The impact of supersaturation level for oral absorption of BCS class IIb drugs, dipyridamole and ketoconazole, using in vivo predictive dissolution system: Gastrointestinal Simulator (GIS)

Publication date: 1 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 102
Author(s): Yasuhiro Tsume, Kazuki Matsui, Amanda L. Searls, Susumu Takeuchi, Gregory E. Amidon, Duxin Sun, Gordon L. Amidon
The development of formulations and the assessment of oral drug absorption for Biopharmaceutical Classification System (BCS) class IIb drugs is often a difficult issue due to the potential for supersaturation and precipitation in the gastrointestinal (GI) tract. The physiological environment in the GI tract largely influences in vivo drug dissolution rates of those drugs. Thus, those physiological factors should be incorporated into the in vitro system to better assess in vivo performance of BCS class IIb drugs. In order to predict oral bioperformance, an in vitro dissolution system with multiple compartments incorporating physiologically relevant factors would be expected to more accurately predict in vivo phenomena than a one-compartment dissolution system like USP Apparatus 2 because, for example, the pH change occurring in the human GI tract can be better replicated in a multi-compartmental platform. The Gastrointestinal Simulator (GIS) consists of three compartments, the gastric, duodenal and jejunal chambers, and is a practical in vitro dissolution apparatus to predict in vivo dissolution for oral dosage forms. This system can demonstrate supersaturation and precipitation and, therefore, has the potential to predict in vivo bioperformance of oral dosage forms where this phenomenon may occur. In this report, in vitro studies were performed with dipyridamole and ketoconazole to evaluate the precipitation rates and the relationship between the supersaturation levels and oral absorption of BCS class II weak base drugs. To evaluate the impact of observed supersaturation levels on oral absorption, a study utilizing the GIS in combination with mouse intestinal infusion was conducted. Supersaturation levels observed in the GIS enhanced dipyridamole and ketoconazole absorption in mouse, and a good correlation between their supersaturation levels and their concentration in plasma was observed. The GIS, therefore, appears to represent in vivo dissolution phenomena and demonstrate supersaturation and precipitation of dipyridamole and ketoconazole. We therefore conclude that the GIS has been shown to be a good biopredictive tool to predict in vivo bioperformance of BCS class IIb drugs that can be used to optimize oral formulations.

Graphical abstract

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Development and characterisation of cellulose based electrospun mats for buccal delivery of non-steroidal anti-inflammatory drug (NSAID)

Publication date: 1 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 102
Author(s): Kazem Nazari, Eleni Kontogiannidou, Rita Haj Ahmad, Aggeliki Gratsani, Manoochehr Rasekh, Muhammad Sohail Arshad, Burde Suheyla Sunar, David Armitage, Nikolaos Bouropoulos, Ming-Wei Chang, Xiang Li, Dimitrios G Fatouros, Zeeshan Ahmad
In this study conventional electrospinning (ESp) was used to prepare a series of buccal films containing indomethacin (INDO, a nonsteroidal anti-inflammatory drug), Ethocel (10), hydroxypropylmethylcellulose (HPMC) and Tween^® 80 at various concentrations. The films were characterized using scanning electron microscopy (SEM) and atomic force microscopy (AFM), fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Drug release behaviour was assessed in vitro (buffer pH6.8). SEM revealed film morphology and mean fibre diameter was dependent on the process formulation. INDO was encapsulated in the amorphous state once electrospun as evidenced from DSC and XRD studies. The presence of other excipients within fibrous matrices was confirmed using FTIR and Raman spectroscopy. Loading and release of INDO from filamentous structures was influenced by formulation composition; indicating potential to 'fine-tune' dosage forms. Given that ESp is a one-step preparation method and operational at ambient conditions; an attractive route for engineering tailored film type dosage forms is presented. This is a valuable approach for optimizing dosage forms as needed in a single step for various age groups.

Graphical abstract

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Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop [Prepublication Draft].

Compared with other disease areas, central nervous system (CNS) disorders have had the highest failure rate for new compounds in advanced clinical trials. Most CNS drugs fail because of efficacy, and the core issue underlying these problems is a poor understanding of disease biology. Concern about the poor productivity in neuroscience drug development has gained intensity over the past decade, amplified by a retraction in investment from the pharmaceutical industry. This retreat by industry has been fueled by the high failure rate of compounds in advanced clinical trials for nervous system disorders.

http://ift.tt/2mFC5Hj

Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis and cost-effectiveness analysis.

The study found that the use of novel oral anticoagulants has advantages over warfarin in patients with atrial fibrillation, but there was no strong evidence that they should replace warfarin or low-molecular-weight heparin in the primary prevention, treatment or secondary prevention of venous thromboembolic disease.

http://ift.tt/2lX3h72

A randomised controlled trial to compare the safety, effectiveness and cost-effectiveness of doxycycline (200 mg/day) with that of oral prednisolone (0.5 mg/kg/day) for initial treatment of bullous pemphigoid: the Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) trial.

The study found that a strategy of starting bullous pemphigoid patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control and considerably safer in the long term.

http://ift.tt/2mFCDNk

Phototoxicity of Doxycycline: A Systematic Review on Clinical Manifestations, Frequency, Cofactors, and Prevention

Background: One of the most important dermatologic side effects of doxycycline is photosensitivity. As doxycycline is important for malaria prophylaxis and malaria is mainly spread in countries with high sun radiation, special attention should be paid to this adverse effect. While there are many publications on the phototoxicity of tetracyclines in general, only a few exist focusing on doxycycline. The objective of this systematic review was to summarize all available reports on clinical manifestations, influencing factors like UV dose or dose of medication, and the possibilities of prevention by sun protection. Methods: This review is based on a systematic search in PubMed for articles in English and German and a manual search between 1990 and 2015. Results: The number of publications is low. Clinical symptoms vary from light sunburn-like sensation (burning, erythema) to large-area photodermatitis. Also, onycholysis is possible. The triggering UV spectrum seems to consist mainly of UVA1 (340-400 nm), so UV-protective products should be used that cover this range. Travelers to tropical countries taking doxycycline for malaria prophylaxis need thorough medical counseling to avoid possibly severe phototoxic reactions. Conclusion: Evidence base must be improved for giving advice on appropriate prevention measures to travelers taking doxycycline and having a risk of significant sun exposure.
Skin Pharmacol Physiol 2017;30:76-80

http://ift.tt/2nAaLt1

Wash or wipe? A comparative study of skin physiological changes between water washing and wiping after skin cleaning

Background/purpose

Presently, skin-cleaning agents that claim to be removed by water or wiping alone are commercially available and have been used for the purpose of bed baths. However, there is a lack of knowledge on how water washing and wiping differently affect skin physiological functions or ceramide content. The aim of this study was to compare the effects of water washing and wiping on skin physiological functions and ceramide content.

Methods

Three kinds of the cleaning agents with different removal techniques (ie, water washing and wiping) were used in this study. Skin physiological functions (ie, transepidermal water loss, skin hydration, and skin pH) and skin ceramide content were measured before and after seven consecutive days of the application of each cleaning agent.

Results

No significant differences in skin physiological functions or ceramide content were observed between water washing and wiping.

Conclusion

Cleaning agents that claim to be removed by water washing or wiping do not affect skin physiological functions or ceramide content by either removal method.

http://ift.tt/2n5nozR

Relationship between the changes in blood flow and volume in the finger during a Braille character discrimination task

Purpose

We hypothesized that skin blood flow (SBF) of fingers are modulated during concentrated finger perception and that the changes in SBF reflect fluctuations in finger volume (FV). The aim of this study, therefore, was examine the relationship between the changes in SBF and FV during Braille reading.

Methods

We measured SBF of the finger, cutaneous vascular conductance (CVC), FV, and arterial blood pressure during Braille reading performed under blind conditions in thirty healthy subjects. The subjects were instructed to read a flat plate with raised letters (Braille reading) for 15 seconds using their forefinger, and to touch a blank plate as a control for the Braille discrimination procedure.

Results

Arterial blood pressure slightly increased during Braille reading but remained unchanged during the touching of the blank plate. SBF, CVC, and FV were reduced during Braille reading (decreased by −26%, −29%, and −0.3 mL/100 mL respectively). Furthermore, a significant relationship was observed between the changes in SBF and FV (r=.613) during Braille reading.

Conclusion

These results suggested that SBF of fingers is modulated during concentrated finger perception, and that the variability of blood flow reflects the response in FV.

http://ift.tt/2nADg9Q

Cutaneous Crohn disease with superimposed psoriasis: a unique case with overlapping histology

Abstract

Crohn disease is an idiopathic, chronic inflammatory disorder of the gastrointestinal tract. We recently encountered a unique case in which a patient with longstanding Crohn disease presented with skin lesions with histopathologic features of both psoriasis and granulomatous inflammation suggestive of cutaneous Crohn disease. To our knowledge, this has not been described concomitantly in the same patient, in the same lesions. Review of the literature suggests that the intersection of these two histopathological reaction patterns may not be pure coincidence. Clinical-pathologic correlation of this case will be discussed, along with a review of the potential mechanisms of this unique disease presentation.

http://ift.tt/2mFp4NU

Injectable and thermally contractible hydroxypropyl methyl cellulose/Fe3O4 for magnetic hyperthermia ablation of tumors

Publication date: June 2017
Source:Biomaterials, Volume 128
Author(s): Fengjuan Wang, Yang Yang, Yi Ling, Jianxin Liu, Xiaojun Cai, Xiaohan Zhou, Xiuzhen Tang, Bing Liang, Yini Chen, Hangrong Chen, Dengming Chen, Chunhong Li, Zhigang Wang, Bing Hu, Yuanyi Zheng
The development of efficient strategies for the magnetic hyperthermia ablation of tumors remains challenging. To overcome the significant safety limitations, we developed a thermally contractible, injectable and biodegradable material for the minimally invasive and highly efficient magnetic hyperthermia ablation of tumors. This material was composed of hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA) and Fe3O4. The thermal contractibility of HPMC/Fe3O4 was designed to avoid damaging the surrounding normal tissue upon heating, which was confirmed by visual inspection, ultrasound imaging and computed tomography (CT). The efficient injectability of HPMC/Fe3O4 was proven using a very small needle. The biosafety of HPMC/Fe3O4 was evaluated by MTT and biochemical assays as well as flow cytometry (FCM). All the aforementioned data demonstrated the safety of HPMC/Fe3O4. The results of in vitro and ex vivo experiments showed that the temperature and necrotic volume of excised bovine liver were positively correlated with the HPMC/Fe3O4 weight, iron content and heating duration. The in vivo experimental results showed that the tumors could be completely ablated using 0.06 ml of HPMC/60%Fe3O4 after 180 s of induction heating. We believe that this novel, safe and biodegradable material will promote the rapid bench-to-bed translation of magnetic hyperthermia technology, and it is also expected to bring a new concept for the biomaterial research field.



