Τετάρτη 5 Ιουλίου 2017
Prognostic factors and patterns of locoregional failure after surgical resection in patients with cholangiocarcinoma without adjuvant radiation therapy: optimal field design for adjuvant radiation therapy
Publication date: Available online 5 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Zahra Ghiassi-Nejad, Paola Tarchi, Erin Moshier, Meng Ru, Parissa Tabrizian, Myron Schwartz, Michael Buckstein
PurposeTo identify prognostic factors and patterns of local failure in patients with cholangiocarcinoma, following surgical resection in the absence of adjuvant radiation, for optimal definition of target volumes encompassing the majority of local recurrences.Methods and MaterialsA chart review was performed in patients who underwent resection for primary CCA (intrahepatic, hilar, and distal) between 1999 and 2014. Local failure was defined as recurrence in a theoretical reasonable post-operative radiation volume. This includes the cut surface of liver, biliary anastomosis, hilum, portal nodes, celiac nodes, peri-pancreatic nodes, gastro-hepatic nodes, and retroperitoneal nodes. Patients who received adjuvant radiation were excluded.Results189 patients underwent surgical resection for CCA, of which 145 patients had sufficient follow up. Median follow up was 41.6 months (95% CI: 35.4-48.7). 102 cases were intrahepatic, and 43 were hilar/distal CCA. Adjuvant chemotherapy was given in 38 (26%) of cases, of which 20 (54%) were gemcitabine based. Eighty six patients (59%) had a documented recurrence, of which 44 (51%) had a locoregional component. Among patients that had a recurrence, 23 (27%) had a recurrence at the biliary anastomosis and/or cut liver surface. Twenty eight (32.6%) patients had a recurrence in the regional lymph nodes, most prevalent in the portal (16.3%), and retroperitoneal (17.4%) lymph nodes. Univariable analysis identified tumor size, any vascular invasion, presence of satellites, stage/nodal status and receipt of chemotherapy were significant prognostic factors of overall recurrence among IHC patients. Presence of satellites, and stage 3/Nx status remained statistically significant in multivariable modeling.ConclusionsThe areas at highest risk for locoregional recurrence following surgical resection are the biliary anastomosis/cut liver surface, portal lymph nodes, and retroperitoneal lymph nodes. While these results need to be validated, adjuvant radiation should possibly cover these areas to maximize locoregional control.
Teaser
Locoergional recurrences following surgical resection for cholangiocarcinoma (CCA) cause significant morbidity and mortality. This retrospective analysis explores risk factors for local failures and maps locoregional recurrences in patients who underwent surgery without adjuvant radiation. The recurrence map provides valuable information for delineating optimal planning target volumes for adjuvant radiation.http://ift.tt/2tjD6cZ
A Complex Code of Extrinsic Influences on Cortical Progenitor Cells of Higher Mammals
Abstract
Development of the cerebral cortex depends critically on the regulation of progenitor cell proliferation and fate. Cortical progenitor cells are remarkably diverse with regard to their morphology as well as laminar and areal position. Extrinsic factors, such as thalamic axons, have been proposed to play key roles in progenitor cell regulation, but the diversity, extent and timing of interactions between extrinsic elements and each class of cortical progenitor cell in higher mammals remain undefined. Here we use the ferret to demonstrate the existence of a complex set of extrinsic elements that may interact, alone or in combination, with subpopulations of progenitor cells, defining a code of extrinsic influences. This code and its complexity vary significantly between developmental stages, layer of residence and morphology of progenitor cells. By analyzing the spatial-temporal overlap of progenitor cell subtypes with neuronal and axonal populations, we show that multiple sets of migrating neurons and axon tracts overlap extensively with subdivisions of the Subventricular Zones, in an exquisite lamina-specific pattern. Our findings provide a framework for understanding the feedback influence of both intra- and extra-cortical elements onto progenitor cells to modulate their dynamics and fate decisions in gyrencephalic brains.http://ift.tt/2uN4cHe
Prenatal Ethanol Exposure and Neocortical Development: A Transgenerational Model of FASD
Abstract
Fetal Alcohol Spectrum Disorders, or FASD, represent a range of adverse developmental conditions caused by prenatal ethanol exposure (PrEE) from maternal consumption of alcohol. PrEE induces neurobiological damage in the developing brain leading to cognitive-perceptual and behavioral deficits in the offspring. Alcohol-mediated alterations to epigenetic function may underlie PrEE-related brain dysfunction, with these changes potentially carried across generations to unexposed offspring. To determine the transgenerational impact of PrEE on neocortical development, we generated a mouse model of FASD and identified numerous stable phenotypes transmitted via the male germline to the unexposed third generation. These include alterations in ectopic intraneocortical connectivity, upregulation of neocortical Rzrβ and Id2 expression accompanied by both promoter hypomethylation of these genes and decreased global DNA methylation levels. DNMT expression was also suppressed in newborn PrEE cortex, providing further insight into how ethanol perturbs DNA methylation leading to altered regulation of gene transcription. These PrEE-induced, transgenerational phenotypes may be responsible for cognitive, sensorimotor, and behavioral deficits seen in humans with FASD. Thus, understanding the possible epigenetic mechanisms by which these phenotypes are generated may reveal novel targets for therapeutic intervention of FASD and lead to advances in human health.http://ift.tt/2tOO4rw
fMRI-based Neuronal Response to New Odorants in the Newborn Brain
Abstract
The sense of smell is one of the oldest and the most primitive senses mammals possess, it helps to evaluate the surrounding environment. From birth, smell is an important sensory modality, highly relevant for neonatal behavioral adaptation. Even though human newborns seem to be able to perceive and react to olfactory stimuli, there is still a lack of knowledge about the ontogeny of smell and the underlying central processing involved in odor perception in newborns. Brain networks involved in chemosensory perception of odorants are well described in adults, however in newborns there is no evidence that central olfaction is functional given the largely unmyelinated neonatal central nervous system. To examine this question, we used functional magnetic resonance imaging (fMRI) in the newborn to characterize cortical response to olfactory and trigeminal odorants. Here we show that brain response to odors can be measured and localized using functional MRI in newborns. Furthermore, we found that the developing brain, only few days after birth, processes new artificial odorants in similar cortical areas than adults, including piriform cortex, orbitofrontal cortex and insula. Our work provides evidence that human olfaction at birth relies on brain functions that involve all levels of the cortical olfactory system.http://ift.tt/2uMELFy
Effects of Adult Female Rat Androgenization on Brain Morphology and Metabolomic Profile
Abstract
Androgenization in adult natal women, as in transsexual men (TM), affects brain cortical thickness and the volume of subcortical structures. In order to understand the mechanism underlying these changes we have developed an adult female rat model of androgenization. Magnetic resonance imaging and spectroscopy were used to monitor brain volume changes, white matter microstructure and ex vivo metabolic profiles over 32 days in androgenized and control subjects. Supraphysiological doses of testosterone prevents aging decrease of fractional anisotropy values, decreased general cortical volume and the relative concentrations of glutamine (Gln) and myo-Inositol (mI). An increase in the N-acetylaspartate (NAA)/mI ratio was detected d. Since mI and Gln are astrocyte markers and osmolytes, we suspect that the anabolic effects of testosterone change astrocyte osmolarity so as to extrude Mi and Gln from these cells in order to maintain osmotic homeostasis. This mechanism could explain the brain changes observed in TM and other individuals receiving androgenic anabolic steroids.http://ift.tt/2tOQwhQ
Parvalbumin-Positive Interneurons Regulate Neuronal Ensembles in Visual Cortex
Abstract
For efficient cortical processing, neural circuit dynamics must be spatially and temporally regulated with great precision. Although parvalbumin-positive (PV) interneurons can control network synchrony, it remains unclear how they contribute to spatio-temporal patterning of activity. We investigated this by optogenetic inactivation of PV cells with simultaneous two-photon Ca2+ imaging from populations of neurons in mouse visual cortex in vivo. For both spontaneous and visually evoked activity, PV interneuron inactivation decreased network synchrony. But, interestingly, the response reliability and spatial extent of coactive neuronal ensembles during visual stimulation were also disrupted by PV-cell suppression, which reduced the functional repertoire of ensembles. Thus, PV interneurons can control the spatio-temporal dynamics of multineuronal activity by functionally sculpting neuronal ensembles and making them more different from each other. In doing so, inhibitory circuits could help to orthogonalize multicellular patterns of activity, enabling neural circuits to more efficiently occupy a higher dimensional space of potential dynamics.http://ift.tt/2uMLGyR
Glibenclamide pretreatment protects against chronic memory dysfunction and glial activation in rat cranial blast traumatic brain injury
Source:Behavioural Brain Research, Volume 333
Author(s): Jesse A. Stokum, Kaspar Keledjian, Erik Hayman, Jason K. Karimy, Adam Pampori, Ziyan Imran, Seung Kyoon Woo, Volodymyr Gerzanich, J. Marc Simard
Blast traumatic brain injury (bTBI) affects both military and civilian populations, and often results in chronic deficits in cognition and memory. Chronic glial activation after bTBI has been linked with cognitive decline. Pharmacological inhibition of sulfonylurea receptor 1 (SUR1) with glibenclamide was shown previously to reduce glial activation and improve cognition in contusive models of CNS trauma, but has not been examined in bTBI. We postulated that glibenclamide would reduce chronic glial activation and improve long-term memory function after bTBI. Using a rat direct cranial model of bTBI (dc-bTBI), we evaluated the efficacy of two glibenclamide treatment paradigms: glibenclamide prophylaxis (pre-treatment), and treatment with glibenclamide starting after dc-bTBI (post-treatment). Our results show that dc-bTBI caused hippocampal astrocyte and microglial/macrophage activation that was associated with hippocampal memory dysfunction (rapid place learning paradigm) at 28days, and that glibenclamide pre-treatment, but not post-treatment, effectively protected against glial activation and memory dysfunction. We also report that a brief transient time-window of blood-brain barrier (BBB) disruption occurs after dc-bTBI, and we speculate that glibenclamide, which is mostly protein bound and does not normally traverse the intact BBB, can undergo CNS delivery only during this brief transient opening of the BBB. Together, our findings indicate that prophylactic glibenclamide treatment may help to protect against chronic cognitive sequelae of bTBI in warfighters and other at-risk populations.
