Beyond the Paradigm: Combining Mass Spectrometry and Nuclear Magnetic Resonance for Metabolomics

Publication date: Available online 11 January 2017
Source:Progress in Nuclear Magnetic Resonance Spectroscopy
Author(s): Darrell D. Marshall, Robert Powers
Metabolomics is undergoing tremendous growth and is being employed to solve a diversity of biological problems from environmental issues to the identification of biomarkers for human diseases. Nuclear magnetic resonance (NMR) and mass spectrometry (MS) are the analytical tools that are routinely, but separately, used to obtain metabolomics data sets due to their versatility, accessibility, and unique strengths. NMR requires minimal sample handling without the need for chromatography, is easily quantitative, and provides multiple means of metabolite identification, but is limited to detecting the most abundant metabolites (⩾ 1 μM). Conversely, mass spectrometry has the ability to measure metabolites at very low concentrations (femtomolar to attomolar) and has a higher resolution (∼10³-10⁴) and dynamic range (∼10³-10⁴), but quantitation is a challenge and sample complexity may limit metabolite detection because of ion suppression. Consequently, liquid chromatography (LC) or gas chromatography (GC) is commonly employed in conjunction with MS, but this may lead to other sources of error. As a result, NMR and mass spectrometry are highly complementary, and combining the two techniques is likely to improve the overall quality of a study and enhance the coverage of the metabolome. While the majority of metabolomic studies use a single analytical source, there is a growing appreciation of the inherent value of combining NMR and MS for metabolomics. An overview of the current state of utilizing both NMR and MS for metabolomics will be presented.

Graphical abstract

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Molecular biomarkers to predict response to neoadjuvant chemotherapy for bladder cancer

Publication date: Available online 11 January 2017
Source:Cancer Treatment Reviews
Author(s): Consuelo Buttigliero, Marcello Tucci, Francesca Vignani, Giorgio V. Scagliotti, Massimo Di Maio
Cystectomy is the gold standard for treatment of localized muscle-invasive bladder cancer. However, about 50% of patients develop metastases within 2 years after cystectomy and subsequently die for the disease. Neoadjuvant cisplatin-based chemotherapy before cystectomy improves the overall survival in patients with muscle-invasive bladder cancer, and pathological response to neoadjuvant treatment (downstaging to ⩽pT1 at cystectomy) is a strong predictor of better disease-specific survival. Nevertheless, some patients do not benefit from neoadjuvant therapy. The identification of reliable biomarkers that could enable the clinicians to identify patients who will really benefit from neoadjuvant chemotherapy is a major issue. This approach could lead to individualized therapy, in order to optimize the chance of response, avoiding the impact of neoadjuvant treatment on quality of life and the delay of cystectomy in non-responder patients. However, no molecular predictive biomarkers have shown clinical utility.This paper aims to review currently available data about biomarkers predictive of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.



http://ift.tt/2iEdK1r

Robust Estimation of Carotid Artery Wall Motion Using the Elasticity-based State-space Approach

Publication date: Available online 10 January 2017
Source:Medical Image Analysis
Author(s): Zhifan Gao, Huahua Xiong, Xin Liu, Heye Zhang, Dhanjoo Ghista, Wanqing Wu, Shuo Li
The dynamics of the carotid artery wall has been recognized as a valuable indicator to evaluate the status of atherosclerotic disease in the preclinical stage. However, it is still a challenge to accurately measure this dynamics from ultrasound images. This paper aims at developing an elasticity-based state-space approach for accurately measuring the two-dimensional motion of the carotid artery wall from the ultrasound imaging sequences. In our approach, we have employed a linear elasticity model of the carotid artery wall, and converted it into the state space equation. Then, the two-dimensional motion of carotid artery wall is computed by solving this state-space approach using the H∞ filter and the block matching method. In addition, a parameter training strategy is proposed in this study for dealing with the parameter initialization problem. In our experiment, we have also developed an evaluation function to measure the tracking accuracy of the motion of the carotid artery wall by considering the influence of the sizes of the two blocks (acquired by our approach and the manual tracing) containing the same carotid wall tissue and their overlapping degree. Then, we have compared the performance of our approach with the manual traced results drawn by three medical physicians on 37 healthy subjects and 103 unhealthy subjects. The results have showed that our approach was highly correlated (Pearson's correlation coefficient equals 0.9897 for the radial motion and 0.9536 for the longitudinal motion), and agreed well (width the 95% confidence interval is 89.62 μm for the radial motion and 387.26 μm for the longitudinal motion) with the manual tracing method. We also compared our approach to the three kinds of previous methods, including conventional block matching methods, Kalman-based block matching methods and the optical flow. Altogether, we have been able to successfully demonstrate the efficacy of our elasticity-model based state-space approach (EBS) for more accurate tracking of the 2-dimensional motion of the carotid artery wall, towards more effective assessment of the status of atherosclerotic disease in the preclinical stage.