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Platelet microparticle-inspired clot-responsive nanomedicine for targeted fibrinolysis

Publication date: June 2017
Source:Biomaterials, Volume 128
Author(s): Christa L. Pawlowski, Wei Li, Michael Sun, Kavya Ravichandran, DaShawn Hickman, Clarissa Kos, Gurbani Kaur, Anirban Sen Gupta
Intravascular administration of plasminogen activators is a clinically important thrombolytic strategy to treat occlusive vascular conditions. A major issue with this strategy is the systemic off-target drug action, which affects hemostatic capabilities and causes substantial hemorrhagic risks. This issue can be potentially resolved by designing technologies that allow thrombus-targeted delivery and site-specific action of thrombolytic drugs. To this end, leveraging a liposomal platform, we have developed platelet microparticle (PMP)-inspired nanovesicles (PMINs), that can protect encapsulated thrombolytic drugs in circulation to prevent off-target uptake and action, anchor actively onto thrombus via PMP-relevant molecular mechanisms and allow drug release via thrombus-relevant enzymatic trigger. Specifically, the PMINs can anchor onto thrombus via heteromultivalent ligand-mediated binding to active platelet integrin GPIIb-IIIa and P-selectin, and release the thrombolytic payload due to vesicle destabilization triggered by clot-relevant enzyme phospholipase-A2. Here we report on the evaluation of clot-targeting efficacy, lipase-triggered drug release and resultant thrombolytic capability of the PMINs in vitro, and subsequently demonstrate that intravenous delivery of thrombolytic-loaded PMINs can render targeted fibrinolysis without affecting systemic hemostasis, in vivo, in a carotid artery thrombosis model in mice. Our studies establish significant promise of the PMIN technology for safe and site-targeted nanomedicine therapies in the vascular compartment.

Graphical abstract

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Bilateral sagittal split osteotomy-parameters and correlations of postoperative pain management

Abstract

Objectives

Postoperative pain management is of utmost interest for patients undergoing orthognathic surgery. Currently, there is a lack of information regarding process and outcome parameters of postoperative pain management after bilateral sagittal split osteotomy.

Materials and methods

In a prospective clinical study, 31 adults were evaluated on the first postoperative day following bilateral sagittal split osteotomy using the standardized questionnaire of the Germany-wide project Quality Improvement in Postoperative Pain Management (QUIPS). It allows a standardized assessment of patients' characteristics, pain parameters, outcome, and pain therapy process parameters.

Results

Pain management consisted mainly of premedication with midazolam, sufentanil, and metamizol intraoperatively; piritramide in the recovery room; and metamizol and tramadol on ward. Twenty patients (64.5%) showed inadequate pain management with pain levels ≥4. Patients receiving tramadol as opioid on ward presented significantly higher maximum pain levels (p = .037). Significantly lower satisfaction with postoperative pain intensity (p > .001) and significantly higher desire for additional pain medication (p = .023) were detected, when duration of surgery was above the median of 107.5 min.

Conclusions

Inadequate pain management on the first postoperative day following bilateral sagittal split osteotomy was widespread on our ward. QUIPS helped us to identify it and thereby gave us the possibility to improve the situation. Prolonged duration of surgery seems to be a predictor of an elevated postoperative pain medication demand.

Clinical relevance

Only the establishment of an ongoing monitoring of postoperative pain management can help to reduce or even avoid inadequate postoperative pain management. In accordance to the existing literature, we found inadequate postoperative pain management more widespread than thought.

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Antimicrobial copper alloys decreased bacteria on stethoscope surfaces

Publication date: Available online 13 March 2017
Source:American Journal of Infection Control
Author(s): Michael G. Schmidt, Rachel E. Tuuri, Arif Dharsee, Hubert H. Attaway, Sarah E. Fairey, Keith T. Borg, Cassandra D. Salgado, Bruce E. Hirsch
BackgroundStethoscopes may serve as vehicles for transmission of bacteria among patients. The aim of this study was to assess the efficacy of antimicrobial copper surfaces to reduce the bacterial concentration associated with stethoscope surfaces.MethodsA structured prospective trial involving 21 health care providers was conducted at a pediatric emergency division (ED) (n = 14) and an adult medical intensive care unit located in tertiary care facilities (n = 7). Four surfaces common to a stethoscope and a facsimile instrument fabricated from U.S. Environmental Protection Agency–registered antimicrobial copper alloys (AMCus) were assessed for total aerobic colony counts (ACCs), methicillin-resistant Staphylococcus aureus, gram-negative bacteria, and vancomycin-resistant enterococci for 90 days.ResultsThe mean ACCs collectively recovered from all stethoscope surfaces fabricated from the AMCus were found to carry significantly lower concentrations of bacteria (pediatric ED, 11.7 vs 127.1 colony forming units [CFU]/cm², P < .00001) than their control equivalents. This observation was independent of health care provider or infection control practices. Absence of recovery of bacteria from the AMCu surfaces (66.3%) was significantly higher (P < .00001) than the control surfaces (22.4%). The urethane rim common to the stethoscopes was the most heavily burdened surface; mean concentrations exceeded the health care–associated infection acquisition concentration (5 CFU/cm²) by at least 25×, supporting that the stethoscope warrants consideration in plans mitigating microbial cross-transmission during patient care.ConclusionsStethoscope surfaces fabricated with AMCus were consistently found to harbor fewer bacteria.

Graphical abstract

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Improving water quality in a dialysis unit using root cause analysis

Publication date: Available online 13 March 2017
Source:American Journal of Infection Control
Author(s): Pallavi Yadav, Dawn England, Caprice Vanderkolk, Pui-Ying Iroh Tam
BackgroundWater quality levels from hemodialysis (HD) and reverse osmosis (RO) machines in dialysis units must meet standards set by the American Association of Medical Instrumentation. Researchers used a root cause analysis (RCA) approach to identify and address factors affecting water quality in the HD and portable RO machines at our institution.MethodsA multidisciplinary team reviewed processes, interviewed staff members, and identified opportunities to improve the current sampling and machine disinfection processes. The RCA team identified and implemented 5 interventions, of which 3 were process (changes in water sampling technique, machine disinfection processes, and allocation of machine maintenance duties) and 2 were structural (regular cleaning of water sampling tubes and spigots and addition of new water sampling sites in the system) measures.ResultsPostimplementation of new protocols, 100% of water cultures of HD and RO machines consistently met the required regulatory standards as recorded over a period of 8 months.ConclusionsRCA approach helped improve patient safety, quality of care, streamlined processes, and improved efficiencies of work for staff within the HD program.



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Changes to physician and nurse time burdens when caring for patients under contact precautions

Publication date: Available online 13 March 2017
Source:American Journal of Infection Control
Author(s): Anna K. Barker, James Codella, Tola Ewers, Adam Dundon, Oguzhan Alagoz, Nasia Safdar
Contact precautions are complex behavioral interventions. To better understand barriers to compliance, we conducted a prospective study that compared the time burden for health care workers caring for contact precautions patients versus other patients. We found that nurses spent significantly more time in the rooms of contact precautions patients. There was no significant change in physician timing. Future studies need to evaluate workflow changes so that barriers to contact precaution implementation can be fully understood and addressed.



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A qualitative study to identify reasons for Clostridium difficile testing in pediatric inpatients receiving laxatives or stool softeners

Publication date: Available online 13 March 2017
Source:American Journal of Infection Control
Author(s): Joanne Kinlay, Thomas J. Sandora
To understand why clinicians send Clostridium difficile tests from hospitalized children receiving laxatives or stool softeners, we performed a mixed-methods study. We prospectively identified tested patients and surveyed their clinicians by e-mail. Reasons for testing included changes in stooling pattern on baseline bowel regimen, other changes in clinical status, and risk factors for C difficile infection. Education targeting discontinuing bowel medications before C difficile testing could improve the specificity of pediatric C difficile infection diagnosis.



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The influence of spatial configuration on the frequency of use of hand sanitizing stations in health care environments

Publication date: Available online 14 March 2017
Source:American Journal of Infection Control
Author(s): Jun Rong Jeffrey Neo, Rana Sagha-Zadeh
BackgroundThe lack of user-friendly, accessible, and visible hand sanitizing stations (HSSs) in health care environments are significant factors affecting low hand hygiene compliance rates among caregivers.ObjectiveTo determine whether the simulated parameters of visibility and global traffic flow score for an HSS can influence the frequency of use of that HSS.MethodsSpace syntax was used to measure virtual simulation of spatial layouts of 3 units to provide quantitative visibility and global traffic flow scores for each HSS. The frequency of use of HSSs was measured for 2 weeks in 3 units in a community hospital through electronic tracking with self-developed motion sensors. Behavioral observations were also conducted during the same period to validate hand hygiene data obtained through electronic tracking. Linear models were used to tests how much variance in use is accounted for when visibility and/or global traffic flow are included in the model.ResultsWhen the visibility score for an HSS increases (decrease), frequency of use of the HSS will increase (decrease) (F [5, 65] = 13.877; P < .001). When the global traffic flow score for an HSS increases (decrease), frequency of use of the HSS will increase (decrease) (F [5, 65] = 13.877; P < .001).ConclusionsThis study proposed and validated a novel approach of using space syntax simulations to predict and optimize hand hygiene behavior.