http://ift.tt/2tP4LTL
HBK-15 protects mice from stress-induced behavioral disturbances and changes in corticosterone, BDNF, and NGF levels
Source:Behavioural Brain Research, Volume 333
Author(s): Karolina Pytka, Monika Głuch-Lutwin, Magdalena Kotańska, Elżbieta Żmudzka, Magdalena Jakubczyk, Anna Waszkielewicz, Paulina Janiszewska, Maria Walczak
Unlike majority of current antidepressants, HBK-15–a 5-HT1A and 5-HT7 receptor antagonist – showed memory-enhancing properties. In this study, we aimed to further characterize pharmacological profile of HBK-15 and investigate its antidepressant- and anxiolytic-like activity in the mouse model of unpredictable chronic mild stress. We used sucrose consumption test, forced swim test and elevated plus maze test as behavioral endpoints. We also evaluated the influence of HBK-15 on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus and prefrontal cortex, as well as body weight, relative adrenal glands weight and plasma corticosterone level in the stressed mice. We utilized LC/MS/MS method to determine HBK-15 concentration in plasma and brain. We evaluated pharmacokinetic profile and distribution to brain of HBK-15 (2.5mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration in CD-1 mice. HBK-15 (2.5mg/kg but not 1.25mg/kg) and fluoxetine (10mg/kg) protected stressed mice from anhedonic-, depressive- and anxiety-like behaviors, decreases in the BDNF and NGF levels in the hippocampus and prefrontal cortex, increases in plasma corticosterone levels and relative adrenal glands weight. The pharmacokinetic analysis demonstrated a rapid absorption of HBK-15 after i.p. administration (tmax=5min), a short half-life (t0.5=74min), large volume of distribution (Vss=3.7L/kg) and bioavailability after i.p. administration equal 25%. HBK-15 administered i.v. and i.p. significantly penetrated brain. Our results suggest that the blockade of serotonergic 5-HT1A and 5-HT7 receptors might be beneficial in the treatment of depressive disorders with cognitive dysfunction.
http://ift.tt/2uMLq2R
Neuromagnetic correlates of voice pitch, vowel type, and speaker size in auditory cortex
Source:NeuroImage, Volume 158
Author(s): Martin Andermann, Roy D. Patterson, Carolin Vogt, Lisa Winterstetter, André Rupp
Vowel recognition is largely immune to differences in speaker size despite the waveform differences associated with variation in speaker size. This has led to the suggestion that voice pitch and mean formant frequency (MFF) are extracted early in the hierarchy of hearing/speech processing and used to normalize the internal representation of vowel sounds. This paper presents a magnetoencephalographic (MEG) experiment designed to locate and compare neuromagnetic activity associated with voice pitch, MFF and vowel type in human auditory cortex. Sequences of six sustained vowels were used to contrast changes in the three components of vowel perception, and MEG responses to the changes were recorded from 25 participants. A staged procedure was employed to fit the MEG data with a source model having one bilateral pair of dipoles for each component of vowel perception. This dipole model showed that the activity associated with the three perceptual changes was functionally separable; the pitch source was located in Heschl's gyrus (bilaterally), while the vowel-type and formant-frequency sources were located (bilaterally) just behind Heschl's gyrus in planum temporale. The results confirm that vowel normalization begins in auditory cortex at an early point in the hierarchy of speech processing.
http://ift.tt/2tL6wla
Longitudinal changes in reading network connectivity related to skill improvement
Source:NeuroImage, Volume 158
Author(s): Jessica Wise Younger, Elliot Tucker-Drob, James R. Booth
Attempts to characterize the neural differences between individuals with and without dyslexia generally point to reduced activation in and connectivity between brain areas in a reading network composed of the inferior frontal gyrus, the ventral occipito-temporal cortex, and the dorsal temporo-parietal circuit. However, developmental work on brain activity during reading has indicated that some brain areas show developmental decreases in activation with age. Thus, reading network connectivity may also show decreases that are positively associated with increases in reading ability. However, the developmental trajectory of reading network connectivity in typically developing readers is not yet well established. In the current study, we use a longitudinal design to determine how connectivity changes over time, and how these changes relate to changes in reading skill. We find that longitudinal increases in reading ability are associated with higher initial connectivity in the dorsal stream between fusiform and inferior parietal cortex, implicated in phonological decoding, followed by decreases in connectivity in this stream over time. We further find that increases in reading ability are supported by maintenance of connectivity in the ventral stream between inferior occipital and fusiform cortex, suggesting a more mature automatic orthographic recognition strategy. Readers who show little reading improvement over time do not attain high levels of connectivity in the dorsal stream at any time point, and their ventral stream connectivity decreases over time. These results together suggest that superior reading ability is initially supported by phonological decoding, with a decreased reliance on this strategy as reading becomes more automated. Our results indicate that development of the dorsal and ventral streams are closely linked, and support the hypothesis that a decrease in the dorsal stream is important for ventral stream development.
http://ift.tt/2ssrzFf
THIRD GENERATION EGFR TKIs IN EGFR-MUTATED NSCLC: WHERE ARE WE NOWAND WHERE ARE WE GOING
Publication date: Available online 5 July 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): A. Russo, T. Franchina, G.R.R. Ricciardi, V. Smiroldo, M. Picciotto, M. Zanghì, C. Rolfo, V. Adamo
The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents. Despite impressive clinical activity against EGFR-mutated NSCLCs, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant. Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M. The discovery of mutant-selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M-harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors.
http://ift.tt/2usUx9A
A potential contribution of psoriasin to vascular and epithelial abnormalities and inflammation in systemic sclerosis
Abstract
Background
Antimicrobial peptides have attracted much attention as a member of disease-associated molecules in systemic sclerosis (SSc), which is pathologically characterized by immune abnormalities, vasculopathy, and tissue fibrosis.
Objective
To investigate the potential contribution of one of the anitimicrobial peptides psoriasin to the development of SSc.
Methods
Psoriasin expression in the skin samples and sera derived from SSc patients and its correlation with clinical parameters were analyzed. Psoriasin expression was evaluated by immunohistochemistry with skin samples from SSc patients and healthy controls. Serum levels of psoriasin were determined by enzyme-linked immunosorbent assay in 51 SSc patients and 19 healthy controls and assessed for the association with clinical symptoms.
Results
The expression of psoriasin was elevated in the epidermis of SSc lesional skin. Serum psoriasin levels were higher in SSc patients, especially in diffuse cutaneous SSc patients with disease duration of <6 years, than in healthy controls. With respect to clinical association, SSc patients with interstitial lung disease, telangiectasia, and pitting scars had significantly augmented levels of serum psoriasin than those without each of these symptoms. In the subgroup of patients with interstitial lung disease, the elevation of serum psoriasin levels was associated with higher ground-glass opacity scores. Furthermore, serum psoriasin levels were decreased after the treatment with intravenous cyclophosphamide pulse as compared to baseline values.
Conclusion
Our findings indicate a possible contribution of psoriasin to the development of clinical symptoms associated with vascular and epithelial abnormalities and inflammation in SSc, further supporting the roles of antimicrobial peptides in the SSc pathogenesis.
This article is protected by copyright. All rights reserved.
http://ift.tt/2tOGdKk
Expression of monoacylglycerol lipase as a marker of tumour invasion and progression in malignant melanoma
Abstract
Background
Accumulating evidence suggests that the lipid lytic enzyme monoacylglycerol lipase (MAGL) promotes tumour invasion and metastasis through up-regulation of pro-tumourigenic signalling lipids in several tumour cell lines. However, the expression status of MAGL in clinical melanoma tissues and its clinico-pathological significance remain unclear.
Objective
To correlate the tumour expression status of MAGL with the clinico-pathological information of patients with malignant melanoma.
Methods
Polymerase chain reaction (PCR) array screening was performed, and the results were validated using immunocytochemical analysis of tumour and non-tumour melanocytic cell lines. Immunohistochemical staining for MAGL was performed for 74 melanoma samples, including 48 primary and 26 metastatic tumours, in which the expression of MAGL was determined by evaluating the percentage of MAGL-positive tumour cells and the MAGL staining intensity. Finally, we analysed the association of MAGL expression status with tumour progression, tumour thickness and vascular invasion of the primary lesion.
Results
Immunocytochemical analysis revealed that MAGL was expressed in all 12 melanoma cell lines, but not in normal human epidermal melanocytes. In the immunohistochemical analysis, positive staining for MAGL was noted in 32 of 48 (64.5%) primary lesions, 14 of 17 (82.4%) lymph node metastatic lesions and 7 of 9 (77.8%) skin metastatic lesions. Metastatic tumours had a significantly higher staining intensity (p=0.033 for lymph node, p=0.010 for skin). In the analysis of primary lesions, higher MAGL expression correlated with greater tumour thickness (p=0.015) and the presence of vascular invasion (p=0.017). On further evaluation of MAGL-positive primary lesions staining intensity of MAGL tended to be higher in deeper areas of the tumour mass.
Conclusions
The expression of MAGL in tumour cells reflects the aggressiveness of melanoma cells and may serve as a marker of tumour progression.
This article is protected by copyright. All rights reserved.
http://ift.tt/2tOGXzt
Tumescent local anaesthesia for early dermatosurgery in infants
Abstract
Background
Early paediatric dermatosurgery reveals excellent cosmetic results due to high skin-elasticity and pronounced capacity to recover from trauma. Furthermore, the size of skin lesions increases during life proportionally to skin growth and therefore early removal is of major importance. Selected local anaesthetics like prilocaine can cause methaemoglobinemia. However, in contrast to general anaesthesia many other local anaesthetics do not bare any major risks for infants.
Objective
In this retrospective study, we analysed infants aged less than 7 months receiving tumescent local anaesthesia (TLA) followed by dermatosurgery at our department between 2005 and 2015. The analysis is mainly based on our records. Additional information for a subset of patients was gained by a postoperative survey.
Methods
92 infants (39 male, 53 female) with a median age of 4.2 months (range: 1.5 months; 6.7 months) were included in this study. Additional postoperative information was available for 33 of the 92 studied patients (35%).
Results
Infants were mainly operated for removal of a melanocytic nevus (n=54), followed by haemangioma (n=23), nevus sebaceous (n=6) and other lesions (n=9). The lesions were located on the scalp or neck (n=31), on the extremities (n=31), on the trunk (n=21), in the face (n=6) or on the buttocks (n=3). The median size of excision was 509mm2 (range: 16mm2; 3600mm2). Primary defect closure was performed by intracutaneous (n=68) or extracutaneous (n=24) suture techniques. No side effects of local anaesthesia were observed in any patient. Postoperative complications include pain (1/33; 3%), wound healing disorder (1/33; 3%) and visible severe scarring (2/33; 6%).
Conclusions
The combination of TLA and dermatosurgery in infants is a suitable outpatient treatment option for small lesions without any major risks or side effects and the benefit of prolonged postoperative analgesia.
This article is protected by copyright. All rights reserved.
http://ift.tt/2uMATEP
Depression and Suicidality in Psoriasis: Review of the Literature Including the Cytokine Theory of Depression
Abstract
Psoriasis can be a socially isolating disease due to debilitating physical symptoms and the stigma patients feel because of the appearance of their skin. Mental health comorbidities such as anxiety, depression, and suicidal ideation and behavior (SIB) are prevalent in patients with psoriasis. Patients with mild psoriasis can experience psychiatric comorbidities; however, disorders such as depression and SIB are more common in patients with severe psoriasis or psoriatic arthritis. Psychiatric disorders can both result from and contribute to progression of psoriasis, suggesting that psoriasis and psychiatric conditions, such as depression, may have overlapping biological mechanisms. Proinflammatory cytokines such as interleukin (IL) 1 and IL-6 are elevated in both psoriasis and depression, indicating that the inflammatory process may be involved in the progression of both diseases. Elevated cytokine levels in the central nervous system cause physiologic and biochemical changes that may contribute to the development of depression. In this review of the literature, we discuss the evidence that supports the association of psoriasis with mental health disorders and the tools used to detect the presence of these comorbidities. Additionally, we review the most prominent hypotheses on the mechanisms by which the inflammatory response and elevated cytokines can cause depression. These results highlight the role that systemic inflammation plays in the various mental health comorbidities associated with psoriasis, including depression and SIB.