Graphical abstract

http://ift.tt/2iey74i

A Framework for Analysis of Linear Ultrasound Videos to Detect Fetal Presentation and Heartbeat

Publication date: Available online 10 January 2017
Source:Medical Image Analysis
Author(s): M.A. Maraci, C.P. Bridge, R. Napolitano, A. Papageorghiou, J.A. Noble
Confirmation of pregnancy viability (presence of fetal cardiac activity) and diagnosis of fetal presentation (head or buttock in the maternal pelvis) are the first essential components of ultrasound assessment in obstetrics. The former is useful in assessing the presence of an on-going pregnancy and the latter is essential for labour management. We propose an automated framework for detection of fetal presentation and heartbeat from a predefined free-hand ultrasound sweep of the maternal abdomen. Our method exploits the presence of key anatomical sonographic image patterns in carefully designed scanning protocols to develop, for the first time, an automated framework allowing novice sonographers to detect fetal breech presentation and heartbeat from an ultrasound sweep. The framework consists of a classification regime for a frame by frame categorization of each 2D slice of the video. The classification scores are then regularized through a conditional random field model, taking into account the temporal relationship between the video frames. Subsequently, if consecutive frames of the fetal heart are detected, a kernelized linear dynamical model is used to identify whether a heartbeat can be detected in the sequence. In a dataset of 323 predefined free-hand videos, covering the mother's abdomen in a straight sweep, the fetal skull, abdomen, and heart were detected with a mean classification accuracy of 83.4%. Furthermore, for the detection of the heartbeat an overall classification accuracy of 93.1% was achieved.

Graphical abstract

http://ift.tt/2iepDKw

Remarks about “A pediatric patient of hemorrhagic acute transverse myelitis”

Publication date: Available online 11 January 2017
Source:Brain and Development
Author(s): Daniele Coraci, Valter Santilli, Silvia Giovannini, Luca Padua




http://ift.tt/2j4x4YL

Reply to the remarks about “A pediatric patient of hemorrhagic acute transverse myelitis”

Publication date: Available online 11 January 2017
Source:Brain and Development
Author(s): Masataka Fukuoka, Ichiro Kuki, Hisashi Kawawaki, Kiyohiro Kim, Yuka Hattori, Hitomi Tsuji, Asako Horino, Megumi Nukui, Shin Okazaki




http://ift.tt/2jhnUWJ

Bilateral blepharoptosis in a juvenile

Publication date: Available online 10 January 2017
Source:Brain and Development
Author(s): Hiroshi Yamaguchi, Tsukasa Tanaka, Daisaku Toyoshima, Azusa Maruyama, Akihiro Ichinose, Hiroaki Nagase
In adults, aponeurotic blepharoptosis is the most common type of ptosis. However, myogenic ptosis is the predominant cause, and bilateral aponeurotic ptosis is very rare among children. Here, we report a previously healthy 10-year-old Japanese girl with bilateral aponeurotic blepharoptosis who presented initially with bilateral blepharoptosis for about 4years. This case report shows that history taking and careful observation of the patient lead to an accurate diagnosis, and aponeurotic ptosis should be considered in the differential diagnosis of bilateral blepharoptosis among children.



http://ift.tt/2j4bWlt

Epigenetic modifications and epigenetic based medication implementations of autoimmune diseases

Publication date: March 2017
Source:Biomedicine & Pharmacotherapy, Volume 87
Author(s): Majid Ahmadi, Tohid Gharibi, Sanam Dolati, Davood Rostamzadeh, Saeed Aslani, Behzad Baradaran, Vahid Younesi, Mehdi Yousefi
Recent genome-wide association studies have documented a number of genetic variants to explain mechanisms underlying autoimmune diseases. However, the precise etiology of autoimmune diseases remains largely unknown. Epigenetic mechanisms like alterations in the post-translational modification of histones and DNA methylation may potentially cause a breakdown of immune tolerance and the perpetuation of autoreactive responses. Recently, several studies both in experimental models and clinical settings proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in autoimmune diseases, in some cases based on mechanistical observations. Epigenetic therapy already being employed in hematopoietic malignancies may also be associated with beneficial effects in autoimmune diseases. In this review, we will discuss on what we know and expect about the treatment of autoimmune disease based on epigenetic aberrations.