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Collection of mullet fish ( Mugil cephalus ) from west coast of India: evaluation of its quality with relation to food safety

Abstract

The present study focuses on bacterial and selected heavy metal contaminations of economically important mullet fish (Mugil cephalus) collected from West coast of Gujarat, India. Molecular identification using 16S rRNA sequencing revealed the presence of Aeromonas veronii, A. mollusorum, A. cavae, A. bivalvum, and V.alginolyticus in the gill and the intestine along with some other non-pathogenic bacteria. Pathogenicity of different Aeromonas species was confirmed by hemolysin assay. Apart from pathogenicity, multidrug resistance pattern was also reported against some commonly used antibiotics. Heavy metal analysis of different parts such as ventral and dorsal muscles as well as gills of M. cephalus revealed maximum concentration of Pb (24.08 ± 4.40 mg/kg), Cd (8.25 ± 3.04 mg/kg), and Cu (33.67 ± 5.34 mg/kg), which were higher than the permissible limit. To the best of our knowledge, this is the first study analyzing different heavy metals and associated bacteria in M. cephalus fish in India. Further, the distribution of heavy metals in M. cephalus fish from other countries was also compared.

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Ibuprofen removal by heterogeneous photocatalysis and ecotoxicological evaluation of the treated solutions

Abstract

Emerging contaminants including pharmaceuticals are a class of compounds that are causing great concern due to several environmental problems. Conventional water and wastewater treatments do not achieve high removal efficiencies for many of these drugs. Therefore, the present work investigated the removal of ibuprofen (IBP) by heterogeneous photocatalysis using TiO2 irradiated with artificial UV light or solar radiation. The treated solutions were tested against Daphnia similis and Raphidocelis subcapitata, which are species commonly used as bioindicators of environmental conditions. The results indicated that IBP removal reached 92% after 1 h of treatment using artificial UV and 1000 mg L⁻¹ of TiO₂, which was the optimum catalyst concentration in the range studied (20–1000 mg L⁻¹). TOC removal reached up to 78% after 60 min of treatment using TiO₂/artificial UV. Ecotoxicological bioassays indicated that the treated solutions had acute effects, with 30% immobilization of D. similis and 40% growth inhibition of R. subcapitata.

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Evaluation of atrazine degradation applied to different energy systems

Abstract

Atrazine is an herbicide widely used in crops and has drawn attention due to potential pollution present in soil, sediment, water, and food. Since conventional methods are not potentially efficient to persistent degradation of organic compounds, new technology has been developed to remove them, especially practices utilizing advanced oxidation processes (AOPs). This work aims to evaluate the use of different energies (ultraviolet (UV), microwaves (MW), and radiations (MW-UV)) to the herbicide atrazine through the process of photo-oxidation. These systems found degradation rates of around 12% (UV), 28% (MW), and 83% (MW-UV), respectively, with time intervals of 120 s. After the photolytic processes, the samples were analyzed at a wavelength scanning the range of 190 to 300 nm, where the spectral analysis of the signal was used to evaluate the degradation of atrazine and the appearance of some other peaks (degradation products). The spectrum evaluation resulting from photolytic processes gave rise to a new signal which was confirmed by chromatography. This spectrum indicated the possible pathway of atrazine degradation by the process of photolytic MW-UV, generating atrazine-2-hydroxy, atrazine-desethyl-2-hidroxy, and atrazine-desisopropyl-2-hydroxy. The process indicated that in all situations, chloride was present in the analytic structure and was substituted by a hydroxyl group, which lowered the toxicity of the compound through the photolytic processMW-UV. Chromatographic analysis ascertained these preliminary assessments using spectrophotometry. It was also significantly observed that the process can be optimized by adjusting the pH of the solution, which was evident by an improvement of 10% in the rate of degradation when subjected to a pH solution equal to 8.37.

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The influence of renewable and non-renewable energy consumption and real income on CO 2 emissions in the USA: evidence from structural break tests

Abstract

The objective of this study is to explore the influence of the real income (GDP), renewable energy consumption and non-renewable energy consumption on carbon dioxide (CO₂) emissions for the United States of America (USA) in the environmental Kuznets curve (EKC) model for the period 1980–2014. The Zivot-Andrews unit root test with a structural break and the Clemente-Montanes-Reyes unit root test with a structural break report that the analyzed variables become stationary at first-differences. The Gregory-Hansen cointegration test with a structural break and the bounds testing for cointegration in the presence of a structural break show CO₂ emissions, the real income, the quadratic real income, renewable and non-renewable energy consumption are cointegrated. The long-run estimates obtained from the ARDL model indicate that increases in renewable energy consumption mitigate environmental degradation whereas increases in non-renewable energy consumption contribute to CO₂ emissions. In addition, the EKC hypothesis is not valid for the USA. Since we use time-series econometric approaches that account for structural break in the data, findings of this study are robust, reliable and accurate. The US government is advised to put more weights on renewable sources in energy mix, to support and encourage the use and adoption of renewable energy and clean technologies, and to increase the public awareness of renewable energy for lower levels of emissions.

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Cadmium exposure and urinary N-acetyl-β-D-glucosaminidase: a meta-analysis

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Effective remediation of low-concentration cadmium in groundwater using nano-scale magnesia

Abstract

Cadmium (Cd), one of the hazardous elements in groundwater, is a severe threat to human health and ecological systems even at low concentrations. This study explores the effectiveness of commercial and self-synthesized nano-scale magnesia (NMgO) for remediating low-concentration Cd in groundwater as well as their associated removal mechanisms. The sorption kinetic data for both NMgOs were well fitted to the pseudo-second-order model and the calculated q _e values matched the experimental q _e values for both commercial and self-synthesized NMgOs. The sorption equilibrium data for both NMgOs were well fitted to the Langmuir isotherm model, with the maximum Cd sorption capacity (q _e) of 19.25 and 16.54 mg/g at an initial concentration range of 5–200 μg/L and a temperature of 25 °C, for commercial and self-synthesized NMgOs, respectively. The combined sorption kinetics and equilibrium data suggest that the sorption onto both NMgOs follows a monolayer chemisorption. The scanning electron microscope-energy dispersive X-ray (SEM-EDX), Fourier transform infrared spectroscopy (FTIR), and X-ray diffractometer (XRD) analyses show that the chemisorption of Cd onto commercial NMgO is due to the formation of Cd(OH)₂, which precipitates on the sorbent surface. For the self-synthesized NMgO, it was demonstrated that the hydroxyl group plays a role in the chemisorption process and the amount of Cd sorbed on the sorbent was quantified. The results of batch experiments showed that both NMgOs removed Cd effectively, obtaining a removal efficiency of more than 99%, under different experimental conditions of pH, sorbent dosage, co-existing ions, and simulated groundwater. Results from both the sorption isotherm and desorption experiments indicated strong bonding between Cd and both NMgOs, suggesting that NMgOs are safe, effective, and practical sorbents to remediate Cd in groundwater.

http://ift.tt/2n4LVVs

Sonophotocatalytic degradation of bisphenol A and its intermediates with graphitic carbon nitride

Abstract

Since bisphenol A (BPA) exhibits endocrine disrupting action and high toxicity in aqueous system, there are high demands to remove it completely. In this study, the BPA removal by sonophotocatalysis coupled with nano-structured graphitic carbon nitride (g-C₃N₄, GCN) was conducted with various batch tests using energy-based advanced oxidation process (AOP) based on ultrasound (US) and visible light (Vis-L). Results of batch tests indicated that GCN-based sonophotocatalysis (Vis-L/US) had higher rate constants than other AOPs and especially two times higher degradation rate than TiO₂-based Vis-L/US. This result infers that GCN is effective in the catalytic activity in Vis-L/US since its surface can be activated by Vis-L to transport electrons from valence band (VB) for utilizing holes (h ⁺_VB) in the removal of BPA. In addition, US irradiation exfoliated the GCN effectively. The formation of BPA intermediates was investigated in detail by using high-performance liquid chromatography-mass spectrometry (HPLC/MS). The possible degradation pathway of BPA was proposed.

http://ift.tt/2mnbkWb

IMMUNOHISTOCHEMICAL EXPRESSION OF P16, KI67 AND P53 IN CERVICAL LESIONS - A SYSTEMATIC REVIEW

Publication date: Available online 14 March 2017
Source:Pathology - Research and Practice
Author(s): Daliana Caldas Silva, Ana Katherine Gonçalves, Ricardo Ney Cobucci, Roberta Cecília Mendonça, Paulo Henrique Lima, Geraldo Cavalcanti Júnior
This study evaluated the immunohistochemical (IHC) expression of p16, p53 and Ki-67 in precancerous lesions and in cervical cancer (CC). Identification and review of publications assessing IHC expression in cervical intraepithelial neoplasia (CIN) and CC until February 15, 2017. Systematic review of studies in women with and without cervical lesions in order to evaluate whether there is overexpression of these biomarkers. A total of 28 publications met the criteria which included 6005 patients. The analysis showed that there is higher IHC expression of these biomarkers associated with the more severe lesions. Nineteen out of 22 evaluated studies have shown that there is a higher p16 expression in more severe lesions (CC), while in P53 expression only 4 out of the 9 studies showed a higher expression among more severe cases. Regarding the Ki67 expression, it was observed that 9 out of 14 studies showed higher expression in more severe lesions. A complete absence of or just minimal IHC expression was observed in the normal cervical epithelium, whilst a significant increase in the expression of these biomarkers was detected according to the severity of lesions. Results suggest that these biomarkers can be considered useful tools for discriminating between the stages of the progressive cervical disease.



http://ift.tt/2nzK7jU

Fat2 and Lar Dance a Pas de Deux during Collective Cell Migration

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Qiyan Mao, Jules Lavalou, Thomas Lecuit
What coordinates the internal leading and trailing edges in collectively migrating cells is largely unknown. In this issue of Developmental Cell, Barlan et al. (2017) delineate a Fat2/Lar planar signaling pathway at the basal, motile cell-cell contacts of Drosophila egg chamber follicle cells.

Teaser

What coordinates the internal leading and trailing edges in collectively migrating cells is largely unknown. In this issue of Developmental Cell, Barlan et al. (2017) delineate a Fat2/Lar planar signaling pathway at the basal, motile cell-cell contacts of Drosophila egg chamber follicle cells.


http://ift.tt/2lWx4Nm

RNA Methylation Clears the Way

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Cassandra Kontur, Antonio Giraldez
During the maternal-to-zygotic transition, maternal mRNAs are cleared by multiple distinct but interrelated pathways. A recent study in Nature by Zhao et al. (2017) finds that YTHDF2, a reader of N⁶- methylation, facilitates maternal mRNA decay, introducing an additional facet of control over transcript fate and developmental reprogramming.