This article is protected by copyright. All rights reserved.
http://ift.tt/2uMQjsm
Association of atopy and tentative diagnosis of skin cancer - results from occupational skin cancer screenings
Abstract
Background
The relationship between atopic conditions and carcinoma of the skin has been described inconsistently. Population-based data providing information on atopic diseases as well as on skin-cancer are sparse.
Objective
To determine the correlation between atopy and prevalence of precanceroses, nonmelanoma skin-cancer and malignant melanoma (MM), while taking into account known risk factors for skin cancer.
Methods
Data from occupational skin cancer screenings were analysed in a cross-sectional study. Dermatologists performed whole body examinations and collected medical histories. Subjects comprised all employees (16 to 70 years) examined from 2006 to 2014. 'Atopy' was defined by clinical screening diagnosis and/or by participant-reported, pre-existing atopic dermatitis, allergic asthma or other specified allergies confirmed by a physician. Tentative screening diagnoses of skin cancer related to actinic keratosis, basal cell carcinoma and malignant melanoma.
Results
The study cohort comprised 90,265 employees (mean age 43 ± 11 years, 58.5% male), 30.7% of whom were ever diagnosed with an atopic disease. Persons with atopic conditions recorded in their medical history and at the time of screening had a significantly lower prevalence of actinic keratosis (AK), basal cell carcinoma (BCC) and MM. After controlling for age, sex and relevant risk factors (skin type, childhood sun burns), atopy remained significantly protective against BCC (OR 0.77) and MM (OR 0.53).
Conclusion
Design limitations of the study include that all findings of skin cancer were based on clinical examination only and must therefore be considered tentative diagnoses. Furthermore, owing to the cross-sectional study design, causal pathways cannot be proven. However, analyses of data from such a large and general population-based cohort afford valuable insights into the relationship of atopic diseases and skin cancer. They provide the grounds for prospective cohort studies to evaluate and dissect the underlying mechanism.
This article is protected by copyright. All rights reserved.
http://ift.tt/2uMVTv2
Infatile hemangiomas with minimal or arrested growth associated with soft tissue hypertrophy: a case series of 10 patients
Abstract
Background
Infantile hemangiomas with minimal or arrested growth (IH-MAGs) are characterized by a proliferative component of less than 25% of its surface area. The co-occurrence of IH-MAGs and soft tissue anomalies is rare and case series of this association are lacking.
Objective
We present ten cases of IH-MAGs associated with soft tissue hypertrophy and describe their clinical features.
Methods
We reviewed all infantile hemangiomas with minimal or arrested growth seen between 2009 to 2016 in the dermatology clinic department at Hospital Santa Creu i Sant Pau, Barcelona. To collect more patients, we also requested cases from the Hemangioma Investigator Group and members of the Spanish Society of Vascular Anomalies.
Results
Ten patients had IH-MAGs associated with soft tissue hypertrophy; seven involving the arm and three involving the leg. All displayed a segmental pattern, a doughy and puffy texture, and prominent surface veins. No significant asymmetries in limbs and no other visceral anomalies were observed at follow-up (range 15 months to 7 years). One patient reported coldness in the limb with infantile hemangioma, but RMI-angiography did not disclose a vascular malformation underneath the lesion. Ulceration was observed in three patients. The proliferative component in all IH -MAGs had faded at one-year follow-up, while soft tissue hypertrophy and prominent vessels remained unchanged.
Conclusions
In this first case series of IH-MAGS associated with soft tissue hypertrophy Soft tissue hypertrophy was not progressive and remained unchanged over time, unlike the proliferative component of classic infantile hemangioma. The origin of the prominent vessels and the higher ulceration risk are unknown; however, these findings are probably related to a minor disruption of local vessels not detected in imaging tests.
This article is protected by copyright. All rights reserved.
http://ift.tt/2tOGUDN
Amenamevir, a novel helicase–primase inhibitor, for treatment of herpes zoster: A randomized, double-blind, valaciclovir-controlled phase 3 study
Abstract
Amenamevir is a potent helicase–primase inhibitor and a novel class of antiviral agent other than nucleoside compounds, such as aciclovir, valaciclovir and famciclovir. This study is the first randomized, double-blind, valaciclovir-controlled phase 3 study to evaluate the efficacy and safety of amenamevir in Japanese patients with herpes zoster when treated within 72 h after onset of rash. A total of 751 patients were randomly assigned to receive either amenamevir 400 mg or 200 mg p.o. once daily or valaciclovir 1000 mg three times daily (daily dose, 3000 mg) for 7 days. The primary efficacy end-point was the proportion of cessation of new lesion formation by day 4 ("day 4 cessation proportion"). The day 4 cessation proportions for amenamevir 400 and 200 mg and valaciclovir were 81.1% (197/243), 69.6% (172/247) and 75.1% (184/245), respectively. Non-inferiority of amenamevir 400 mg to valaciclovir was confirmed by a closed testing procedure. Days to cessation of new lesion formation, complete crusting, healing, pain resolution and virus disappearance were evaluated as secondary end-points. No significant differences were observed in any of the treatment groups. Amenamevir 400 and 200 mg were well tolerated as well as valaciclovir. The proportions of patients who experienced drug-related adverse events were 10.0% (25/249), 10.7% (27/252) and 12.0% (30/249) with amenamevir 400 and 200 mg and valaciclovir, respectively. In conclusion, amenamevir 400 mg appears to be effective and well tolerated for treatment of herpes zoster in immunocompetent Japanese patients.
http://ift.tt/2usPaaq
Recruitment of Staufen2 Enhances Dendritic Localization of an Intron-Containing CaMKIIα mRNA
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Raúl Ortiz, Maya V. Georgieva, Sara Gutiérrez, Neus Pedraza, Sandra M. Fernández-Moya, Carme Gallego
Regulation of mRNA localization is a conserved cellular process observed in many types of cells and organisms. Asymmetrical mRNA distribution plays a particularly important role in the nervous system, where local translation of localized mRNA represents a key mechanism in synaptic plasticity. CaMKIIα is a very abundant mRNA detected in neurites, consistent with its crucial role at glutamatergic synapses. Here, we report the presence of CaMKIIα mRNA isoforms that contain intron i16 in dendrites, RNA granules, and synaptoneurosomes from primary neurons and brain. This subpopulation of unspliced mRNA preferentially localizes to distal dendrites in a synaptic-activity-dependent manner. Staufen2, a well-established marker of RNA transport in dendrites, interacts with intron i16 sequences and enhances its distal dendritic localization, pointing to the existence of intron-mediated mechanisms in the molecular pathways that modulate dendritic transport and localization of synaptic mRNAs.
Graphical abstract
Teaser
Ortiz et al. have found that a subset of the total CaMKIIα mRNA population retains an intron in dendrites. Staufen2 interacts with this intron and enhances the distal dendritic localization of unspliced CaMKIIα mRNA. These findings suggest that intron retention could be a mechanism to modulate dendritic localization of synaptic mRNAs.http://ift.tt/2trXkj9
Periadolescent Maturation of GABAergic Hyperpolarization at the Axon Initial Segment
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Gina Rinetti-Vargas, Khanhky Phamluong, Dorit Ron, Kevin J. Bender
Neuronal chloride levels are developmentally regulated. Early in life, high intracellular concentrations support chloride efflux and depolarization at GABAergic synapses. In mouse, intracellular chloride decreases over the first postnatal week in the somatodendritic compartment, eventually supporting mature, hyperpolarizing GABAergic inhibition. In contrast to this dendritic switch, it is less clear how GABAergic signaling at the axon initial segment (AIS) functions in mature pyramidal cells, as reports of both depolarization and hyperpolarization have been reported in the AIS past the first postnatal week. Here, we show that GABAergic signaling at the AIS of prefrontal pyramidal cells, indeed, switches polarity from depolarizing to hyperpolarizing but does so over a protracted periadolescent period. This is the most delayed maturation in chloride reversal in any structure studied to date and suggests that chandelier cells, which mediate axo-axonic inhibition, play a unique role in the periadolescent maturation of prefrontal circuits.
Graphical abstract
Teaser
Rinetti-Vargas et al. examine the development of chloride reversal potential (ECl), which determines GABAergic synapse polarity, in the axon initial segment of mouse prefrontal layer 2/3 pyramidal cells. They find that axon initial segment ECl hyperpolarizes over a periadolescent development period, eventually matching dendritic values.http://ift.tt/2tsfIbA
The Ubiquitination of PINK1 Is Restricted to Its Mature 52-kDa Form
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Yuhui Liu, Cristina Guardia-Laguarta, Jiang Yin, Hediye Erdjument-Bromage, Brittany Martin, Michael James, Xuejun Jiang, Serge Przedborski
Along with Parkin, PINK1 plays a critical role in maintaining mitochondrial quality control. Although PINK1 is expressed constitutively, its level is kept low in healthy mitochondria by polyubiquitination and ensuing proteasomal degradation of its mature, 52 kDa, form. We show here that the target of PINK1 polyubiquitination is the mature form and is mediated by ubiquitination of a conserved lysine at position 137. Notably, the full-length protein also contains Lys-137 but is not ubiquitinated. On the basis of our data, we propose that cleavage of full-length PINK1 at Phe-104 disrupts the major hydrophobic membrane-spanning domain in the protein, inducing a conformation change in the resultant mature form that exposes Lys-137 to the cytosol for subsequent modification by the ubiquitination machinery. Thus, the balance between the full-length and mature PINK1 allows its levels to be regulated via ubiquitination of the mature form and ensures that PINK1 functions as a mitochondrial quality control factor.
Graphical abstract
Teaser
PINK1 mutations cause Parkinson's disease. PINK1 is cleaved into a shorter 52-kDa form at the mitochondrial membrane, but regulation of the turnover of cleaved PINK1 is unknown. Liu et al. show that polyubiquitination of cleaved PINK1 regulates its degradation via the proteasome.http://ift.tt/2ts6UT0
Stromal Cell-Derived Factor 1 Mediates Immune Cell Attraction upon Urinary Tract Infection
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Batya Isaacson, Tehila Hadad, Ariella Glasner, Chamutal Gur, Zvi Granot, Gilad Bachrach, Ofer Mandelboim
Urinary tract infection (UTI) is the most common type of bacterial infection in humans. Fifty percent of all women will experience at least one UTI in their lifetime, with uropathogenic Escherichia coli (UPEC) accounting for 80% of reported cases. UTI evokes a complex, well-timed immune response that is crucial for bacterial clearance. The majority of immune cells participating in the immune response are absent from the healthy bladder, and the mechanisms used to recruit them upon UTI are not fully understood. Here, we show that immediately after UPEC infection, bladder epithelial cells secrete stromal cell-derived factor 1 (SDF-1), initiating immune cell accumulation at the site of infection. SDF-1 blockade significantly reduced immune cell migration to the infected bladder, resulting in severe exacerbation of infection. We also show that FimH, the adhesin of type 1 fimbria, one of UPEC's virulence factors, is directly involved in the secretion of SDF-1 upon UTI.