http://ift.tt/2iDTwoC

Clinical effectiveness of low-level laser treatment on peripheral somatosensory neuropathy

Abstract

Peripheral sensory neuropathy treatment is one of the common treatment problems and causes morbidity and mortality in people suffering from that. Although treatment depends on the underlying cause of the condition, nevertheless, in some cases, there is no cure for it, and it requires palliative and symptomatic treatment. In laboratory studies, low-level laser has been effective in the nerves protection and restoration. The aim of this article is to investigate the clinical efficacy of low-level laser on improvement of the peripheral somatosensory neuropathy. Search in the articles published up to 30 October 2015 (full text and abstracts) in databases PubMed (Medline), Cochrane library, Physiotherapy Evidence Database was performed. The studies of low-level laser trials on patients with peripheral neuropathy were carried out and evaluated in terms of the exclusion criteria. There are 35 articles among which 10 articles had the intended and required criteria. 1, 3, and 6 articles study the patients with diabetes, neuropathy caused by trauma, and carpal tunnel syndrome, respectively. In six studies, laser led to a reduction in sensory impairment and improvement of the physiological function of the sensory nerves. In these articles, lasers (Diode, GaAlAs, He-Ne) had wavelength range 660–860 nm, radiation power 20–250 mW, energy density 0.45–70 J/cm². The intervention sessions range was 6–21 times and patient follow-up was 0–6 months. According to the results of these studies, low-level laser therapy can improve sensory function in patients with peripheral somatosensory neuropathy, although little research have not been done, laser treatment regimens are varied and do not recommend a specific treatment protocol. It seems it requires more research to sum up better, particularly in relation to diabetes.

http://ift.tt/2jh3Cwn

Clinical Thyroidology for the Public – Highlighted Article

From Clinical Thyroidology for the Public: Hypothyroidism (underactive thyroid) is very common, especially in women and is diagnosed most of the time by an increased TSH level. Read More….

The post Clinical Thyroidology for the Public – Highlighted Article appeared first on American Thyroid Association.

http://ift.tt/2jh9XIl

BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in peripheral nerve injury

Publication date: March 2017
Source:Biomaterials, Volume 121
Author(s): Cátia D.F. Lopes, Nádia P. Gonçalves, Carla P. Gomes, Maria J. Saraiva, Ana P. Pêgo
Neuron-targeted gene delivery is a promising strategy to treat peripheral neuropathies. Here we propose the use of polymeric nanoparticles based on thiolated trimethyl chitosan (TMCSH) to mediate targeted gene delivery to peripheral neurons upon a peripheral and minimally invasive intramuscular administration. Nanoparticles were grafted with the non-toxic carboxylic fragment of the tetanus neurotoxin (HC) to allow neuron targeting and were explored to deliver a plasmid DNA encoding for the brain-derived neurotrophic factor (BDNF) in a peripheral nerve injury model. The TMCSH-HC/BDNF nanoparticle treatment promoted the release and significant expression of BDNF in neural tissues, which resulted in an enhanced functional recovery after injury as compared to control treatments (vehicle and non-targeted nanoparticles), associated with an improvement in key pro-regenerative events, namely, the increased expression of neurofilament and growth-associated protein GAP-43 in the injured nerves. Moreover, the targeted nanoparticle treatment was correlated with a significantly higher density of myelinated axons in the distal stump of injured nerves, as well as with preservation of unmyelinated axon density as compared with controls and a protective role in injury-denervated muscles, preventing them from denervation. These results highlight the potential of TMCSH-HC nanoparticles as non-viral gene carriers to deliver therapeutic genes into the peripheral neurons and thus, pave the way for their use as an effective therapeutic intervention for peripheral neuropathies.



http://ift.tt/2ibqHPt

Targeted delivery of in situ PCR-amplified Sleeping Beauty transposon genes to cancer cells with lipid-based nanoparticle-like protocells