Teaser

During the maternal-to-zygotic transition, maternal mRNAs are cleared by multiple distinct but interrelated pathways. A recent study in Nature by Zhao et al. (2017) finds that YTHDF2, a reader of N⁶- methylation, facilitates maternal mRNA decay, introducing an additional facet of control over transcript fate and developmental reprogramming.


http://ift.tt/2mFeFBH

Buffering Global Variability of Morphogen Gradients

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Ben-Zion Shilo, Naama Barkai
Morphogen gradients determine tissue pattern by triggering differential cell responses to distinct morphogen concentrations. The strict quantitative dependence of the emerging patterns on morphogen distribution raises the challenge of buffering variability in morphogen profile to ensure a reproducible outcome. We describe the underlying principles of two modules for buffering morphogen distribution: buffering morphogen amplitude by storing excess morphogen in a limited spatial region, and buffering morphogen spread by pinning morphogen levels at a distal position through global feedback that adjusts morphogen diffusion or degradation across the tissue. We also present concrete examples of patterning systems that implement these modules.

Teaser

Morphogen gradients determine tissue pattern by triggering differential cell responses to distinct morphogen concentrations. How is variability in morphogen profile buffered to ensure a reproducible outcome? Shilo and Barkai describe underlying principles of two modules for buffering morphogen distribution and present concrete examples of patterning systems that implement them.


http://ift.tt/2lWEPmt

A Wnt5 Activity Asymmetry and Intercellular Signaling via PCP Proteins Polarize Node Cells for Left-Right Symmetry Breaking

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Katsura Minegishi, Masakazu Hashimoto, Rieko Ajima, Katsuyoshi Takaoka, Kyosuke Shinohara, Yayoi Ikawa, Hiromi Nishimura, Andrew P. McMahon, Karl Willert, Yasushi Okada, Hiroshi Sasaki, Dongbo Shi, Toshihiko Fujimori, Toshihisa Ohtsuka, Yasunobu Igarashi, Terry P. Yamaguchi, Akihiko Shimono, Hidetaka Shiratori, Hiroshi Hamada
Polarization of node cells along the anterior-posterior axis of mouse embryos is responsible for left-right symmetry breaking. How node cells become polarized has remained unknown, however. Wnt5a and Wnt5b are expressed posteriorly relative to the node, whereas genes for Sfrp inhibitors of Wnt signaling are expressed anteriorly. Here we show that polarization of node cells is impaired in Wnt5a^–/–Wnt5b^–/– and Sfrp mutant embryos, and also in the presence of a uniform distribution of Wnt5a or Sfrp1, suggesting that Wnt5 and Sfrp proteins act as instructive signals in this process. The absence of planar cell polarity (PCP) core proteins Prickle1 and Prickle2 in individual cells or local forced expression of Wnt5a perturbed polarization of neighboring wild-type cells. Our results suggest that opposing gradients of Wnt5a and Wnt5b and of their Sfrp inhibitors, together with intercellular signaling via PCP proteins, polarize node cells along the anterior-posterior axis for breaking of left-right symmetry.

Graphical abstract

Teaser

Polarization of node cells along the anterior-posterior axis of mouse embryos is responsible for left-right symmetry breaking. Opposing gradients of Wnt5a and Wnt5b and of their Sfrp inhibitors, together with intercellular signaling via PCP proteins, polarize node cells along the anterior-posterior axis for breaking of left-right symmetry.


http://ift.tt/2mF7Vng

BTBD18 Regulates a Subset of piRNA-Generating Loci through Transcription Elongation in Mice

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Liquan Zhou, Bertram Canagarajah, Yangu Zhao, Boris Baibakov, Keizo Tokuhiro, Dragan Maric, Jurrien Dean
PIWI-interacting RNAs (piRNAs) are small non-coding RNAs essential for animal germ cell development. Despite intense investigation of post-transcriptional processing, chromatin regulators for piRNA biogenesis in mammals remain largely unexplored. Here we document that BTBD18 is a pachytene nuclear protein in mouse testes that occupies a subset of pachytene piRNA-producing loci. Ablation of Btbd18 in mice disrupts piRNA biogenesis, prevents spermiogenesis, and results in male sterility. Transcriptome profiling, chromatin accessibility, and RNA polymerase II occupancy demonstrate that BTBD18 facilitates expression of pachytene piRNA precursors by promoting transcription elongation. Thus, our study identifies BTBD18 as a specific controller for transcription activation through RNA polymerase II elongation at a subset of genomic piRNA loci.

Graphical abstract

Teaser

piRNAs are small non-coding RNAs primarily expressed in animal gonads. Zhou et al. implicate BTBD18, a nuclear protein, in piRNA biogenesis as key for male fertility. BTBD18 binds to a subset of pachytene piRNA-producing loci in mouse testes, promotes transcription elongation, and promotes piRNA precursor expression for successful germ cell development.


http://ift.tt/2mEXEru

Wnt/PCP Instructions for Cilia in Left-Right Asymmetry

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Jun Wu, Marek Mlodzik
Wnt-Frizzled/planar cell polarity (PCP) signaling establishes cell orientation within the epithelial plane, but whether Wnts are instructive or permissive is debated. Reporting in Developmental Cell, Minegishi et al. (2017) uncover an instructive link from Wnt5a/b gradients to PCP-factor-regulated polarized cilia positioning that is essential to mouse embryo left-right asymmetry establishment.

Teaser

Wnt-Frizzled/planar cell polarity (PCP) signaling establishes cell orientation within the epithelial plane, but whether Wnts are instructive or permissive is debated. Reporting in Developmental Cell, Minegishi et al. (2017) uncover an instructive link from Wnt5a/b gradients to PCP-factor-regulated polarized cilia positioning that is essential to mouse embryo left-right asymmetry establishment.


http://ift.tt/2mFbZEa

Fat2 and Lar Define a Basally Localized Planar Signaling System Controlling Collective Cell Migration

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Kari Barlan, Maureen Cetera, Sally Horne-Badovinac
Collective migration of epithelial cells underlies diverse tissue-remodeling events, but the mechanisms that coordinate individual cell migratory behaviors for collective movement are largely unknown. Studying the Drosophila follicular epithelium, we show that the cadherin Fat2 and the receptor tyrosine phosphatase Lar function in a planar signaling system that coordinates leading and trailing edge dynamics between neighboring cells. Fat2 signals from each cell's trailing edge to induce leading edge protrusions in the cell behind, in part by stabilizing Lar's localization in these cells. Conversely, Lar signals from each cell's leading edge to stimulate trailing edge retraction in the cell ahead. Fat2/Lar signaling is similar to planar cell polarity signaling in terms of sub-cellular protein localization; however, Fat2/Lar signaling mediates short-range communication between neighboring cells instead of transmitting long-range information across a tissue. This work defines a key mechanism promoting epithelial migration and establishes a different paradigm for planar cell-cell signaling.

Teaser

Barlan and colleagues examine how the cadherin Fat2 and the receptor tyrosine phosphatase Lar promote epithelial migration in the context of the Drosophila egg chamber. They show that these proteins form the core of a planar signaling system that coordinates leading and trailing edge dynamics between neighboring cells.


http://ift.tt/2lWHOuY

Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Ting Su, Michael Z. Ludwig, Jiajie Xu, Richard G. Fehon
The Hippo pathway is emerging as a key evolutionarily conserved signaling mechanism that controls organ size. Three membrane-associated proteins, Kibra, Merlin, and Expanded, regulate pathway activity, but the precise molecular mechanism by which they function is still poorly understood. Here we provide evidence that Merlin and Kibra activate Hippo signaling in parallel to Expanded at a spatially distinct cellular domain, the medial apical cortex. Merlin and Kibra together recruit the adapter protein Salvador, which in turn recruits the core kinase Hippo. In addition, we show that Crumbs has a dual effect on Hippo signaling. Crumbs promotes the ability of Expanded to activate the pathway but also sequesters Kibra to downregulate Hippo signaling. Together, our findings elucidate the mechanism of Hippo pathway activation by Merlin and Kibra, identify a subcellular domain for Hippo pathway regulation, and demonstrate differential activity of upstream regulators in different subcellular domains.

Teaser

Merlin, Kibra, and Expanded are believed to act in a complex at intercellular junctions to control Hippo pathway activity. Su et al. show that instead Merlin and Kibra function at the Drosophila apical medial cortex separately from Crumbs and Expanded, thereby identifying an additional subcellular domain for Hippo pathway regulation.


http://ift.tt/2mF385t

Planarian Epidermal Stem Cells Respond to Positional Cues to Promote Cell-Type Diversity

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Omri Wurtzel, Isaac M. Oderberg, Peter W. Reddien
Successful regeneration requires that progenitors of different lineages form the appropriate missing cell types. However, simply generating lineages is not enough. Cells produced by a particular lineage often have distinct functions depending on their position within the organism. How this occurs in regeneration is largely unexplored. In planarian regeneration, new cells arise from a proliferative cell population (neoblasts). We used the planarian epidermal lineage to study how the location of adult progenitor cells results in their acquisition of distinct functional identities. Single-cell RNA sequencing of epidermal progenitors revealed the emergence of distinct spatial identities as early in the lineage as the epidermal neoblasts, with further pre-patterning occurring in their post-mitotic migratory progeny. Establishment of dorsal-ventral epidermal identities and functions, in response to BMP signaling, required neoblasts. Our work identified positional signals that activate regionalized transcriptional programs in the stem cell population and subsequently promote cell-type diversity in the epidermis.

Graphical abstract

Teaser

Wurtzel et al. examine how in planarian regeneration, adult progenitor cell location contributes to acquisition of distinct functional identities. They provide insight for how progenitors in the epidermis read their position in the animal to activating region-specific transcription, which is ultimately propagated to differentiated progeny to generate the required cellular functions.


http://ift.tt/2lWsxdK

Cell-Cell Contact Area Affects Notch Signaling and Notch-Dependent Patterning

Publication date: 13 March 2017
Source:Developmental Cell, Volume 40, Issue 5
Author(s): Oren Shaya, Udi Binshtok, Micha Hersch, Dmitri Rivkin, Sheila Weinreb, Liat Amir-Zilberstein, Bassma Khamaisi, Olya Oppenheim, Ravi A. Desai, Richard J. Goodyear, Guy P. Richardson, Christopher S. Chen, David Sprinzak
During development, cells undergo dramatic changes in their morphology. By affecting contact geometry, these morphological changes could influence cellular communication. However, it has remained unclear whether and how signaling depends on contact geometry. This question is particularly relevant for Notch signaling, which coordinates neighboring cell fates through direct cell-cell signaling. Using micropatterning with a receptor trans-endocytosis assay, we show that signaling between pairs of cells correlates with their contact area. This relationship extends across contact diameters ranging from micrometers to tens of micrometers. Mathematical modeling predicts that dependence of signaling on contact area can bias cellular differentiation in Notch-mediated lateral inhibition processes, such that smaller cells are more likely to differentiate into signal-producing cells. Consistent with this prediction, analysis of developing chick inner ear revealed that ligand-producing hair cell precursors have smaller apical footprints than non-hair cells. Together, these results highlight the influence of cell morphology on fate determination processes.