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Urinary tract infections (UTIs) are mainly caused by uropathogenic Escherichia coli (UPEC) and evoke a complex immune response. Isaacson et al. show that upon UPEC infection, bladder epithelial cells secrete the chemokine stromal cell-derived factor 1, triggering the migration and accumulation of immune cells at the site of infection.http://ift.tt/2tsanB1
Identification of a Druggable Pathway Controlling Glioblastoma Invasiveness
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Nora Pencheva, Mark C. de Gooijer, Daniel J. Vis, Lodewyk F.A. Wessels, Tom Würdinger, Olaf van Tellingen, René Bernards
Diffuse and uncontrollable brain invasion is a hallmark of glioblastoma (GBM), but its mechanism is understood poorly. We developed a 3D ex vivo organotypic model to study GBM invasion. We demonstrate that invading GBM cells upregulate a network of extracellular matrix (ECM) components, including multiple collagens, whose expression correlates strongly with grade and clinical outcome. We identify interferon regulatory factor 3 (IRF3) as a transcriptional repressor of ECM factors and show that IRF3 acts as a suppressor of GBM invasion. Therapeutic activation of IRF3 by inhibiting casein kinase 2 (CK2)—a negative regulator of IRF3—downregulated the expression of ECM factors and suppressed GBM invasion in ex vivo and in vivo models across a panel of patient-derived GBM cell lines representative of the main molecular GBM subtypes. Our data provide mechanistic insight into the invasive capacity of GBM tumors and identify a potential therapy to inhibit GBM invasion.
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Pencheva et al. describe an ex vivo organotypic brain slice model of glioblastoma invasiveness. Using this model, the authors discover a pro-invasive network of extracellular matrix collagens that are transcriptionally repressed by interferon regulatory factor 3. Small-molecule targeting of casein kinase 2 inhibits invasion by activating interferon regulatory factor 3.http://ift.tt/2trKfXa
Inhibition of the Schizophrenia-Associated MicroRNA miR-137 Disrupts Nrg1α Neurodevelopmental Signal Transduction
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Kristen Therese Thomas, Bart Russell Anderson, Niraj Shah, Stephanie Elaine Zimmer, Daniel Hawkins, Arielle Nicole Valdez, Qiaochu Gu, Gary Jonathan Bassell
Genomic studies have repeatedly associated variants in the gene encoding the microRNA miR-137 with increased schizophrenia risk. Bioinformatic predictions suggest that miR-137 regulates schizophrenia-associated signaling pathways critical to neural development, but these predictions remain largely unvalidated. In the present study, we demonstrate that miR-137 regulates neuronal levels of p55γ, PTEN, Akt2, GSK3β, mTOR, and rictor. All are key proteins within the PI3K-Akt-mTOR pathway and act downstream of neuregulin (Nrg)/ErbB and BDNF signaling. Inhibition of miR-137 ablates Nrg1α-induced increases in dendritic protein synthesis, phosphorylated S6, AMPA receptor subunits, and outgrowth. Inhibition of miR-137 also blocks mTORC1-dependent responses to BDNF, including increased mRNA translation and dendritic outgrowth, while leaving mTORC1-independent S6 phosphorylation intact. We conclude that miR-137 regulates neuronal responses to Nrg1α and BDNF through convergent mechanisms, which might contribute to schizophrenia risk by altering neural development.
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Thomas et al. show that the schizophrenia-associated microRNA miR-137 regulates neuronal responses to neuregulin-1α and BDNF signaling. miR-137 targets multiple components of the PI3K-Akt-mTOR pathway, which act downstream of both neuregulin and BDNF. Inhibition of miR-137 blocks stimulus-induced dendritic protein synthesis and outgrowth among other responses critical to neuronal development.http://ift.tt/2trQDh5
DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Adone Mohd-Sarip, Miriam Teeuwssen, Alice G. Bot, Maria J. De Herdt, Stefan M. Willems, Robert J. Baatenburg de Jong, Leendert H.J. Looijenga, Diana Zatreanu, Karel Bezstarosti, Job van Riet, Edwin Oole, Wilfred F.J. van Ijcken, Harmen J.G. van de Werken, Jeroen A. Demmers, Riccardo Fodde, C. Peter Verrijzer
The Nucleosome Remodeling and Deacetylase (NURD) complex is a key regulator of cell differentiation that has also been implicated in tumorigenesis. Loss of the NURD subunit Deleted in Oral Cancer 1 (DOC1) is associated with human oral squamous cell carcinomas (OSCCs). Here, we show that restoration of DOC1 expression in OSCC cells leads to a reversal of epithelial-mesenchymal transition (EMT). This is caused by the DOC1-dependent targeting of NURD to repress key transcriptional regulators of EMT. NURD recruitment drives extensive epigenetic reprogramming, including eviction of the SWI/SNF remodeler, formation of inaccessible chromatin, H3K27 deacetylation, and binding of PRC2 and KDM1A, followed by H3K27 methylation and H3K4 demethylation. Strikingly, depletion of SWI/SNF mimics the effects of DOC1 re-expression. Our results suggest that SWI/SNF and NURD function antagonistically to control chromatin state and transcription. We propose that disturbance of this dynamic equilibrium may lead to defects in gene expression that promote oncogenesis.
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Mohd-Sarip et al. find that DOC1-dependent recruitment of NURD leads to reversal of the epithelial-mesenchymal transition (EMT) in oral cancer cells. Promoter binding of NURD drives SWI/SNF eviction, formation of repressive chromatin, and transcriptional repression of master regulators of EMT. The authors propose that remodeler antagonism controls reprogramming of EMT at the chromatin level.http://ift.tt/2trZVtm
Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Laura T. Haas, Santiago V. Salazar, Levi M. Smith, Helen R. Zhao, Timothy O. Cox, Charlotte S. Herber, Andrew P. Degnan, Anand Balakrishnan, John E. Macor, Charles F. Albright, Stephen M. Strittmatter
Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrPC) bound to Aβo. The SAM compound prevents Aβo-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1ΔE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1ΔE9 transgenic mouse brain. Our data show that mGluR5's role in Aβo-dependent AD phenotypes is separate from its role in glutamate signaling and silent allosteric modulation of mGluR5 has promise as a disease-modifying AD intervention with a broad therapeutic window.
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Haas et al. investigate the role of mGluR5 in Alzheimer's disease. They describe a compound that blocks the action of amyloid β through this receptor but preserves glutamate signaling. This amyloid-selective blocker rescues transgenic mouse models of Alzheimer's disease and, by sparing glutamate signaling, avoids the side effects of typical mGluR5 antagonists.http://ift.tt/2tsamwX
Laminin Levels Regulate Tissue Migration and Anterior-Posterior Polarity during Egg Morphogenesis in Drosophila
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): María C. Díaz de la Loza, Alfonsa Díaz-Torres, Federico Zurita, Alicia E. Rosales-Nieves, Emad Moeendarbary, Kristian Franze, María D. Martín-Bermudo, Acaimo González-Reyes
Basement membranes (BMs) are specialized extracellular matrices required for tissue organization and organ formation. We study the role of laminin and its integrin receptor in the regulation of tissue migration during Drosophila oogenesis. Egg production in Drosophila involves the collective migration of follicle cells (FCs) over the BM to shape the mature egg. We show that laminin content in the BM increases with time, whereas integrin amounts in FCs do not vary significantly. Manipulation of integrin and laminin levels reveals that a dynamic balance of integrin-laminin amounts determines the onset and speed of FC migration. Thus, the interplay of ligand-receptor levels regulates tissue migration in vivo. Laminin depletion also affects the ultrastructure and biophysical properties of the BM and results in anterior-posterior misorientation of developing follicles. Laminin emerges as a key player in the regulation of collective cell migration, tissue stiffness, and the organization of anterior-posterior polarity in Drosophila.
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Collective cell migration requires cell-ECM interactions. Using the fruit fly ovary, Díaz de la Loza et al. find that the ECM component laminin controls the onset and speed of epithelial sheet migration. Because laminin depletion also results in aberrant anterior-posterior polarity, laminin regulates coordinated migration during organogenesis and maintains axial polarity.http://ift.tt/2ts9LeD
Somatostatin Neurons in the Basal Forebrain Promote High-Calorie Food Intake
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Chen Zhu, Yun Yao, Yan Xiong, Mingxiu Cheng, Jing Chen, Rui Zhao, Fangzhou Liao, Runsheng Shi, Sen Song
Obesity has become a global issue, and the overconsumption of food is thought to be a major contributor. However, the regulatory neural circuits that regulate palatable food consumption remain unclear. Here, we report that somatostatin (SOM) neurons and GABAergic (VGAT) neurons in the basal forebrain (BF) play specific roles in regulating feeding. Optogenetic stimulation of BF SOM neurons increased fat and sucrose intake within minutes and promoted anxiety-like behaviors. Furthermore, optogenetic stimulation of projections from BF SOM neurons to the lateral hypothalamic area (LHA) selectively resulted in fat intake. In addition, activation of BF VGAT neurons rapidly induced general food intake and gnawing behaviors. Whole-brain mapping of inputs and outputs showed that BF SOM neurons form bidirectional connections with several brain areas important in feeding and regulation of emotion. Collectively, these results suggest that BF SOM neurons play a selective role in hedonic feeding.
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Zhu et al. uncover a crucial neuronal population in the mouse basal forebrain (BF) that induces hedonic feeding. Activation of BF somatostatin neurons specifically leads to high-calorie food intake and induces anxiety-like behaviors. This may be related to stress-induced overeating of palatable food, which contributes to obesity problems.http://ift.tt/2tsdV6u
Time-Resolved Fast Mammalian Behavior Reveals the Complexity of Protective Pain Responses
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Liam E. Browne, Alban Latremoliere, Brendan P. Lehnert, Alyssa Grantham, Catherine Ward, Chloe Alexandre, Michael Costigan, Frédéric Michoud, David P. Roberson, David D. Ginty, Clifford J. Woolf
Potentially harmful stimuli are detected at the skin by nociceptor sensory neurons that drive rapid protective withdrawal reflexes and pain. We set out to define, at a millisecond timescale, the relationship between the activity of these sensory neurons and the resultant behavioral output. Brief optogenetic activation of cutaneous nociceptors was found to activate only a single action potential in each fiber. This minimal input was used to determine high-speed behavioral responses in freely behaving mice. The localized stimulus generated widespread dynamic repositioning and alerting sub-second behaviors whose nature and timing depended on the context of the animal and its position, activity, and alertness. Our findings show that the primary response to injurious stimuli is not limited, fixed, or localized, but is dynamic, and that it involves recruitment and gating of multiple circuits distributed throughout the central nervous system at a sub-second timescale to effectively both alert to the presence of danger and minimize risk of harm.