Publication date: March 2017
Source:Biomaterials, Volume 121
Author(s): Kun Ma, Duo Fu, Dongli Yu, Changhao Cui, Li Wang, Zhaoming Guo, Chuanbin Mao
A Sleeping Beauty (SB) transposon system is made of a transposon plasmid (containing gene encoding a desired functional or therapeutic protein) and a transposase plasmid (encoding an enzyme capable of cutting and pasting the gene into the host cell genome). It is a kind of natural, nonviral gene delivery vehicle, which can achieve efficient genomic insertion, providing long-term transgenic expression. However, before the SB transposon system could play a role in promoting gene expression, it has to be delivered efficiently first across cell membrane and then into cell nuclei. Towards this end, we used a nanoparticle-like lipid-based protocell, a closed bilayer of the neutral lipids with the DNA encapsulated inside, to deliver the SB transposon system to cancer cells. The SB transposon system was amplified in situ inside the protocells by a polymerase chain reaction (PCR) process, realizing more efficient loading and delivery of the target gene. To reach a high transfection efficiency, we introduced two targeting moieties, folic acid (FA) as a cancer cell-targeting motif and Dexamethasone (DEX) as a nuclear localization signaling molecule, into the protocells. As a result, the FA enabled the modified targeting protocells to deliver the DNA into the cancer cells with an increased efficiency and the DEX promoted the DNA to translocate to cell nuclei, eventually leading to the increased chromosome insertion efficiency of the SB transposon. In vivo study strongly suggested that the transfection efficiency of FA-modified protocells in the tumor tissue was much higher than that in other tissues, which was consistent with the in vitro results. Our studies implied that with the targeting ligand modification, the protocells could be utilized as an efficient targeting gene carrier. Since the protocells were made of neutral lipids without cationic charges, the cytotoxicity of protocells was significantly lower than that of traditional cationic gene carriers such as cationic liposomes and polyethylenimine, enabling the protocells to be employed in a wider dosage range in gene therapy. Our work shows that the protocells are a promising gene carrier for future clinical applications.



http://ift.tt/2idEfgx

Blood-brain barrier dysfunction induced by silica NPs in vitro and in vivo: Involvement of oxidative stress and Rho-kinase/JNK signaling pathways

Publication date: March 2017
Source:Biomaterials, Volume 121
Author(s): Xin Liu, Baiyan Sui, Jiao Sun
Silica nanoparticles (SiO2-NPs) has been extensively exploited in biomedical fields and mostly designed to enter the circulatory system, however, few studies focused on the potential adverse effects of SiO2-NPs exposure on the blood-brain barrier (BBB) that serves as a critical barrier between the central nervous system (CNS) and the peripheral circulation. This study attempts to provide an understanding of whether and how SiO2-NPs disrupts the BBB in vitro and in vivo. Through a human BBB model, we found that SiO2-NPs could induce tight junction loss and cytoskeleton arrangement, and increase inflammatory response and the release of vascular endothelial growth factor (VEGF) of brain microvessel endothelial cells (BMECs), which further activates astrocytes to amplify the generation of VEGF and increase the aquaporin-4 expression, and thus causing BBB disruption through a complex immunoregulatory loop between BMECs and astrocytes under SiO2-NPs exposure. Additionally, our data show that inhibition of reactive oxygen species (ROS) and Rho-kinase (ROCK) could effectively protect the SiO2-NPs-induced BBB dysfunction. In vivo studies further confirmed that SiO2-NPs could cause the BBB paracellular opening, oxidative stress and astrocyte activation in brains of Sprague–Dawley (SD) rats. These findings demonstrate that SiO2-NPs could disturb BBB structure and function and induce BBB inflammation, and suggest that these effects may occur through ROS and ROCK-mediated pathways, which not only improve neurotoxicity evaluation for SiO2-NPs but also provide useful information in development of SiO2-NPs in neuro-therapeutics and nanodiagnostics.



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In vitro evaluation of biodegradable lignin-based nanoparticles for drug delivery and enhanced antiproliferation effect in cancer cells