Graphical abstract

Teaser

Cell geometry varies considerably between cells in almost every tissue. Shaya et al. show that Notch signaling between pairs of cells correlates with their contact area. This dependence of signaling on contact area can bias Notch-mediated cell fate decisions such as those occurring in chick inner ear development.


http://ift.tt/2mn2PLp

The effect of low-level laser therapy on tooth movement during canine distalization

Abstract

The aim of the study is to determine the effects of low level laser therapy on tooth movement during canine distalization by evaluating IL-1β, TGF-β1 levels in gingival crevicular fluid. Maxillary first premolars of the 15 Angle Class II division I patients (12–19 years old) were extracted. Right maxillary canines were distalized by standard protocol as control group whereas the left maxillary canines distalized by laser application. A gallium-aluminum-arsenide diode laser with an output power of 20 mW was applied as five doses from the buccal and the palatal side on the day 0, and the 3rd, 7th, 14th, 21th 30th, 33st, 37th, 60th, 63th, and 67th days. Gingival crevicular fluid samples were obtained with filtration paper at the initial, 7th, 14th, and 21th days, and the IL-1ß and TGF-ß1 cytokine levels were analyzed. Orthodontic models and periodontal indices were taken initially and on the days 30th, 60th, and 90th of canine distalization period. Tooth movement was assessed by scanning models (3Shape). The amount of tooth movement in the laser group was 40% more than the control group. First day IL-1ß levels were statistically higher than initial and 21st day levels (P= 0.003, P = 0.012). The rise in IL-1ß levels caused the negative correlations between 7th day IL-1β and 21st day TGF-β1 levels describes the tissue effects of laser application. Periodontal indices showed no sign of gingival inflammation during canine distalization period. As conclusion, laser does accelerate tooth movement and could shorten the whole treatment duration.

http://ift.tt/2mFd7HI

Anti-Depressant Therapy Brightens the Outlook for Prostate Cancer Bone Metastases

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Michael D. Nyquist, Peter S. Nelson
In this issue of Cancer Cell, Wu et al. identify MAOA as a key mediator of osteolytic bone responses that involve complex paracrine interactions between tumor cells, osteoblasts, and osteoclasts. Pharmacological inhibition of MAOA enzymatic activity effectively interrupted osteolysis and metastatic progression in preclinical models, suggesting a new treatment opportunity.

Teaser

In this issue of Cancer Cell, Wu et al. identify MAOA as a key mediator of osteolytic bone responses that involve complex paracrine interactions between tumor cells, osteoblasts, and osteoclasts. Pharmacological inhibition of MAOA enzymatic activity effectively interrupted osteolysis and metastatic progression in preclinical models, suggesting a new treatment opportunity.


http://ift.tt/2mn6EAh

Antibodies Create Killer Bonds in Myeloma

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Marta Chesi, Rafael Fonseca
In this issue of Cancer Cell, Li et al. and Seckinger et al. describe promising results of two T-cell-dependent bi-specific antibodies for the treatment of multiple myeloma: one targets FcRH5 expressed on B cells, whereas the other targets the B cell maturation antigen expressed on plasma cells.

Teaser

In this issue of Cancer Cell, Li et al. and Seckinger et al. describe promising results of two T-cell-dependent bi-specific antibodies for the treatment of multiple myeloma: one targets FcRH5 expressed on B cells, whereas the other targets the B cell maturation antigen expressed on plasma cells.


http://ift.tt/2mHZQ2N

ETO2-GLIS2: A Chimeric Transcription Factor Drives Leukemogenesis through a Neomorphic Transcription Network

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Justin C. Wheat, Ulrich Steidl
Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease with a relatively poorly understood pathogenesis. In this issue of Cancer Cell, Thirant and colleagues systematically examine unique transcriptional and functional effects of ETO2-GLIS2, an oncogenic fusion protein frequently encountered in AMKL, and elucidate a therapeutic vulnerability in this poor-prognosis leukemia.

Teaser

Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease with a relatively poorly understood pathogenesis. In this issue of Cancer Cell, Thirant and colleagues systematically examine unique transcriptional and functional effects of ETO2-GLIS2, an oncogenic fusion protein frequently encountered in AMKL, and elucidate a therapeutic vulnerability in this poor-prognosis leukemia.


http://ift.tt/2mnaGZF

Pancreatic Cancer Genomics 2.0: Profiling Metastases

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Eric A. Collisson, Anirban Maitra
Pancreatic ductal adenocarcinoma, even when diagnosed early, nearly always metastasizes. Recurrent mutations and genomic instability are early events in the disease. Two recent papers advance our understanding of how the cancer genome evolves as the primary tumor migrates from its origin in the pancreas to colonize distant metastatic sites.

Teaser

Pancreatic ductal adenocarcinoma, even when diagnosed early, nearly always metastasizes. Recurrent mutations and genomic instability are early events in the disease. Two recent papers advance our understanding of how the cancer genome evolves as the primary tumor migrates from its origin in the pancreas to colonize distant metastatic sites.


http://ift.tt/2mn5HrW

Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Kristin G. Anderson, Ingunn M. Stromnes, Philip D. Greenberg
T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles.

Teaser

T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles.


http://ift.tt/2mHJLKK

Dangerous Liaisons: Deviant Endothelium NOTCHes toward Tumor Metastasis

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Peipei Guo, Shahin Rafii
In this issue of Cancer Cell, Wieland et al. uncover a feedback loop in which tumor cells, by augmenting Notch signaling, provoke a senescent and pro-inflammatory state in endothelial cells, promoting neutrophil infiltration, tumor cell adhesion, and metastasis. Interfering with this Notch-dependent crosstalk may be a therapeutic approach to block metastasis.

Teaser

In this issue of Cancer Cell, Wieland et al. uncover a feedback loop in which tumor cells, by augmenting Notch signaling, provoke a senescent and pro-inflammatory state in endothelial cells, promoting neutrophil infiltration, tumor cell adhesion, and metastasis. Interfering with this Notch-dependent crosstalk may be a therapeutic approach to block metastasis.


http://ift.tt/2mnfpur

The Microenvironmental Landscape of Brain Tumors

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Daniela F. Quail, Johanna A. Joyce
The brain tumor microenvironment (TME) is emerging as a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of this organ require a specific framework for designing TME-targeted interventions. Here, we discuss a number of these distinct features, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment. We also highlight recent advances in therapeutically targeting the brain TME in cancer. By developing a comprehensive understanding of the complex and interconnected microenvironmental landscape of brain malignancies we will greatly expand the range of therapeutic strategies available to target these deadly diseases.

Teaser

The brain tumor microenvironment (TME) is emerging as a critical regulator of cancer progression in primary and metastatic brain malignancies. The unique properties of this organ require a specific framework for designing TME-targeted interventions. Here, we discuss a number of these distinct features, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment. We also highlight recent advances in therapeutically targeting the brain TME in cancer. By developing a comprehensive understanding of the complex and interconnected microenvironmental landscape of brain malignancies we will greatly expand the range of therapeutic strategies available to target these deadly diseases.


http://ift.tt/2mHMNhM

Nerve Dependence: From Regeneration to Cancer

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Benoni Boilly, Sam Faulkner, Phillip Jobling, Hubert Hondermarck
Nerve dependence has long been described in animal regeneration, where the outgrowth of axons is necessary to the reconstitution of lost body parts and tissue remodeling in various species. Recent discoveries have demonstrated that denervation can suppress tumor growth and metastasis, pointing to nerve dependence in cancer. Regeneration and cancer share similarities in regard to the stimulatory role of nerves, and there are indications that the stem cell compartment is a preferred target of innervation. Thus, the neurobiology of cancer is an emerging discipline that opens new perspectives in oncology.

Teaser

Nerve dependence has long been described in animal regeneration, where the outgrowth of axons is necessary to the reconstitution of lost body parts and tissue remodeling in various species. Recent discoveries have demonstrated that denervation can suppress tumor growth and metastasis, pointing to nerve dependence in cancer. Regeneration and cancer share similarities in regard to the stimulatory role of nerves, and there are indications that the stem cell compartment is a preferred target of innervation. Thus, the neurobiology of cancer is an emerging discipline that opens new perspectives in oncology.


http://ift.tt/2mn3koX

MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Jason Boyang Wu, Lijuan Yin, Changhong Shi, Qinlong Li, Peng Duan, Jen-Ming Huang, Chunyan Liu, Fubo Wang, Michael Lewis, Yang Wang, Tzu-Ping Lin, Chin-Chen Pan, Edwin M. Posadas, Haiyen E. Zhau, Leland W.K. Chung
Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.

Graphical abstract

Teaser

Wu et al. show that monoamine oxidase A (MAOA) is an important mediator of prostate cancer bone and visceral metastases by activating paracrine Shh-IL6-RANKL signaling in tumor-stromal interactions. Pharmacological inhibition of MAOA restricts metastasis and extends survival in a mouse prostate cancer model.


http://ift.tt/2mHZRUl

Integrated Molecular Characterization of Uterine Carcinosarcoma

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Andrew D. Cherniack, Hui Shen, Vonn Walter, Chip Stewart, Bradley A. Murray, Reanne Bowlby, Xin Hu, Shiyun Ling, Robert A. Soslow, Russell R. Broaddus, Rosemary E. Zuna, Gordon Robertson, Peter W. Laird, Raju Kucherlapati, Gordon B. Mills, John N. Weinstein, Jiashan Zhang, Rehan Akbani, Douglas A. Levine
We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.

