevacizumab demonstrates efficacy in the conversion setting with considerable long-term outcome results independent of clinical and molecular prognostic factors (NCT00719797, NCT01163396 and NCT02271464).



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Screening Breast MRI Outcomes in Routine Clinical Practice: Comparison to BI-RADS Benchmarks

Publication date: Available online 13 December 2016
Source:Academic Radiology
Author(s): Roberta M. Strigel, Jennifer Rollenhagen, Elizabeth S. Burnside, Mai Elezaby, Amy M. Fowler, Frederick Kelcz, Lonie Salkowski, Wendy B. DeMartini
Rationale and ObjectivesThe BI-RADS Atlas 5th Edition includes screening breast magnetic resonance imaging (MRI) outcome benchmarks. However, the metrics are from expert practices and clinical trials of women with hereditary breast cancer predispositions, and it is unknown if they are appropriate for routine practice. We evaluated screening breast MRI audit outcomes in routine practice across a spectrum of elevated risk patients.Materials and MethodsThis Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study included all consecutive screening breast MRI examinations from July 1, 2010 to June 30, 2013. Examination indications were categorized as gene mutation carrier (GMC), personal history (PH) breast cancer, family history (FH) breast cancer, chest radiation, and atypia/lobular carcinoma in situ (LCIS). Outcomes were determined by pathology and/or ≥12 months clinical and/or imaging follow-up. We calculated abnormal interpretation rate (AIR), cancer detection rate (CDR), positive predictive value of recommendation for tissue diagnosis (PPV2) and biopsy performed (PPV3), and median size and percentage of node-negative invasive cancers.ResultsEight hundred and sixty examinations were performed in 566 patients with a mean age of 47 years. Indications were 367 of 860 (42.7%) FH, 365 of 860 (42.4%) PH, 106 of 860 (12.3%) GMC, 14 of 860 (1.6%) chest radiation, and 8 of 22 (0.9%) atypia/LCIS. The AIR was 134 of 860 (15.6%). Nineteen cancers were identified (13 invasive, 4 DCIS, two lymph nodes), resulting in CDR of 19 of 860 (22.1 per 1000), PPV2 of 19 of 88 (21.6%), and PPV3 of 19 of 80 (23.8%). Of 13 invasive breast cancers, median size was 10 mm, and 8 of 13 were node negative (61.5%).ConclusionsPerformance outcomes of screening breast MRI in routine clinical practice across a spectrum of elevated risk patients met the American College of Radiology Breast Imaging Reporting and Data System benchmarks, supporting broad application of these metrics. The indication of a personal history of treated breast cancer accounted for a large proportion (42%) of our screening examinations, with breast MRI performance in this population at least comparable to that of other screening indications.



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Effects of Iterative Reconstruction Algorithms on Computer-assisted Detection (CAD) Software for Lung Nodules in Ultra-low-dose CT for Lung Cancer Screening

Publication date: Available online 13 December 2016
Source:Academic Radiology
Author(s): Yukihiro Nomura, Toru Higaki, Masayo Fujita, Soichiro Miki, Yoshikazu Awaya, Toshio Nakanishi, Takeharu Yoshikawa, Naoto Hayashi, Kazuo Awai
Rationale and ObjectivesThis study aimed to evaluate the effects of iterative reconstruction (IR) algorithms on computer-assisted detection (CAD) software for lung nodules in ultra-low-dose computed tomography (ULD-CT) for lung cancer screening.Materials and MethodsWe selected 85 subjects who underwent both a low-dose CT (LD-CT) scan and an additional ULD-CT scan in our lung cancer screening program for high-risk populations. The LD-CT scans were reconstructed with filtered back projection (FBP; LD-FBP). The ULD-CT scans were reconstructed with FBP (ULD-FBP), adaptive iterative dose reduction 3D (AIDR 3D; ULD-AIDR 3D), and forward projected model-based IR solution (FIRST; ULD-FIRST). CAD software for lung nodules was applied to each image dataset, and the performance of the CAD software was compared among the different IR algorithms.ResultsThe mean volume CT dose indexes were 3.02 mGy (LD-CT) and 0.30 mGy (ULD-CT). For overall nodules, the sensitivities of CAD software at 3.0 false positives per case were 78.7% (LD-FBP), 9.3% (ULD-FBP), 69.4% (ULD-AIDR 3D), and 77.8% (ULD-FIRST). Statistical analysis showed that the sensitivities of ULD-AIDR 3D and ULD-FIRST were significantly higher than that of ULD-FBP (P < .001).ConclusionsThe performance of CAD software in ULD-CT was improved by using IR algorithms. In particular, the performance of CAD in ULD-FIRST was almost equivalent to that in LD-FBP.