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Browne et al. find that the responses evoked by noxious stimuli, when examined at a millisecond resolution, are not fixed, localized, or limited to reflex withdrawal but are instead coordinated globally across the body in a sub-second time frame to alert the animal and limit potential harm.http://ift.tt/2trMnxN
An Ancient Pseudoknot in TNF-α Pre-mRNA Activates PKR, Inducing eIF2α Phosphorylation that Potently Enhances Splicing
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Lise Sarah Namer, Farhat Osman, Yona Banai, Benoît Masquida, Rodrigo Jung, Raymond Kaempfer
Tumor necrosis factor alpha (TNF-α) is expressed promptly during inflammatory responses. Efficient TNF-α mRNA splicing is achieved through a 3′ UTR element that activates RNA-dependent eIF2α protein kinase (PKR). The TNF-α RNA activator, we show, folds into a pseudoknot conserved from teleost fish to humans, critical for PKR activation and mRNA splicing. The pseudoknot constrains the RNA into two double-helical stacks having parallel axes, permitting facile PKR dimerization and trans-autophosphorylation needed for kinase activation. Mutations show that the PKR activator potently enhances splicing without inhibiting translation. eIF2α phosphorylation represses translation and is essential for coping with cellular stress, yet PKR-enabled TNF mRNA splicing depends strictly on eIF2α phosphorylation. Indeed, eIF2α phosphorylation at Serine51 is necessary and sufficient to achieve highly efficient splicing, extending its role from negative control of translation to positive control of splicing. This mechanism, operational in human peripheral blood mononuclear cells (PBMCs), links stress signaling to protective immunity through TNF mRNA splicing rendered efficient upon eIF2α phosphorylation.
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Tumor necrosis factor (TNF) is expressed promptly during inflammatory responses. Namer et al. define the structure and function of a TNF RNA element that promotes mRNA splicing. It enables splicing by inducing phosphorylation of eIF2α by the RNA-activated enzyme PKR, a cellular stress response previously thought only to block translation.http://ift.tt/2trQDO7
Post-termination Ribosome Intermediate Acts as the Gateway to Ribosome Recycling
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Arjun Prabhakar, Mark C. Capece, Alexey Petrov, Junhong Choi, Joseph D. Puglisi
During termination of translation, the nascent peptide is first released from the ribosome, which must be subsequently disassembled into subunits in a process known as ribosome recycling. In bacteria, termination and recycling are mediated by the translation factors RF, RRF, EF-G, and IF3, but their precise roles have remained unclear. Here, we use single-molecule fluorescence to track the conformation and composition of the ribosome in real time during termination and recycling. Our results show that peptide release by RF induces a rotated ribosomal conformation. RRF binds to this rotated intermediate to form the substrate for EF-G that, in turn, catalyzes GTP-dependent subunit disassembly. After the 50S subunit departs, IF3 releases the deacylated tRNA from the 30S subunit, thus preventing reassembly of the 70S ribosome. Our findings reveal the post-termination rotated state as the crucial intermediate in the transition from termination to recycling.
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Ribosome intersubunit conformation plays a critical role in ribosome recycling after translation termination. Prabhakar et al. use single-molecule techniques to temporally resolve the post-termination intersubunit rotation that promotes factor-mediated disassembly of the ribosome. The observed ribosome conformational dynamics clarified the roles of the protein factors and timing of recycling events.http://ift.tt/2trTtSW
Exosomes Mediate Mobilization of Autocrine Wnt10b to Promote Axonal Regeneration in the Injured CNS
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Nardos G. Tassew, Jason Charish, Alireza P. Shabanzadeh, Valbona Luga, Hidekiyo Harada, Nahal Farhani, Philippe D'Onofrio, Brian Choi, Ahmad Ellabban, Philip E.B. Nickerson, Valerie A. Wallace, Paulo D. Koeberle, Jeffrey L. Wrana, Philippe P. Monnier
Developing strategies that promote axonal regeneration within the injured CNS is a major therapeutic challenge, as axonal outgrowth is potently inhibited by myelin and the glial scar. Although regeneration can be achieved using the genetic deletion of PTEN, a negative regulator of the mTOR pathway, this requires inactivation prior to nerve injury, thus precluding therapeutic application. Here, we show that, remarkably, fibroblast-derived exosomes (FD exosomes) enable neurite growth on CNS inhibitory proteins. Moreover, we demonstrate that, upon treatment with FD exosomes, Wnt10b is recruited toward lipid rafts and activates mTOR via GSK3β and TSC2. Application of FD exosomes shortly after optic nerve injury promoted robust axonal regeneration, which was strongly reduced in Wnt10b-deleted animals. This work uncovers an intercellular signaling pathway whereby FD exosomes mobilize an autocrine Wnt10b-mTOR pathway, thereby awakening the intrinsic capacity of neurons for regeneration, an important step toward healing the injured CNS.
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Tassew et al. find that FD exosomes induce relocalization of Wnt10b into lipid rafts, thereby activating mTOR and promoting axonal growth in an inhibitory environment. These exosomes also promote axonal regeneration following optic nerve injury. Thus, they represent a powerful tool to stimulate axonal regrowth in the injured CNS.http://ift.tt/2trXjM7
RORα Induces KLF4-Mediated M2 Polarization in the Liver Macrophages that Protect against Nonalcoholic Steatohepatitis
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Yong-Hyun Han, Hyeon-Ji Kim, Hyelin Na, Min-Woo Nam, Ju-Yeon Kim, Jun-Seok Kim, Seung-Hoi Koo, Mi-Ock Lee
The regulation of M1/M2 polarization in liver macrophages is closely associated with the progression of nonalcoholic steatohepatitis (NASH); however, the mechanism involved in this process remains unclear. Here, we describe the orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) as a key regulator of M1/M2 polarization in hepatic residential Kupffer cells (KCs) and infiltrated monocyte-derived macrophages. RORα enhanced M2 polarization in KCs by inducing the kruppel-like factor 4. M2 polarization was defective in KCs and bone-marrow-derived macrophages of the myeloid-specific RORα null mice, and these mice were susceptible to HFD-induced NASH. We found that IL-10 played an important role in connecting the function of M2 KCs to lipid accumulation and apoptosis in hepatocytes. Importantly, M2 polarization was controlled by a RORα activator, JC1-40, which improved symptoms of NASH. Our results suggest that the M2-promoting effects of RORα in liver macrophages may provide better therapeutic strategies against NASH.
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Han et al. find that RORα is a key regulator of M1/M2 polarization in liver macrophages. Myeloid-specific knockout of RORα display decreased M2/M1 ratio in Kupffer cells and enhanced susceptibility to nonalcoholic steatohepatitis. This function of RORα may suggest therapeutic strategies for nonalcoholic steatohepatitis.http://ift.tt/2trYCul
Microbial-Host Co-metabolites Are Prodromal Markers Predicting Phenotypic Heterogeneity in Behavior, Obesity, and Impaired Glucose Tolerance
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Marc-Emmanuel Dumas, Alice R. Rothwell, Lesley Hoyles, Thomas Aranias, Julien Chilloux, Sophie Calderari, Elisa M. Noll, Noémie Péan, Claire L. Boulangé, Christine Blancher, Richard H. Barton, Quan Gu, Jane F. Fearnside, Chloé Deshayes, Christophe Hue, James Scott, Jeremy K. Nicholson, Dominique Gauguier
The influence of the gut microbiome on metabolic and behavioral traits is widely accepted, though the microbiome-derived metabolites involved remain unclear. We carried out untargeted urine 1H-NMR spectroscopy-based metabolic phenotyping in an isogenic C57BL/6J mouse population (n = 50) and show that microbial-host co-metabolites are prodromal (i.e., early) markers predicting future divergence in metabolic (obesity and glucose homeostasis) and behavioral (anxiety and activity) outcomes with 94%–100% accuracy. Some of these metabolites also modulate disease phenotypes, best illustrated by trimethylamine-N-oxide (TMAO), a product of microbial-host co-metabolism predicting future obesity, impaired glucose tolerance (IGT), and behavior while reducing endoplasmic reticulum stress and lipogenesis in 3T3-L1 adipocytes. Chronic in vivo TMAO treatment limits IGT in HFD-fed mice and isolated pancreatic islets by increasing insulin secretion. We highlight the prodromal potential of microbial metabolites to predict disease outcomes and their potential in shaping mammalian phenotypic heterogeneity.
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Dumas et al. study the metabolic and behavioral phenotypic heterogeneity induced by a high-fat diet intervention in an isogenic mouse population model. Using 1H-NMR spectroscopy, they identify pre-interventional urinary metabolic signatures (including microbial-host co-metabolites) predicting future phenotypic heterogeneity. In particular, TMAO corrects endoplasmic reticulum stress and glucose tolerance.http://ift.tt/2trNmOH
The Complete Structure of the Mycobacterium smegmatis 70S Ribosome
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Jendrik Hentschel, Chloe Burnside, Ingrid Mignot, Marc Leibundgut, Daniel Boehringer, Nenad Ban
The ribosome carries out the synthesis of proteins in every living cell. It consequently represents a frontline target in anti-microbial therapy. Tuberculosis ranks among the leading causes of death worldwide, due in large part to the combination of difficult-to-treat latency and antibiotic resistance. Here, we present the 3.3-Å cryo-EM structure of the 70S ribosome of Mycobacterium smegmatis, a close relative to the human pathogen Mycobacterium tuberculosis. The structure reveals two additional ribosomal proteins and localizes them to the vicinity of drug-target sites in both the catalytic center and the decoding site of the ribosome. Furthermore, we visualized actinobacterium-specific rRNA and protein expansions that extensively remodel the ribosomal surface with implications for polysome organization. Our results provide a foundation for understanding the idiosyncrasies of mycobacterial translation and reveal atomic details of the structure that will facilitate the design of anti-tubercular therapeutics.
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The M. tuberculosis ribosome is an important target for antibiotics in anti-tubercular therapy. Hentschel et al. determine the high-resolution structure of the related Mycobacterium smegmatis ribosome and provide a structural framework for antibiotic development and for the understanding of species-specific peculiarities of translation in Actinobacteria.http://ift.tt/2trRQVD
Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Katherine S. Bridge, Kunal M. Shah, Yigen Li, Daniel E. Foxler, Sybil C.K. Wong, Duncan C. Miller, Kathryn M. Davidson, John G. Foster, Ruth Rose, Michael R. Hodgkinson, Paulo S. Ribeiro, A. Aziz Aboobaker, Kenta Yashiro, Xiaozhong Wang, Paul R. Graves, Michael J. Plevin, Dimitris Lagos, Tyson V. Sharp
As core components of the microRNA-induced silencing complex (miRISC), Argonaute (AGO) proteins interact with TNRC6 proteins, recruiting other effectors of translational repression/mRNA destabilization. Here, we show that LIMD1 coordinates the assembly of an AGO-TNRC6 containing miRISC complex by binding both proteins simultaneously at distinct interfaces. Phosphorylation of AGO2 at Ser 387 by Akt3 induces LIMD1 binding, which in turn enables AGO2 to interact with TNRC6A and downstream effector DDX6. Conservation of this serine in AGO1 and 4 indicates this mechanism may be a fundamental requirement for AGO function and miRISC assembly. Upon CRISPR-Cas9-mediated knockout of LIMD1, AGO2 miRNA-silencing function is lost and miRNA silencing becomes dependent on a complex formed by AGO3 and the LIMD1 family member WTIP. The switch to AGO3 utilization occurs due to the presence of a glutamic acid residue (E390) on the interaction interface, which allows AGO3 to bind to LIMD1, AJUBA, and WTIP irrespective of Akt signaling.