Teaser

Cherniack et al. perform integrated molecular analyses of uterine carcinosarcomas and identify alterations in canonical pathways containing therapeutic targets currently in clinical trials. They also dissect the interaction between genomic and epigenomic regulations of epithelial-to-mesenchymal transition.


http://ift.tt/2mHZMQE

A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): QiWen Fan, Ozlem Aksoy, Robyn A. Wong, Shirin Ilkhanizadeh, Chris J. Novotny, William C. Gustafson, Albert Yi-Que Truong, Geraldine Cayanan, Erin F. Simonds, Daphne Haas-Kogan, Joanna J. Phillips, Theodore Nicolaides, Masanori Okaniwa, Kevan M. Shokat, William A. Weiss
Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (mTOR) is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with rapamycin and Rapalink-1, TORKi showed poor durability. RapaLink-1 associated with FKBP12, an abundant mTOR-interacting protein, enabling accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR. Our study re-establishes mTOR as a central target in glioma and traces the failure of existing drugs to incomplete/nondurable inhibition of mTORC1.

Teaser

Fan et al. target mTORC1 activity in glioblastoma (GBM) with RapaLink-1, which is comprised of rapamycin linked to an mTOR kinase inhibitor. RapaLink-1 decreases mTORC1 activity in the brain and suppresses the growth of GBM xenografts and a genetically engineered mouse model of brain cancer in vivo.


http://ift.tt/2mn8FfY

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Mirjam Blattner, Deli Liu, Brian D. Robinson, Dennis Huang, Anton Poliakov, Dong Gao, Srilakshmi Nataraj, Lesa D. Deonarine, Michael A. Augello, Verena Sailer, Lalit Ponnala, Michael Ittmann, Arul M. Chinnaiyan, Andrea Sboner, Yu Chen, Mark A. Rubin, Christopher E. Barbieri
Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor signaling, effectively uncoupling the normal negative feedback between these two pathways.

Graphical abstract

Teaser

Blattner et al. develop a mouse model and use it to demonstrate that human SPOP mutation can drive prostate tumorigenesis through coordinate deregulation of both PI3K/mTOR and AR pathways. The study provides insights to both unique and common features of molecular subtypes of human prostate cancer.


http://ift.tt/2mHTUXI

ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Cécile Thirant, Cathy Ignacimouttou, Cécile K. Lopez, M'Boyba Diop, Lou Le Mouël, Clarisse Thiollier, Aurélie Siret, Phillipe Dessen, Zakia Aid, Julie Rivière, Philippe Rameau, Céline Lefebvre, Mehdi Khaled, Guy Leverger, Paola Ballerini, Arnaud Petit, Hana Raslova, Catherine L. Carmichael, Benjamin T. Kile, Eric Soler, John D. Crispino, Christian Wichmann, Françoise Pflumio, Jürg Schwaller, William Vainchenker, Camille Lobry, Nathalie Droin, Olivier A. Bernard, Sébastien Malinge, Thomas Mercher
Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.

Graphical abstract

Teaser

Thirant et al. show that the ETO2-GLIS2 fusion protein found in acute megakaryoblastic leukemia confers megakaryocytic identity via the GLIS2 moiety, but requires both ETO2 and GLIS2 domains to drive self-renewal. Disruption of ETO2-GLIS2 oligomerization inhibits the maintenance of ETO2-GLIS2⁺ human AMKL blasts.


http://ift.tt/2mHYlBV

Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Maria Romina Girotti, Filipa Lopes, Natasha Preece, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Steven Whittaker, Grazia Saturno, Amaya Viros, Malin Pedersen, Bart M.J.M. Suijkerbuijk, Delphine Menard, Robert McLeary, Louise Johnson, Laura Fish, Sarah Ejiama, Berta Sanchez-Laorden, Juliane Hohloch, Neil Carragher, Kenneth Macleod, Garry Ashton, Anna A. Marusiak, Alberto Fusi, John Brognard, Margaret Frame, Paul Lorigan, Richard Marais, Caroline Springer




http://ift.tt/2mHWi0A

Phospholipid oxidation and carotenoid supplementation in Alzheimer’s disease patients

Publication date: Available online 14 March 2017
Source:Free Radical Biology and Medicine
Author(s): O.S. Ademowo, H.K.I. Dias, I. Milic, A. Devitt, R. Moran, R. Mulcahy, A.N. Howard, J.M. Nolan, H.R. Griffiths
Alzheimer's disease (AD) is a progressive, neurodegenerative disease, characterised by decline of memory, cognitive function and changes in behaviour. Generic markers of lipid peroxidation are increased in AD, therefore reactive oxygen species have been suggested to be involved in the aetiology of cognitive decline. Carotenoids are depleted in AD serum, therefore we have compared serum lipid oxidation between AD and age-matched control subjects before and after carotenoid supplementation. The novel oxidised phospholipid biomarker 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) was analysed using electrospray ionization tandem mass spectrometry (MS) with multiple reaction monitoring (MRM), 8-isoprostane (IsoP) was measured by ELISA and ferric reducing antioxidant potential (FRAP) was measured by a colorimetric assay.AD patients (n=21) and healthy age-matched control subjects (n=16) were supplemented with either Macushield™ (10mg meso-zeaxanthin, 10mg lutein, 2mg zeaxanthin) or placebo (sunflower oil) for six months.The MRM-MS method determined serum POVPC sensitively (from 10µl serum) and reproducibly (CV=7.9%). At baseline, AD subjects had higher serum POVPC compared to age-matched controls, (p=0.017) and cognitive function was correlated inversely with POVPC (r=−0.37; p=0.04). After six months of carotenoid intervention, serum POVPC was not different in AD patients compared to healthy controls. However, POVPC was significantly higher in control subjects after six months of carotenoid intervention compared to their baseline (p=0.03). Serum IsoP concentration was unrelated to disease or supplementation. Serum FRAP was significantly lower in AD than healthy controls but was unchanged by carotenoid intervention (p=0.003).In conclusion, serum POVPC is higher in AD patients compared to control subjects, is not reduced by carotenoid supplementation and correlates with cognitive function.

Graphical abstract

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Thyroid V40 Predicts Primary Hypothyroidism Following Intensity Modulated Radiotherapy for Nasopharyngeal Carcinoma

Publication date: Available online 14 March 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kiattisa Sommat, Whee Sze Ong, Ashik Hussain, Yoke Lim Soong, Terence Tan, Joseph Wee, Kam Weng Fong
PurposePrimary hypothyroidism (HT) is a common occurrence after intensity modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). The aim of this study is to investigate the various clinical and thyroid dosimetric parameters that could predict the risk of primary HT after IMRT and to determine useful thyroid dose constraints to guide radiotherapy planning.Methods& Materials From September 2009 to August 2012, 102 clinically euthyroid NPC patients were included in this study. All patients were treated with IMRT and randomized to induction chemo followed by concurrent chemo-IMRT or concurrent chemo-IMRT alone. Thyroid function was evaluated by measuring TSH (thyroid stimulating hormone) and fT4 (free thyroxine) at each annual follow up visit. Various clinical and dosimetric parameters (e.g. V40 – percentage of thyroid volume receiving >40Gy) were obtained. Univariate and multivariate logistic regression analyses were performed to identify predictors of HT.ResultsMedian follow up was 48.8 months. Among the 102 patients, 44 (43.1%) patients developed HT within 2 years post radiotherapy. The median time to HT was 36.7 months (range: 24.9 – 49.0 months). The 1-year and 2-year cumulative incidence rate of HT was 33% and 44.5%. Univariate analysis revealed that younger age, early T stage, minimum dose to the thyroid gland, V40 and V45 were associated with HT. On multivariate analysis, younger age (p=0.017), early T stage (p=0.005) and V40 (p=0.009) remained statistically significant. Patients with V40>85% had significantly higher cumulative incidence rates of HT than patients with V40≤85% (p=0.007).ConclusionsThyroid V40 is predictive of primary HT following IMRT for NPC and V40≤85% can be a useful dose constraint to adopt during IMRT planning without compromising tumor coverage.

Teaser

Primary hypothyroidism (HT) is a common occurrence after intensity modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This is a study to investigate the various clinical and thyroid dosimetric parameters that could predict the risk of primary hypothyroidism after IMRT and to determine useful thyroid dose constraints to guide radiotherapy planning. Thyroid V40 is predictive of primary hypothyroidism following intensity modulated radiotherapy for nasopharyngeal carcinoma and V40≤85% can be a useful dose constraint to adopt during IMRT planning without compromising tumor coverage.


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Continuous Effect of Radial Resection Margin on Recurrence and Survival in Rectal Cancer Patients Who Receive Preoperative Chemoradiation and Curative Surgery: A Multicenter Retrospective Analysis

Publication date: Available online 14 March 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Soo-Yoon Sung, Sung Hwan Kim, Joo Hwan Lee, Taek Keun Nam, Songmi Jeong, Hong Seok Jang, Jin Ho Song, Jeong Won Lee, Jung Min Bae, Jong Hoon Lee
PurposeResection margin status is a well-known prognostic factor after curative surgery in colorectal cancer. However, proper length and significance of circumferential resection margin (CRM) and distal resection margin (DRM) in rectal cancer patients who received neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has not been clearly determined yet.Methods and materialsA total of 1476 rectal cancer patients staging cT3-4N0-2M0 were analyzed. All patients received radiation dose of 50.4 Gy in 28 fractions with concurrent 5-fluorouracil or capecitabine. TME was performed 4 to 8 weeks after radiotherapy.ResultsThe recurrence-free survival (RFS) at 5 years showed a significant difference between three groups; patients with CRM ≤ 1mm, CRM 1.1-5mm, and CRM > 5mm (46.2% vs. 68.6% vs. 77.5%, P<0.001). Patients with CRM ≤ 1mm showed significantly higher cumulative incidence of locoregional (P<0.001) recurrence and distant (P<0.001) metastasis at 5 years compared to the other two groups. Patients with CRM 1.1-5mm showed a significantly higher cumulative incidence of distant metastasis (P<0.001), not locoregional recurrence (P=0.192) than those with CRM > 5mm. DRM (≤ 5 vs. > 5mm) did not show any significant difference in cumulative incidence of locoregional recurrence (P=0.310) and distant metastasis (P=0.926).ConclusionThe rectal cancer patients with CRM ≤ 1mm is a high-risk group with the lowest RFS. Patients with CRM 1.1-5mm may be at intermediate risk with moderately increased distant recurrence. DRM was not significantly associated with the RFS in rectal cancer after neoadjuvant CRT and TME.