Publication date: March 2017
Source:Biomaterials, Volume 121
Author(s): Patrícia Figueiredo, Kalle Lintinen, Alexandros Kiriazis, Ville Hynninen, Zehua Liu, Tomás Bauleth-Ramos, Antti Rahikkala, Alexandra Correia, Tomáš Kohout, Bruno Sarmento, Jari Yli-Kauhaluoma, Jouni Hirvonen, Olli Ikkala, Mauri A. Kostiainen, Hélder A. Santos
Currently, nanosystems have been developed and applied as promising vehicles for different biomedical applications. We have developed three lignin nanoparticles (LNPs): pure lignin nanoparticles (pLNPs), iron(III)-complexed lignin nanoparticles (Fe-LNPs), and Fe3O4-infused lignin nanoparticles (Fe3O4-LNPs) with round shape, narrow size distribution, reduced polydispersity and good stability at pH 7.4. The LNPs showed low cytotoxicity in all the tested cell lines and hemolytic rates below 12% after 12 h of incubation. Additionally, they induced hydrogen peroxide production in a small extent and time-dependent manner, and the interaction with the cells increased over time, exhibiting a dose-dependent cell uptake. Concerning the drug loading, pLNPs showed the capacity to efficiently load poorly water-soluble drugs and other cytotoxic agents, e.g. sorafenib and benzazulene (BZL), and improve their release profiles at pH 5.5 and 7.4 in a sustained manner. Furthermore, the BZL-pLNPs presented an enhanced antiproliferation effect in different cells compared to the pure BZL and showed a maximal inhibitory concentration ranging from 0.64 to 12.4 μM after 24 h incubation. Overall, LNPs are promising candidates for drug delivery applications, and the superparamagnetic behavior of Fe3O4-LNPs makes them promising for cancer therapy and diagnosis, such as magnetic targeting and magnetic resonance imaging.



http://ift.tt/2idKd17

Correlation between Antigenicity and Variability in the vls Antigenic Variation System of Borrelia burgdorferi

Publication date: Available online 10 January 2017
Source:Microbes and Infection
Author(s): Wei Zhou, Dustin Brisson
Many parasites have evolved antigenic variation systems that alter surface proteins in order to evade recognition by presently expressed antibodies and subsequent death. Although the amino acid positions in antigens to which antibodies most commonly target are expected to be the most variable, this assumption has not been investigated. Using the vls antigenic variation system of Borrelia burgdorferi as a model, we first investigated this assumption computationally and then developed a sensitive immunoassay to experimentally validate the computational results. There was a strong correlation between variability at an amino acid position and each of the computational metrics associated with antibody reactivity. However, empirical measures of antibody reactivity were not consistently greater at the variable amino acid positions than at the invariant amino acid positions. The inconsistent experimental support for this hypothesis suggests that the biological effect of variability at an amino acid position is obfuscated by other factors.



http://ift.tt/2jgZP29

An observational study of phagocytes and Klebsiella pneumoniae relationships: different behaviors

Publication date: Available online 10 January 2017
Source:Microbes and Infection
Author(s): Elodie Maisonneuve, Estelle Cateau, Marion Delouche, Nathalie Quellard, Marie-Helene Rodier
Klebsiella pneumoniae is a bacterium that can be in relation with free living amoebae like Acanthamoeba castellanii in natural environments such as soil and water. This pathogen, which is responsible for community-acquired pneumonia and for nosocomial infections, also has interactions with host defence mechanisms like macrophages. As it has been shown that A. castellanii shares some traits with macrophages, in particular the ability to phagocyte bacteria, we have studied the uptake and the fate of the bacteria after contact with the two phagocytic cells. In our conditions, K. pneumoniae growth was increased in coculture in presence of A. castellanii or Thp-1 macrophagic cells and bacterial development was also increased by A. castellanii supernatant. In addition, we showed that the presence of the bacteria had a negative effect on the macrophages whereas it does not affect amoeba viability. Using gentamicin, which kills bacteria outside cells, we showed that only macrophages were able to internalize K. pneumoniae. This result was confirmed by electron microscopy. We have consequently reported some differences in bacterial uptake and internalization between a free living amoeba and macrophagic cells, highlighting the fact that results obtained with this amoebal model should not be extrapolated to the relationships between K. pneumoniae and macrophages.