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Argonaute (AGO) proteins mediate post-transcriptional gene silencing through formation of the microRNA-induced silencing complex (miRISC). Bridge et al. identify LIM-domain-containing proteins as essential for miRISC formation through a phosphorylation-dependent mechanism. This is critical for post-transcriptional gene silencing and reveals that miRISC functionality is maintained by "AGO switching."http://ift.tt/2trPbuY
Entosis Is Induced by Glucose Starvation
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Jens C. Hamann, Alexandra Surcel, Ruoyao Chen, Carolyn Teragawa, John G. Albeck, Douglas N. Robinson, Michael Overholtzer
Entosis is a mechanism of cell death that involves neighbor cell ingestion. This process occurs in cancers and promotes a form of cell competition, where winner cells engulf and kill losers. Entosis is driven by a mechanical differential that allows softer cells to eliminate stiffer cells. While this process can be induced by matrix detachment, whether other stressors can activate entosis is unknown. Here, we find that entosis is induced in adherent cells by glucose withdrawal. Glucose withdrawal leads to a bimodal distribution of cells based on their deformability, where stiffer cells appear in a manner requiring the energy-sensing AMP-activated protein kinase (AMPK). We show that loser cells with high levels of AMPK activity are eliminated by winners through entosis, which supports winner cell proliferation under nutrient-deprived conditions. Our findings demonstrate that entosis serves as a cellular response to metabolic stress that enables nutrient recovery through neighbor cell ingestion.
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Entosis has been shown to occur in human cancers and promotes cell competition. Hamann et al. now show that nutrient deprivation, in the form of glucose withdrawal, induces entosis to support the outgrowth of winner cells that feed off of losers.http://ift.tt/2trKem4
Positive Regulation of Interleukin-1β Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation
Publication date: 5 July 2017
Source:Cell Reports, Volume 20, Issue 1
Author(s): Xue Zhang, Peng Liu, Christie Zhang, Direkrit Chiewchengchol, Fan Zhao, Hongbo Yu, Jingyu Li, Hiroto Kambara, Kate Y. Luo, Arvind Venkataraman, Ziling Zhou, Weidong Zhou, Haiyan Zhu, Li Zhao, Jiro Sakai, Yuanyuan Chen, Ye-Shih Ho, Besnik Bajrami, Bing Xu, Leslie E. Silberstein, Tao Cheng, Yuanfu Xu, Yuehai Ke, Hongbo R. Luo
Reactive oxygen species (ROS)-induced cysteine S-glutathionylation is an important posttranslational modification (PTM) that controls a wide range of intracellular protein activities. However, whether physiological ROS can modulate the function of extracellular components via S-glutathionylation is unknown. Using a screening approach, we identified ROS-mediated cysteine S-glutathionylation on several extracellular cytokines. Glutathionylation of the highly conserved Cys-188 in IL-1β positively regulates its bioactivity by preventing its ROS-induced irreversible oxidation, including sulfinic acid and sulfonic acid formation. We show this mechanism protects IL-1β from deactivation by ROS in an in vivo system of irradiation-induced bone marrow (BM) injury. Glutaredoxin 1 (Grx1), an enzyme that catalyzes deglutathionylation, was present and active in the extracellular space in serum and the BM, physiologically regulating IL-1β glutathionylation and bioactivity. Collectively, we identify cysteine S-glutathionylation as a cytokine regulatory mechanism that could be a therapeutic target in the treatment of various infectious and inflammatory diseases.
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Zhang et al. reveal that cysteine S-glutathionylation of the highly conserved Cys-188 residue of IL-1β positively regulates its bioactivity by preventing its irreversible ROS-elicited deactivation. ROS-induced cysteine glutathionylation and its modulation by Glutaredoxin 1 (Grx1) are key physiological regulatory mechanisms controlling IL-1β activity, providing a potential therapeutic target in the treatment of infectious and inflammatory diseases.http://ift.tt/2tsceWk
A Molecular and Preclinical Comparison of the PD-1 targeted T cell Checkpoint Inhibitors Nivolumab and Pembrolizumab
Publication date: Available online 4 July 2017
Source:Seminars in Oncology
Author(s): Petros Fessas, Hassal Lee, Shinji Ikemizu, Tobias Janowitz
T cell checkpoint inhibition has a profound impact on cancer care and the two Programmed cell death protein 1 (PD-1) targeted antibodies nivolumab and pembrolizumab have been leading this therapeutic revolution. Their clinical comparability is a highly relevant topic of discussion, but to a significant degree is a consequence of their molecular properties. Here we provide a molecular, preclinical, and early clinical comparison of the two antibodies, based on the available data and recent literature. We acknowledge the limitations of such comparisons, but suggest that based on the available data, differences in clinical trial outcomes between nivolumab and pembrolizumab are more likely drug-independent than drug-dependent.
http://ift.tt/2usA6tp
Co-delivery of a growth factor and a tissue-protective molecule using elastin biopolymers accelerates wound healing in diabetic mice
Source:Biomaterials, Volume 141
Author(s): Julie Devalliere, Kevin Dooley, Yong Yu, Sarah S. Kelangi, Basak E. Uygun, Martin L. Yarmush
Growth factor therapy is a promising approach for chronic diabetic wounds, but strategies to efficiently and cost-effectively deliver active molecules to the highly proteolytic wound environment remain as major obstacles. Here, we re-engineered keratinocyte growth factor (KGF) and the cellular protective peptide ARA290 into a protein polymer suspension with the purpose of increasing their proteolytic resistance, thus their activity in vivo. KGF and ARA290 were fused with elastin-like peptide (ELP), a protein polymer derived from tropoelastin, that confers the ability to separate into a colloidal suspension of liquid-like coacervates. ELP fusion did not diminish peptides activities as demonstrated by ability of KGF-ELP to accelerate keratinocyte proliferation and migration, and ARA290-ELP to protect cells from apoptosis. We examined the healing effect of ARA290-ELP and KGF-ELP alone or in combination, in a full-thickness diabetic wound model. In this model, ARA290-ELP was found to accelerate healing, notably by increasing angiogenesis in the wound bed. We further showed that co-delivery of ARA290 and KGF, with the 1:4 KGF-ELP to ARA290-ELP ratio, was the most effective wound treatment with the fastest healing rate, the thicker granulation tissue and regenerated epidermis after 28 days. Overall, this study shows that ARA290-ELP and KGF-ELP constitute promising new therapeutics for treatment of chronic wounds.
http://ift.tt/2tOgd1S
Enhanced osteogenic activity of poly(ester urea) scaffolds using facile post-3D printing peptide functionalization strategies
Source:Biomaterials, Volume 141
Author(s): Shan Li, Yanyi Xu, Jiayi Yu, Matthew L. Becker
Additive manufacturing has the potential to revolutionize regenerative medicine, but the harsh thermal or photochemical conditions during the 3D printing process limit the inclusion of drugs, growth factors and other biologics within the resulting scaffolds. Functionalization strategies that enable specific placement of bioactive species on the surface of 3D printed structures following the printing process afford a promising approach to sidestep the harsh conditions and incorporate these valuable bioactive molecules with precise control over concentration. Herein, resorbable polymer scaffolds were prepared from propargyl functionalized L-phenylalanine-based poly(ester urea)s (PEUs). Osteogenic growth peptide (OGP) or bone morphogenic protein-2 (BMP-2) peptides were immobilized on PEU scaffolds through surface available propargyl groups via copper-catalyzed azide alkyne cycloaddition (CuAAC) post 3D printing. The presence of either OGP or BMP-2 significantly enhanced hMSCs osteogenic differentiation compared to unfunctionalized scaffolds.
http://ift.tt/2uMjY5e
A strategy for actualization of active targeting nanomedicine practically functioning in a living body
Source:Biomaterials, Volume 141
Author(s): Kyoung Jin Lee, Seol Hwa Shin, Jae Hee Lee, Eun Jin Ju, Yun-Yong Park, Jung Jin Hwang, Young-Ah Suh, Seung-Mo Hong, Se Jin Jang, Jung Shin Lee, Si Yeol Song, Seong-Yun Jeong, Eun Kyung Choi
Designing nanocarriers with active targeting has been increasingly emphasized as for an ideal delivery mechanism of anti-cancer therapeutic agents, but the actualization has been constrained by lack of reliable strategy ultimately applicable. Here, we designed and verified a strategy to achieve active targeting nanomedicine that works in a living body, utilizing animal models bearing a patient's tumor tissue and subjected to the same treatments that would be used in the clinic. The concept for this strategy was that a novel peptide probe and its counterpart protein, which responded to a therapy, were identified, and then the inherent ability of the peptide to target the designated tumor protein was used for active targeting in vivo. An initial dose of ionizing radiation was locally delivered to the gastric cancer (GC) tumor of a patient-derived xenograft mouse model, and phage-displayed peptide library was intravenously injected. The peptides tightly bound to the tumor were recovered, and the counterpart protein was subsequently identified. Peptide-conjugated liposomal drug showed dramatically improved therapeutic efficacy and possibility of diagnostic imaging with radiation. These results strongly suggested the potential of our strategy to achieve in vivo functional active targeting and to be applied clinically for human cancer treatment.
http://ift.tt/2urgQMB
Riboflavin-containing telodendrimer nanocarriers for efficient doxorubicin delivery: High loading capacity, increased stability, and improved anticancer efficacy
Source:Biomaterials, Volume 141
Author(s): Dandan Guo, Changying Shi, Xu Wang, Lili Wang, Shengle Zhang, Juntao Luo
We have developed two linear-dendritic telodendrimers (TDs) with rational design using amphiphilic riboflavin (Rf) as building blocks for efficient doxorubicin (DOX) delivery. Micellar TD nanoparticles (NPs) are composed of a hydrophilic polyethylene glycol (PEG) shell and a Rf-containing affinitive core for DOX encapsulation. Strong DOX-Rf interactions and amphiphilic Rf structure render these nanocarriers with an ultra-high DOX loading capacity (>1/1, DOX/TD, w/w), ∼100% loading efficiency, the sustained drug release and the optimal particle sizes (20–40 nm) for efficient tumor-targeted drug delivery. These nanoformulations significantly prolonged DOX circulation time in the blood without the accelerated clearance observed after multiple injections. DOX-TDs target several types of tumors efficiently in vivo, e.g. Raji lymphoma, MDA-MB-231 breast cancer, and SKOV-3 ovarian cancer. In vivo maximum tolerated dose (MTD) of DOX was increased by 2–2.5 folds for the nanoformulations in mice relative to those of free DOX and Doxil®. These nanoformulations significantly inhibited tumor growth and prolonged survival of mice bearing SKOV-3 ovarian cancer xenografts. In summary, Rf-containing nanoformulations with high DOX loading capacity, improved stability and efficient tumor targeting lead to superior antitumor efficacy, which merit the further development for clinical application.
http://ift.tt/2tOEFjD
Spiny keratoderma: case series and review
Abstract
Background
Spiny keratoderma is a rare, possibly under-reported, condition characterized by discrete keratotic plugs arising from the palms, soles, or both. It has been associated with malignancies though there is debate as to whether spiny keratoderma is a true paraneoplastic phenomenon. It has also been linked to a variety of non-neoplastic conditions, and several cases appear to be familial.