Teaser

When the association between resection margin and recurrence-free survival (RFS) is assessed in rectal cancer patients who have received neoadjuvant chemoradiotherapy and curative surgery, patients with circumferential resection margin (CRM) ≤ 1mm, 1.1-5mm, and > 5mm showed an increasing RFS rate in order with a significant difference (P<0.001). However, distal resection margin was not a significant prognostic factor for the RFS in rectal cancer.


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Saturated fatty acids recognition by the CD14-TLR4-MD2 complex may engage in the presurgical anxiety-induced persistent postsurgical pain

Publication date: Available online 14 March 2017
Source:Medical Hypotheses
Author(s): Zuoxia Zhang, Zhengliang Ma
It has been proved that presurgical anxiety can induce the development and progression of persistent postsurgical pain through elevating circulating corticosterone levels and activating the glucocorticoids receptor. Under stressful circumstances, the concentration of blood saturated fatty acids (SFAs) increases rapidly to provide enough ATP for individuals' survival owing to stress hormones such as glucocorticoid, catecholamine and glucagon. It is reported that SFAs can trigger an inflammatory response through CD14-TLR4-MD2 complex. The role of TLR4 and its downstream signaling pathway has been confirmed in the pathogenesis of cancer pain and inflammatory pain. Furthermore, a newly clinical research uncovers that the children with recurrent abdominal pain, which is triggered by early psychosomatic stress, have higher levels of SFAs than healthy individuals. We therefore put forward the hypothesis that the elevated level of SFAs induced by stress hormones may be engaged in the presurgical anxiety-induced persistent postsurgical pain. If established, it's of important clinical significance, which will make great contributions to the prevention and treatment of the presurgical anxiety-induced persistent postsurgical pain.



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Periodontal disease as a potential factor of migraine chronification

Publication date: Available online 14 March 2017
Source:Medical Hypotheses
Author(s): Pablo Ameijeira, Yago Leira, Juan Blanco, Rogelio Leira
Migraine is a hereditary constitutional base disorder, which is characterized by recurrent episodes of headache pulsatile characteristics associated with photophobia/phonophobia, nausea and / or vomiting. The main complication in migraine is the chronicity of the process, now recognized as a chronic migraine. Although pathogenic mechanisms that may influence the pathophysiology of migraine and its possible chronicity are not fully understood, previous studies have shown in patients with migraine molecular alterations of systemic inflammation, neurogenic inflammation, endothelial dysfunction, innate immunity, dysfunction of matrix proteases and blood-brain barrier. Periodontal disease is an inflammatory lesion caused by bacteria. After the bacterial infection begins, an immune response that will be responsible for individual susceptibility appears. More advanced forms of periodontitis have demonstrated molecular alterations of inflammation, endothelial dysfunction, dysfunction of matrix proteases and innate immunity, similar to those observed in migraine. Furthermore, the main molecular mediators of neurogenic inflammation related to activation of the trigeminovascular system, which are characteristic of migraine, are overexpressed in gingival crevicular fluid and mucosa in patients with periodontal disease. Hypertension, hypercholesterolemia, insulin resistance, stroke or coronary artery disease are comorbidities that periodontal disease and migraine could share. Therefore, several mechanisms and hypotheses could explain the possible association between both diseases. However, epidemiological and molecular studies will be necessary to provide a better understanding of this potential association, which could be implicated in the chronification of migraine.



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Interleukin-1beta May Act on Hepatocytes to Boost Plasma Homocysteine – The Increased Cardiovascular Risk Associated with Elevated Homocysteine May be Mediated by this Cytokine

Publication date: Available online 14 March 2017
Source:Medical Hypotheses
Author(s): Mark F McCarty, James H O'Keefe, James J DiNicolantonio
The results of multi-center trials of B vitamin supplementation reveal that, whereas moderately elevated homocysteine predicts increased risk for coronary disease, it does not play a mediating role in this regard. This essay proposes that interleukin 1-beta can act on hepatocytes to suppress expression of the hepatocyte-specific forms of methionine adenosyltransferase; this in turn can be expected to decrease hepatic activity of cystathionine-β-synthase, leading to an increase in plasma homocysteine. It is further proposed that interleukin 1-beta (IL-1β) is a true mediating risk factor for cardiovascular disease, and that elevated homocysteine predicts coronary disease because it can serve as a marker for increased IL-1β activity. Potent statin therapy may decrease IL-1β production by suppressing inflammasome activation – thereby accounting for the marked protection from cardiovascular events observed in the classic JUPITER study, in which the enrolled subjects had low-normal low density lipoprotein cholesterol but elevated C-reactive protein.



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Surveillance of antibiotic susceptibility in a Swedish Burn Center 1994-2012.

Related Articles

Surveillance of antibiotic susceptibility in a Swedish Burn Center 1994-2012.

Burns. 2016 Sep;42(6):1295-303

Authors: Fransén J, Huss FR, Nilsson LE, Rydell U, Sjöberg F, Hanberger H

Abstract
UNLABELLED: Patients with burn trauma are at risk for infections caused by antibiotic resistant bacteria (ABR) with subsequent increase in morbidity and mortality. As part of the Swedish strategic program against antibiotic resistance in intensive care (ICU-Strama), we have surveyed the distribution of species and ABR in isolates from patients admitted to a Swedish burn center at Linköping University Hospital from 1994 through 2012. In an international comparison Strama has been successful in reducing the antibiotic consumption among animals and humans in primary care. The aim of this study was to investigate the antibiotic consumption pressure and resistance rates in a Swedish burn unit.
METHODS: Microbiology data, total body surface area (TBSA), patient days, and mortality were collected from a hospital database for all patients admitted to the Burn Center at the University Hospital of Linköping from April 1994 through December 2012.
RESULTS: A total of 1570 patients were admitted with a mean annual admission rate of 83 patients (range: 57-152). 15,006 microbiology cultures (approximately 10 per patient) were collected during the study period and of these 4531 were positive (approximately 3 per patient). The annual mean total body surface area (TBSA) was 13.4% (range 9.5-18.5) with an annual mortality rate of 5.4% (range 1-8%). The MRSA incidence was 1.7% (15/866) which corresponds to an MRSA incidence of 0.34/1000 admission days (TAD). Corresponding figures were for Escherichia coli resistant to 3(rd) generation cephalosporins (ESBL phenotype) 8% (13/170) and 0.3/TAD, Klebsiella spp. ESBL phenotype 5% (6/134) and 0.14/TAD, carbapenem resistant Pseudomonas aeruginosa 26% (56/209) and 1.28/TAD, and carbapenem resistant Acinetobacter spp. 3% (2/64) and 0.04/TAD.
CONCLUSIONS: Our results show a sustained low risk for MRSA and high, although not increasing, risk for carbapenem resistant P. aeruginosa.

PMID: 27241732 [PubMed - indexed for MEDLINE]

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Stingless Bee Honey, the Natural Wound Healer: A Review

Background: The stingless bee is a natural type of bee that exists in almost every continent. The honey produced by this bee has been widely used across time and space. The distinctive feature of this honey is that it is stored naturally in the pot (cerumen), thus contributing to its beneficial properties, especially in the wound healing process. Methods: In this article, several studies on stingless bee honey that pointed out the numerous therapeutic profiles of this honey in terms of its antioxidant, antimicrobial, anti-inflammatory, as well as moisturizing properties are reviewed. All of these therapeutic properties are related to wound healing properties. Results: Antioxidant in stingless bee honey could break the chain of free radicals that cause a detrimental effect to the wounded area. Furthermore, the antimicrobial properties of stingless bee honey could overcome the bacterial contamination and thus improve the healing rate. Moreover, the anti-inflammatory attribute in this honey could protect the tissue from highly toxic inflammatory mediators. The moisturizing properties of the honey could improve wound healing by promoting angiogenesis and oxygen circulation. Conclusion: The application of honey to the wound has been widely used since ancient times. As a result, it is essential to understand the pharmacological mechanism of the honey towards the physiology of the wounded skin in order to optimize the healing rate in the future.
Skin Pharmacol Physiol 2017;30:66-75

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Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two

Publication date: Available online 14 March 2017
Source:Clinical Immunology
Author(s): M Bravo García-Morato, S García-Miñaúr, J Molina Garicano, F Santos Simarro, E López-Grandos, A Ferreira Cerdán, R Rodríguez Pena
Mutations in PIK3R1 gene have been associated to two different conditions: a primary immunodeficiency, called APDS2, of recent description and SHORT syndrome. 47 patients with APDS2 have been reported to date, only one of them sharing both PIK3R1-related phenotypes. Here we describe two more patients affected by APDS2 and SHORT syndrome, which highlights that this association may not be so infrequent. We recommend that patients with mutations in PIK3R1 gene should be assessed by both clinical immunologists and clinical geneticists.



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Influence of cobalt addition on microstructure and hot workability of IN713C superalloy

Publication date: 15 May 2017
Source:Materials & Design, Volume 122
Author(s): Yunping Li, Xianjuan Ye, Jiaxiang Li, Yi Zhang, Yuichiro Koizumi, Akihiko Chiba
In the present research, the influence of Co addition on the microstructure and hot workability of IN713C alloy was investigated in detail by scanning electron microscope (SEM), transition electron microscope (TEM) and electron backscattering diffraction (EBSD) etc. Substitution of Ni by Co leads to lower driving force for formation of γ′ phase. In addition, with the increase of Co fraction, the γ′ phase precipitates turned finer and more cuboidal shape. As a result, the hot workability of IN713C alloy was improved significantly by Co addition. This can be ascribed to the decrease in activation energy, misfit between γ/γ′ phase lattice, the stacking fault energy as well as the fraction of γ′ phase at elevated temperature after adding Co.

Graphical abstract

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Topical Botanical Agents for the Treatment of Psoriasis: A Systematic Review

Abstract

Background

Patients with psoriasis often enquire about the use of numerous botanical therapeutics. It is important for dermatologists to be aware of the current evidence regarding these agents.

Methods

We conducted a systematic literature search using the PubMed, MEDLINE, and EMBASE databases for controlled and uncontrolled clinical trials that assessed the use of topical botanical therapeutics for psoriasis. The search included the following keywords: 'psoriasis' and 'plant' or 'herbal' or 'botanical'. We also reviewed citations within articles to identify additional relevant sources. We then further refined the results by route of administration and the topical botanical agents are reviewed herein.