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The Power of Promotion: Using Social Media to Promote a Radiology Department

Publication date: Available online 13 December 2016
Source:Academic Radiology
Author(s): Saad Ranginwala, Alexander J. Towbin
The emergence of social media has provided medical practices with a new means of delivering content to a wide and varied audience. There are a number of different social media channels; however, each allows users to interact with each other, sharing and consuming content in a manner governed by rules unique to the specific social media platform. In this paper, we will introduce several common platforms, describe the advantages and disadvantages of each, and discuss how we have used each platform to connect to a target audience, highlight our department's educational content, and showcase our research.



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Mitochondrial Adaptation in Nonalcoholic Fatty Liver Disease: Novel Mechanisms and Treatment Strategies

Publication date: Available online 13 December 2016
Source:Trends in Endocrinology & Metabolism
Author(s): Nishanth E. Sunny, Fernando Bril, Kenneth Cusi
Nonalcoholic fatty liver disease (NAFLD) is prevalent in patients with obesity or type 2 diabetes. Nonalcoholic steatohepatitis (NASH), encompassing steatosis with inflammation, hepatocyte injury, and fibrosis, predisposes to cirrhosis, hepatocellular carcinoma, and even cardiovascular disease. In rodent models and humans with NAFLD/NASH, maladaptation of mitochondrial oxidative flux is a central feature of simple steatosis to NASH transition. Induction of hepatic tricarboxylic acid cycle closely mirrors the severity of oxidative stress and inflammation in NASH. Reactive oxygen species generation and inflammation are driven by upregulated, but inefficient oxidative flux and accumulating lipotoxic intermediates. Successful therapies for NASH (weight loss alone or with incretin therapy, or pioglitazone) likely attenuate mitochondrial oxidative flux and halt hepatocellular injury. Agents targeting mitochondrial dysfunction may provide a novel treatment strategy for NAFLD.



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oRGs and mitotic somal translocation — a role in development and disease

Publication date: February 2017
Source:Current Opinion in Neurobiology, Volume 42
Author(s): Bridget Ostrem, Elizabeth Di Lullo, Arnold Kriegstein
The evolution of the human brain has been characterized by an increase in the size of the neocortex. Underlying this expansion is a significant increase in the number of neurons produced by neural stem cells during early stages of cortical development. Here we highlight recent advances in our understating of these cell populations, consisting of ventricular radial glia and outer radial glia. We highlight how gene expression studies have identified molecular signatures for radial glial cell populations and outline what has been learned about the mechanisms underlying the characteristic mode of division observed in outer radial glia cells, mitotic somal translocation. Understanding the significance of this behavior may help us explain human cortical expansion and further elucidate neurodevelopmental diseases.



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Adult NSC diversity and plasticity: the role of the niche

Publication date: February 2017
Source:Current Opinion in Neurobiology, Volume 42
Author(s): Enric Llorens-Bobadilla, Ana Martin-Villalba
Adult somatic stem cells are generally defined as cells with the ability to differentiate into multiple different lineages and to self-renew during long periods of time. These features were long presumed to be represented in one single tissue-specific stem cell. Recent development of single-cell technologies reveals the existence of diversity in fate and activation state of somatic stem cells within the blood, skin and intestinal compartments [1] but also in the adult brain. Here we review how recent advances have expanded our view of neural stem cells (NSCs) as a diverse pool of cells and how the specialized microenvironment in which they reside acts to maintain this diversity. In addition, we discuss the plasticity of the system in the injured brain.



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Division modes and physical asymmetry in cerebral cortex progenitors

Publication date: February 2017
Source:Current Opinion in Neurobiology, Volume 42
Author(s): Delphine Delaunay, Ayano Kawaguchi, Colette Dehay, Fumio Matsuzaki
Neural stem cells go through a sequence of timely regulated gene expression and pattern of division mode to generate diverse neurons during brain development. During vertebrate cerebral cortex development, neural stem cells begin with proliferative symmetric divisions, subsequently undergo neurogenic asymmetric divisions, and finally gliogenic divisions. In this review, we explore the relationship between stem cell versus neural fate specification and the division mode. Specifically, we discuss recent findings on the mechanisms of asymmetric divisions, division mode, and developmental progression of neural progenitor identity.



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Timing temporal transitions during brain development

Publication date: February 2017
Source:Current Opinion in Neurobiology, Volume 42
Author(s): Anthony M Rossi, Vilaiwan M Fernandes, Claude Desplan
During development a limited number of progenitors generate diverse cell types that comprise the nervous system. Neuronal diversity, which arises largely at the level of neural stem cells, is critical for brain function. Often these cells exhibit temporal patterning: they sequentially produce neurons of distinct cell fates as a consequence of intrinsic and/or extrinsic cues. Here, we review recent advances in temporal patterning during neuronal specification, focusing on conserved players and mechanisms in invertebrate and vertebrate models. These studies underscore temporal patterning as an evolutionarily conserved strategy to generate neuronal diversity. Understanding the general principles governing temporal patterning and the molecular players involved will improve our ability to direct neural progenitors towards specific neuronal fates for brain repair.



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Αλέξανδρος Γ. Σφακιανάκης

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