Methods
We describe two additional cases of this rare entity and review the literature.
Results
Thirty-seven cases of spiny keratoderma, including ours, have been reported in the literature. Average age at presentation was 63 years. Earliest age of onset was 11 months. A variety of ethnicities were represented. Ten cases were associated with malignancies. Six cases appeared to be inherited in an autosomal dominant fashion. Several cases were reported in healthy individuals as an incidental finding though it is possible that an associated malignancy or systemic disease will declare itself with time.
Treatment is generally unsatisfying with keratotic spines often recurring on cessation. Interestingly, in some patients, the spines resolve after treatment of an underlying malignancy.
Conclusions
This small case series provides an opportunity to revisit the fascinating phenomena of spiny keratoderma, its possible associations, and implications for follow-up. Due to the association with cancer, all patients presenting with spiny keratoderma should undergo baseline age-appropriate malignancy screening, thence 1-2 times yearly, or as symptoms arise.
http://ift.tt/2tOlWF0
Role of oxidative stress in melasma: a prospective study on serum and blood markers of oxidative stress in melasma patients
Abstract
Background
Melasma is a common pigmentary disorder presenting in the dermatological clinic. Many factors have been implicated in the pathogenesis, however, the cause still remains elusive. Recently the effect of oxidative damage has been proposed in the etiopathogenesis of melasma. This study was undertaken to evaluate the role of oxidative stress in patients with melasma.
Material and methods
Fifty patients with melasma, age 18 years of age and older, and an equal number of age and sex-matched controls were included in the study. Baseline severity assessment using the modified Melasma Area and Severity Index (modified MASI score) was done in all patients. Serum malondialdehyde, blood superoxide dismutase, and blood glutathione peroxidase levels were measured in cases and controls group and results were compared.
Result
The serum levels of malondialdehyde, superoxide dismutase, and blood glutathione were significantly higher among the cases compared to controls. The difference in the serum concentrations was significant between the two groups (P < 0.01). A positive correlation was found between these enzyme levels and severity of melasma (modified MASI score); however, this correlation was statistically significant with serum malondialdehyde only. The level of oxidative stress among the male and female melasma patients was not statistically different.
Conclusion
Oxidative stress was found to be increased in cases of melasma compared to the control group in this study. This substantiates the role of oxidative stress in etiopathogenesis of melasma; however, further studies are required to reach a definitive conclusion.
http://ift.tt/2tOOH4c
Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: a randomized trial
Abstract
Background
Toll-like receptor 7 (TLR7) stimulation in the airways may reduce responses to aeroallergens by induction of type 1 interferons (IFNs). GSK2245035 is a novel selective TLR7 agonist in pharmaceutical development.
Objective
Assessment of safety, pharmacodynamics and nasal allergic reactivity following repeated weekly intranasal (i.n.) GSK2245035.
Methods
This randomized, double-blind, placebo-controlled study (TL7116958) was conducted over two pollen seasons (2013–2014) and follow-up study (204509) conducted one year later. Participants with allergic rhinitis (n=42) were randomized to receive eight weekly doses of i.n. GSK2245035 (20 ng [2014 Cohort; n=14] or 80 ng [2013 Cohort; n=14]) or placebo (n=14). Adverse events (AEs), including cytokine release syndrome-AEs (CytoRS-AEs) and nasal symptoms were assessed. Nasal and serum IFN-inducible protein 10 (IP-10) were measured after doses 1 and 8, then 1 (follow-up visit [FUV] 1) and 3 (FUV2) weeks after final dose. Nasal allergen challenges (NAC) and allergic biomarkers assessment (nasal, serum) were conducted at baseline, FUV1, FUV2 and at a follow-up visit 1-year post final dose (FUV3; 2014 Cohort only). A Bayesian framework enabled probability statements for mean effect sizes.
Results
GSK2245035 induced CytoRS-AEs (most commonly headache, median duration <1 day) in 93% of participants at 80 ng, while AE incidence at 20 ng was similar to placebo. There was no evidence of nasal inflammation. Dose-related increases in nasal and serum IP-10 were observed 24h after doses 1 and 8 (>95% certainty). Both doses showed a trend in reducing Total Nasal Symptom Score 15 minutes post NAC at FUV1 and FUV2 but there was no reduction evident at FUV3. Nasal levels of selected allergic biomarkers demonstrated trends for reductions at FUV1, FUV2 and FUV3.
Conclusions and clinical relevance
Weekly i.n. GSK2245035 20 ng was well-tolerated and reduced allergic reactivity to nasal challenge for 3 weeks post treatment.
Clinicaltrials. gov identifiers
NCT01788813/NCT02446613
GSK identifiers
TL7116958/204509
This article is protected by copyright. All rights reserved.
http://ift.tt/2uMvJIZ
Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: a randomized trial
Abstract
Background
Toll-like receptor 7 (TLR7) stimulation in the airways may reduce responses to aeroallergens by induction of type 1 interferons (IFNs). GSK2245035 is a novel selective TLR7 agonist in pharmaceutical development.
Objective
Assessment of safety, pharmacodynamics and nasal allergic reactivity following repeated weekly intranasal (i.n.) GSK2245035.
Methods
This randomized, double-blind, placebo-controlled study (TL7116958) was conducted over two pollen seasons (2013–2014) and follow-up study (204509) conducted one year later. Participants with allergic rhinitis (n=42) were randomized to receive eight weekly doses of i.n. GSK2245035 (20 ng [2014 Cohort; n=14] or 80 ng [2013 Cohort; n=14]) or placebo (n=14). Adverse events (AEs), including cytokine release syndrome-AEs (CytoRS-AEs) and nasal symptoms were assessed. Nasal and serum IFN-inducible protein 10 (IP-10) were measured after doses 1 and 8, then 1 (follow-up visit [FUV] 1) and 3 (FUV2) weeks after final dose. Nasal allergen challenges (NAC) and allergic biomarkers assessment (nasal, serum) were conducted at baseline, FUV1, FUV2 and at a follow-up visit 1-year post final dose (FUV3; 2014 Cohort only). A Bayesian framework enabled probability statements for mean effect sizes.
Results
GSK2245035 induced CytoRS-AEs (most commonly headache, median duration <1 day) in 93% of participants at 80 ng, while AE incidence at 20 ng was similar to placebo. There was no evidence of nasal inflammation. Dose-related increases in nasal and serum IP-10 were observed 24h after doses 1 and 8 (>95% certainty). Both doses showed a trend in reducing Total Nasal Symptom Score 15 minutes post NAC at FUV1 and FUV2 but there was no reduction evident at FUV3. Nasal levels of selected allergic biomarkers demonstrated trends for reductions at FUV1, FUV2 and FUV3.
Conclusions and clinical relevance
Weekly i.n. GSK2245035 20 ng was well-tolerated and reduced allergic reactivity to nasal challenge for 3 weeks post treatment.
Clinicaltrials. gov identifiers
NCT01788813/NCT02446613
GSK identifiers
TL7116958/204509
This article is protected by copyright. All rights reserved.
http://ift.tt/2uMvJIZ
Predictors of readmissions after head and neck cancer surgery: A national perspective
Hospital readmissions cost Medicare alone more than $17billion annually in avoidable expenses, with over 17.5% of patients getting readmitted within 30-days of hospital discharge [1–3]. Only 10% of these Medicare readmissions are considered planned readmissions [1]. In order to encourage hospitals to reduce readmissions, the Affordable Care Act, which was passed in March 2010, created the Hospital Readmissions Reduction Program. Since October 2012, the Centers for Medicare and Medicaid Services (CMS) has levied a penalty on hospitals with readmissions in excess of the expected national rate.
http://ift.tt/2sOLzkL
Partner’s survivorship care needs: An analysis in head and neck cancer patients
There are approximately 5000 new cases of Head and Neck cancer per year in Canada [1]. Head and neck anatomy plays a critical role in an individual's function, body image and socialization. The nature of treatment for head and neck cancer thus places patients at a particularly high risk of psychological, physical and emotional morbidity [2–4]. Treatment often leads to physical disability, psychological distress and increased health care needs when compared with other cancers [5]. HNC patients are at risk of significant side effects, such as xerostomia, neck fibrosis, and swallowing dysfunction, which can often be permanent [6,7].
http://ift.tt/2us9nwN
The long-term oncological and functional outcomes of transoral robotic surgery in patients with hypopharyngeal cancer
Hypopharyngeal cancer has the worst prognosis of all head-and-neck cancers. Despite the introduction of various new treatment modalities, the survival rate has not changed significantly over the past several decades [1–3]. Moreover, radical surgery, such as laryngopharyngectomy with reconstruction of the pharynx, can reduce a patient's quality of life after surgery, because it inevitably causes loss of normal speech and swallowing function [1,4–6]. Meanwhile, concurrent chemoradiotherapy (CCRTx), which is used as an organ preservation strategy, could preserve organ function with comparable oncologic results compared to conventional radical surgery [7–9].
http://ift.tt/2usBaNB
Early detection of squamous cell carcinoma in carcinogen induced oral cancer rodent model by ratiometric activatable cell penetrating peptides
Head and neck squamous cell carcinoma (HNSCC), which comprises cancer of the oral cavity, pharynx and larynx, is the 6th leading malignancy worldwide. With a reported annual burden of 633,000 incident cases, 355,000 deaths, and a 5year overall survival rate ∼60%, patient prognosis remains poor as diagnosis often occurs late into disease progression when advanced stage cancer is unresponsive to therapy [1–3]. Established risk factors for HNSCC include tobacco use and alcohol consumption [4]. Human Papilloma Virus (HPV) status has also been identified as a risk factor for HNSCC [5,6].