Results

A total of 27 controlled and uncontrolled clinical trials addressing the use of topical botanical agents for psoriasis were assessed in this review. We found that the most highly studied and most efficacious topical botanical therapeutics were Mahonia aquifolium, indigo naturalis, aloe vera, and, to a lesser degree, capsaicin. The most commonly reported adverse effects were local skin irritation, erythema, pruritus, burning, and pain. However, the overall evidence for these therapeutics remains limited in quantity and quality.

Conclusion

The literature addresses a large number of studies in regard to botanicals for the treatment of psoriasis. While most agents appear to be safe, further research is necessary before topical botanical agents can be consistently recommended to patients.

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Avoiding Facial Incisions with Midface Free Tissue Transfer

Background: We have adopted an intraoral microsurgical anastomosis to the facial vessels to eliminate the need for any visible facial incisions. Methods: Cadaveric dissection was used to demonstrate accessibility of the facial artery and vein through an intraoral approach. Additionally, 5 patients underwent free tissue transfer for reconstruction of major defects of the midface through an intraoral, transmucosal approach, obviating the need for visible skin incisions. Results: The pathology included palatal defects due to mucoepidermoid carcinoma and ischemic necrosis from cocaine abuse, maxillary defects secondary to fibrous dysplasia and avascular necrosis from traumatic blast injury, and a residual posttraumatic bony deformity of the zygoma. Reconstructions were performed with a free ulnar forearm flap, a free vastus lateralis muscle flap, a deep circumflex iliac artery myoosseous flap, a free fibula flap, and a deep circumflex iliac artery osseous flap, respectively. The facial artery and vein were used as recipient vessels for microvascular anastomosis for all cases. Mean follow-up was 12.2 months. All free tissue transfers were successful, and each patient had a satisfactory aesthetic outcome with no associated facial scars. Conclusion: This technique can be employed during reconstruction of an array of bony or soft-tissue midface deficits with minimal morbidity. This small series effectively demonstrates the varied pathologies and tissue deficiencies that can be successfully reconstructed with free tissue transfer using an entirely intraoral approach to the recipient facial vessels, resulting in no visible scars on the face and an improvement in the overall aesthetic outcome.

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Comments on: “Intralipotherapy, the State of the Art”

No abstract available

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RNA Chromogenic in situ Hybridization Assay with Clinical Automated Platform is a Sensitive Method in Detecting High-risk Human Papillomavirus in Squamous Cell Carcinoma

Publication date: Available online 14 March 2017
Source:Human Pathology
Author(s): Javier E. Mendez-Pena, Peter M. Sadow, Vania Nose, Mai P. Hoang
Detection of active human papillomavirus (HPV) is clinically important, as its presence has been shown to correlate with favorable clinical outcomes and better response to treatment in oropharyngeal squamous cell carcinomas (SCC). Using a clinical automated platform, we compared the performance of commercially available HPV DNA and RNA in situ hybridization (ISH) probes in archival tissues of 57 SCC. Importantly, a clinical automated platform gives 1) consistent and reproducible results for HPV ISH and 2) better standardization across clinical laboratories. Compared to polymerase chain reaction (PCR) results, RNA ISH exhibited 93% concordance versus 81% of DNA ISH. RNA ISH was more sensitive than DNA ISH (100% versus 88%), and more specific (87% versus 74%). When only accounting for 2–3+ positivity, sensitivity was 92% for RNA ISH versus 73% for DNA ISH, highlighting the ease of interpretation. p16 exhibited 96% sensitivity while specificity was only 55%. In 3 cases both RNA and DNA ISH were positive while PCR results were negative, suggesting that ISH methods might be a more sensitive method. Performing on a clinical automated platform, RNA ISH is sensitive in determining high-risk HPV status in formalin-fixed paraffin-embedded tissues and has the potential of being a standalone clinical test.



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MCM2 expression in serrated polyps demonstrates aberrant cellular proliferation

Publication date: Available online 14 March 2017
Source:Human Pathology
Author(s): Danielle Fortuna, Bruce Boman, Raymond O'Neil, Juan Palazzo
In normal colonic epithelium, the proliferative zone is limited to the lower half of the colonic crypt. Evaluating the changes in the colonic epithelial proliferation can be useful in understanding pathophysiology of various diseases. Our aim was to investigate the proliferative compartment of serrated polyps (SPs) using MCM2, a protein involved in DNA replication, and assess for changes along the SP spectrum. Immunohistochemistry was performed on serrated polyps (16 microvesicular-type hyperplastic polyps (HP), 58 sessile serrated adenomas (SSA), seven SSAs with dysplasia) and six sections of normal colon using anti-MCM2 antibody. Multiple sections of normal colon showed the following pattern for MCM2 and Ki-67 staining: positive nuclear staining of the lower half of the colonic crypts and/or slightly expanded to the lower two-thirds of the crypt. By MCM2, SPs show expansion of the proliferative compartments. 81.3% of HPs and 100% of SSAs showed some degree of full crypt MCM2 staining. SSAs with dysplasia showed consistent diffuse polyp staining. Aberrant staining in adjacent normal mucosa was also seen in SSAs with dysplasia and in a subset of non-dysplastic SSAs. By using MCM2, we show that serrated polyps exhibit changes in proliferation during progression along the pathway. HPs and SSAs show a similar highly proliferative profile. Aberrant proliferative cell staining patterns in adjacent normal colonic mucosa as seen in SSAs with dysplasia and a subset of SSAs suggest a field effect phenomenon. This indicates that changes in the colonic micro-environment may promote adenoma morphogenesis and predisposition to malignancy.



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Discovery of (2-aminophenyl)methanol as a new molecular chaperone that rescues the localization of P123S mutant pendrin stably expressed in HEK293 cells

Publication date: Available online 14 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Wataru Nabeyama, Kenji Ishihara, Hyun Seung Ban, Hiroshi Wada, Hiroyuki Nakamura
Pendred syndrome is the most common form of syndromic deafness. It is associated with a mutation in the SLC26A4 gene that encodes pendrin, which is thought to maintain the ion concentration of endolymph in the inner ear most likely by acting as a chloride/bicarbonate transporter. Mutations in the SLC26A4 gene are responsible for sensorineural hearing loss. In this study, we established a stable HEK293 cell line expressing P123S mutant pendrin and developed screening methods for compounds that show pharmacological chaperone activity by image analysis using CellInsight^TM. Morphological analysis of stained cells in each well of 96-well plates yielded six compounds in the compound library. Furthermore, fluorescence intensity analysis of the intracellular localization of P123S mutant pendrin in HEK293 cells using FLUOVIEW^TM and cytotoxicity experiments revealed that (2-aminophenyl)methanol 8 is the most promising molecular chaperone to rescue P123S mutant pendrin: the plasma membrane (M)/cytoplasm (C) ratios are 1.5 and 0.9 at the concentrations of 0.3 and 0.1 mM, respectively, and a sustained effect was observed 12 h after removal of the compound from the cell medium. Because the M/C ratio of salicylate, which was previously discovered as a molecular chaperone of P123S mutant pendrin, was approximately 1 at 10 mM concentration and a sustained effect was not observed even at 6 h, (2-aminophenyl)methanol 8 was 100 times more potent and exhibited a longer sustained effect than salicylate. These findings suggest that (2-aminophenyl)methanol 8 is an attractive candidate for therapeutic agent for Pendred syndrome patients.

Graphical abstract

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Novel pyrazolo[1,5-a]pyridines as orally active EP1 receptor antagonists: synthesis, structure-activity relationship studies, and biological evaluation

Publication date: Available online 14 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kentaro Umei, Yosuke Nishigaya, Atsushi Kondo, Kazuya Tatani, Nobuyuki Tanaka, Yasushi Kohno, Shigeki Seto
Novel pyrazolo[1,5-a]pyridine derivatives were designed, synthesized and evaluated as orally active EP1 antagonists for the treatment of overactive bladder. Matched molecular pair analysis (MMPA) allowed the design of a new series of pyrazolo[1,5-a]pyridine derivatives 4-6. Structure-activity relationships (SAR) studies of 4-6 were performed, leading to identification of the nanomolar-level EP1 antagonist 4c, which exhibited good pharmacological effect through intraduodenal (id) administration in a 17-phenyltrinor prostaglandin E2-induced bladder contraction model in rats.

Graphical abstract

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National Radiation Oncology Survey on Palliative Care Education in Radiation Oncology Training

Publication date: Available online 14 March 2017
Source:Practical Radiation Oncology
Author(s): Monica Krishnan, Margarita Racsa, Joshua Jones, Eva Chittenden, Kristen G. Schaefer, Alex Spektor, Andrea Enzinger, Randy Wei, Tracy Balboni
PurposeWhile palliative care is recognized as integral to oncology care, limited data exists regarding the extent to which palliative care training is incorporated into radiation oncology residency training in the United States (US). We aim to characterize US radiation oncology residents' perceived palliative care educational needs and experience to guide future palliative oncology educational interventions.MethodsAn 8-person expert panel developed a survey to assess resident perceptions of generalist palliative care education within radiation oncology residency. Domains of palliative oncology education, derived from national guidelines, included: symptom management (pain and non-pain), communication about goals of care, advance care planning, psychosocial issues, cultural considerations, spiritual needs, care coordination, and ethical/legal issues. Residents rated adequacy of their training and their perceived competency in each domain. A total of 433U.S. radiation oncology residents were identified for participation; 404 completed the survey (response rate=93%).ResultsResidents characterized themselves as "not at all/minimally/somewhat confident" in their ability to take care of patients with palliative care issues in the following domains: symptom management (36% pain, 44% non-pain), communication about goals of care (31%), advance care planning (48%), psychosocial (55%), cultural (22%), spiritual (44%), care coordination (50%), and ethical/legal (50%).On average, 79% of residents rated their training as "not/minimally/somewhat" adequate across all domains. Most (96%) view palliative care as an important competency within radiation oncology and 81% desire more palliative care education.ConclusionAlthough the majority of residents view palliative care as an important competency for radiation oncologists, a majority perceived their educational training as inadequate across multiple domains. Most residents desire further palliative oncology care training. These findings suggest efforts should be made to improve palliative care education during radiation oncology training.



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