http://ift.tt/2tLitHs
Inflammation in the assessment of salivary cytokines in oral squamous cell carcinoma diagnosis
During a literature search about the role of molecular markers in accurate diagnosis and prognosis of oral malignant lesions, we have encountered a valuable paper entitled "Oral squamous cell carcinoma detection by salivary biomarkers in a Serbian population", authored by Brinkmann O, Kastratovic DA, Dimitrijevic MV, Konstantinovic VS, Jelovac DB, Antic J, Nesic VS, Markovic SZ, Martinovic ZR, Akin D, Spielmann N, Zhou H, Wong DT, published in Oral Oncology 2011 January; 47(1): 51–55. In that study, the authors investigated six transcriptome (DUSP1, IL8, IL1β, OAZ1, SAT1, S100P) and three proteome (IL1β, IL8, M2BP) biomarkers on 18 early and 17 late stage OSCC patients and 51 healthy controls with quantitative PCR and ELISA.
http://ift.tt/2tOydJj
Hardware complications in oromandibular defects: Comparing scapular and fibular based free flap reconstructions
The advent of microvascular free tissue transfer has revolutionized oromandibular reconstruction. The combination of osseocutaneous or osseomyogeneous free flaps in addition to advances in instrumentation with locking screw technology and low profile plates has greatly improved the functional and cosmetic outcomes for patients with mandibular defects [1]. Despite these advances, hardware complications remains a significant challenge with roughly 15% of patients experiencing hardware related complications [2].
http://ift.tt/2urSWAL
Predictive and prognostic value of CT based radiomics signature in locally advanced head and neck cancers patients treated with concurrent chemoradiotherapy or bioradiotherapy and its added value to Human Papillomavirus status
The current standard of care for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) is concurrent chemoradiotherapy (CRT), although it is associated with frequent severe acute and late toxicities [1]. In the recent years there has been a growing interest in increasing the benefit/risk ratio in human papillomavirus (HPV)-positive patients [2,3]. Due to improved prognosis, CRT could be safely postponed in HPV positive patients, reducing toxicity while not jeopardizing survival.
http://ift.tt/2tTl4jf
Treatment guidelines and patterns of care in oral cavity squamous cell carcinoma: Primary surgical resection vs. nonsurgical treatment
The 2017 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines provide level 2A recommendations for surgical excision with neck dissection or for definitive radiation therapy (RT) in early-stage oral cavity cancers, as well as 2A recommendations for surgery with postoperative adjuvant therapy or multimodality clinical trials for resectable late-stage oral cavity lesions [1]. Despite this, with significant advancements in reconstructive techniques and subsequent improvements in functional outcomes, surgical resection has become the preferred treatment modality for resectable oral cavity malignancies [2,3].
http://ift.tt/2tTgm57
Long-term toxicities in 10-year survivors of radiation treatment for head and neck cancer
There are approximately 436,000 HNC survivors living in the United States [1] and it is estimated that more than 60,000 new head and neck cancers (HNC) will be diagnosed in the United States in 2016 [2]. Historically, HNC was a disease of the elderly associated with tobacco/ethanol abuse and comorbidity [3]. Due to changing demographics with increasing human papillomavirus (HPV)-associated oropharyngeal cancer [4–6], patients with HNC are generally younger at diagnosis and living longer after treatment than historical expectation.
http://ift.tt/2tTy3BB
Neighborhood deprivation and risk of head and neck cancer: A multilevel analysis from France
Social inequalities in cancer incidence have been reported worldwide and for many cancer sites. An increased incidence in deprived populations has been observed for lung [1–4] head and neck [1,3–5], liver[1,5], cervix [1,4–6], bladder [4], stomach [1,5] and esophagus [1,5,7] and an increased incidence in affluent populations has been observed for breast [1,4,5,8] and prostate cancer [1,4,5,9], and for melanoma, [1,4,5,10]. The influence of area-based socioeconomic level on the incidence of cancer is well documented in the literature but the underlying mechanisms that create these associations are rarely addressed.
http://ift.tt/2tKA96g
Decoding the signaling pathway initiating cellular migration in cancer metastasis
The most common reason for mortality in cancer is Metastasis. The spread of cancer cells to vital structures leading to its dysfunction culminates in either severe morbidity or mortality. Researchers have formulated multiple therapeutic agents to combat the rapid proliferation of cancer cells. Preventing the cellular proliferation is just half the battle, as highly invasive tumors have a tendency to have low proliferative but high invasive properties. In such cases, although the anti-proliferative agent's blocks/inhibits the primary tumor growth, it is largely ineffective in preventing the rise of secondary tumors.
http://ift.tt/2tTytrB
A phase I study of cabazitaxel in combination with platinum and 5-fluorouracil (PF) in locally advanced squamous cell carcinoma of head and neck (LA-SCCHN)
There is a clinical need to improve outcomes for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), especially in Human Papilloma Virus (HPV) negative and HPV positive subtypes with a significant history of tobacco use. In animal models bearing SCCHN, Cabazitaxel showed an excellent response rate compared to docetaxel and might prove useful in treatment of patients. The primary objective of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of cabazitaxel when combined with cisplatin and 5-fluorouracil (PF) in induction chemotherapy (IC) for patients with SCCHN.
http://ift.tt/2tKQTKs
Prediction of distant metastases from nasopharyngeal carcinoma: Improved diagnostic performance of MRI using nodal volume in N1 and N2 stage disease: Methodological issues
We read the study conducted by Ai and colleagues that was published in Oral Oncology, enthusiastically and meticulously [1]. The authors tried to examine the predictive performance of the magnetic resonance imaging (MRI) of the head and neck for distant metastases (DM) from nasopharyngeal carcinoma (NPC). The results have suggested MRI nodal stage (N) stage and total nodal volume (NV) have an important predictive effects for DM and distant metastases free survival (DMFS) [1].
http://ift.tt/2tTeFV1
Dose-dependent enhancement of T-lymphocyte priming and CTL lysis following ionizing radiation in an engineered model of oral cancer
While many patients with head and neck squamous cell carcinoma (HNSCC) display a T-cell inflamed phenotype [1], only a small subset respond to programmed death (PD) pathway checkpoint inhibition [2]. Strategies to enhance response rates to checkpoint inhibition in HNSCC are needed. PD-based checkpoint blockade has the potential to unleash an existing anti-tumor immune response being blocked by the expression of PD-1/PD-L1, but cannot induce a de novo anti-tumor immunity [3]. The addition of PD-based checkpoint blockade to other anti-cancer treatments that have the potential to induce adaptive anti-tumor immune responses may be additive or synergistic due to reversal of adaptive immune resistance [3,4].
http://ift.tt/2usbErO
Transoral thyroidectomy and parathyroidectomy – A North American series of robotic and endoscopic transoral approaches to the central neck
Since its description by Kocher in the late 1880's, the transcervical incision has constituted the primary surgical approach to the thyroid and parathyroid glands [1]. The utility of this incision design is clear, as it provides the surgeon with excellent exposure and a direct route to the central neck. Despite meticulous closure of the incision, a scar of variable prominence is inevitable and patients can find it disagreeable [2–4].
http://ift.tt/2tTa1Xc
Prognostic value of the eighth edition AJCC TNM classification for differentiated thyroid carcinoma
The American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) system is the most widely used indicator of cancer mortality in patients with differentiated thyroid carcinoma (DTC) [1,2]. Unlike most malignancies, age at diagnosis is almost always identified as an independent predictor of cancer mortality in DTC. Accordingly, the TNM system of DTC has incorporated both anatomic and nonanatomic (an age cutoff of 45years) prognostic factors since its second edition was published in 1983 [3].
http://ift.tt/2tjk86a
Nutritional changes in patients with locally advanced head and neck cancer during treatment
Head and neck squamous cell carcinoma (HNSCC) includes a wide range of malignant tumors that originate in the different structures of this region of the body. Its presentation causes aesthetic alterations and disturbance of functions as phonation, swallowing, hearing and breathing [1]. The surgical option compromises all these basic functions, therefore an alternative for the treatment of these tumors in advanced stages is a conservative treatment [2]. These are based on the association of radiotherapy (RT) with concomitant chemotherapy [3], or bioradiotherapy [4,5] and, in some cases previous induction chemotherapy (iCT) [6].
http://ift.tt/2tOqN98
Very accelerated radiotherapy or concurrent chemoradiotherapy for N3 head and neck squamous cell carcinoma: Pooled analysis of two GORTEC randomized trials
Treatment of inoperable or non-operated locally advanced head and neck squamous cell carcinomas (HNSCC)is typically based on radiotherapy (RT) delivering 70Gy/7weeks combined with chemotherapy [1]. Indeed, concurrent chemoradiotherapy (CRT) has become a standard treatment of locally advanced HNSCC, as reported in the meta-Analysis of Chemotherapy in Head & Neck Cancer (MACH-NC) with an absolute 5-year survival benefit of 6.5% [2]. In another meta-analysis, altered fractionated radiotherapy (AFRT) was associated with an absolute 5-year survival benefit of 3.4% [3].
http://ift.tt/2srFhs8
Why are we still unable to accurately determine the malignant potential or the behavior of oral mucosal lesions?
We read with great interest an editorial by Guneri et al. [1] titled 'Why are we still unable to accurately determine the malignant potential or the behavior of oral mucosal lesions?' It is appropriately said that despite extensive advances in diagnostic research, there are still no biomarkers (clinical, biochemical or molecular) available in clinical practice that can truthfully determine the malignant potential or behavior of oral potentially malignant disorders (OPMDs). The oldest paper available in the PubMed in this regard was published in 1948 [2].
http://ift.tt/2tKTnbF
HCV-induced oxidative stress by inhibition of Nrf2 triggers autophagy and favors release of viral particles
Publication date: September 2017
Source:Free Radical Biology and Medicine, Volume 110
Author(s): Regina Medvedev, Daniela Ploen, Catrina Spengler, Fabian Elgner, Huimei Ren, Sarah Bunten, Eberhard Hildt
Viruses are known to exploit the autophagic machinery for their own benefit. In case of the hepatitis C virus autophagy is induced. As autophagy serves as a degradation pathway to maintain cellular homeostasis, it is activated in response to cellular stress such as elevated levels of reactive oxygen species (ROS). Elevated levels of ROS trigger phosphorylation of the autophagic adaptor protein p62 on Ser349 (pS[349] p62) that is involved in the induction of autophagy. Consequently, pS[349] p62 binds with a higher affinity to Keap1 thereby releasing Nrf2 from the complex with Keap1. Although the released Nrf2 should induce as a heterodimer with the sMaf proteins the expression of Nrf2/ARE-dependent genes, in HCV-positive cells no activation of cytoprotective genes occurs even though elevated amounts of pS[349] p62 are present. In HCV-positive cells, free Nrf2 is trapped via delocalized sMaf proteins at the replicon complexes on the cytoplasmic face of the ER and is therefore prevented from its entry into the nucleus. Scavenging of ROS leads to decreased levels of pS[349] p62 and impaired induction of autophagy. Both, inhibition of autophagy and scavenging of ROS result in decreased amounts of released viral particles. Taken together, these data identify an intricate mechanism of HCV-dependent inhibition of Nrf2/ARE-mediated gene expression which counteracts pS[349] p62-induced activation of Nrf2. Thereby elevated ROS-levels are preserved that in turn activate autophagy to favor HCV particle release.
Graphical abstract
http://ift.tt/2trYjQf
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