http://ift.tt/2j3Z8Ma

The impact of ISGylation during Mycobacterium tuberculosis infection in mice

Publication date: Available online 10 January 2017
Source:Microbes and Infection
Author(s): Jacqueline M. Kimmey, Jessica A. Campbell, Leslie A. Weiss, Kristen J. Monte, Deborah J. Lenschow, Christina L. Stallings
Mycobacterium tuberculosis infection results in 1.5 million deaths annually. Type I interferon (IFN) signaling through its receptor IFNAR correlates with increased severity of disease, although how this increases susceptibility to M. tuberculosis remains uncertain. ISG15 is one of the most highly induced interferon stimulated genes (ISGs) during M. tuberculosis infection. ISG15 functions by conjugation to target proteins (ISGylation), by noncovalent association with intracellular proteins, and by release from the cell. Recent studies indicated that ISG15 can function via conjugation-independent mechanisms to suppress the type I IFN response. These data raised the question of whether ISG15 may have diverse and sometimes opposing functions during M. tuberculosis infection. To address this, we analyzed ISGylation during M. tuberculosis infection and show that ISGylated proteins accumulate following infection in an IFNAR-dependent manner. Type I IFN and ISG15 both play transient roles in promoting bacterial replication. However, as the disease progresses, ISGylation deviates from the overall effect of type I IFN and, ultimately, mice deficient in ISGylation are significantly more susceptible than IFNAR mice. Our data demonstrate that ISGs can both protect against and promote disease and are the first to report a role for ISGylation during M. tuberculosis infection.



http://ift.tt/2jh3RYd

Synthesis and characterization of gold nanostructured Chorin e6 for Photodynamic Therapy

Publication date: Available online 10 January 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): L. Vieira, M.L. Castilho, I. Ferreira, J. Ferreira-Strixino, K.C. Hewitt, L. Raniero
Photodynamic therapy is an alternative treatment for cancer based on cellular uptake of a photosensitizer, illuminated with an appropriate wavelength in the presence of oxygen. A cascade of reactions generates reactive oxygen species leading to cell death. Using carbodiimide chemistry, chlorin e6 (Ce6) was covalently bonded to thiourea, and (via the sulphur end group) to gold nanoparticles (AuNPs), forming the Ce6-AuNP complex. Ce6 absorbs in the range 650–680nm, where the coefficient of biological tissue absorption is low (part of the therapeutic window), which is ideal for biological application. Transmission Electron Microscopy, UV–vis spectroscopy, Fourier transform Infrared Spectroscopy and Zeta potential measurements were completed to characterize the Ce6-AuNP complex. The bare AuNPs have an average diameter of 18±4nm. A line of human breast carcinoma cells (MDA-MB-468) were used to determine whether Ce6 functionalization to AuNPs potentiate its activity. Trypan blue assays were used to assess cell viability. In the absence of light, Ce6 either alone or bounded to AuNPs was not cytotoxic. When irradiated at 660nm, the cytotoxicity of Ce6-AuNP was higher than Ce6 alone for MDA-MB-468 cells using 4h incubation. AuNPs without Ce6 showed no cytotoxic.



http://ift.tt/2ielczo

Thyroid hormones induce browning of white fat

The canonical view about the effect of thyroid hormones (THs) on thermogenesis assumes that the hypothalamus acts merely as a modulator of the sympathetic outflow on brown adipose tissue (BAT). Recent data have challenged that vision by demonstrating that THs act on the ventromedial nucleus of the hypothalamus (VMH) to inhibit AMP-activated protein kinase (AMPK), which regulates the thermogenic program in BAT, leading to increased thermogenesis and weight loss. Current data have shown that in addition to activation of brown fat, the browning of white adipose tissue (WAT) might also be an important thermogenic mechanism. However, the possible central effects of THs on the browning of white fat remain unclear. Here, we show that 3,3',5,5' tetraiodothyroxyne (T₄)-induced hyperthyroidism promotes a marked browning of WAT. Of note, central or VMH-specific administration of 3,3',5-triiodothyronine (T₃) recapitulates that effect. The specific genetic activation of hypothalamic AMPK in the VMH reversed the central effect of T₃ on browning. Finally, we also showed that the expression of browning genes in human WAT correlates with serum T₄. Overall, these data indicate that THs induce browning of WAT and that this mechanism is mediated via the central effects of THs on energy balance.

http://ift.tt/2jBGj3I

Coreference and Antecedent Representation Across Languages.

Author: Lago, Sol; Sloggett, Shayne; Schlueter, Zoe; Chow, Wing Yee; Williams, Alexander; Lau, Ellen; Phillips, Colin

DOI: 10.1037/xlm0000343

Publication Date: POST AUTHOR CORRECTIONS, 9 January 2017

http://ift.tt/2ih8IKy

Using Perspective to Resolve Reference: The Impact of Cognitive Load and Motivation.

Author: Cane, James E.; Ferguson, Heather J.; Apperly, Ian A.

DOI: 10.1037/xlm0000345

Publication Date: POST AUTHOR CORRECTIONS, 9 January 2017

http://ift.tt/2jgW4cV

Cognitive Effort Is Modulated Outside of the Explicit Awareness of Conflict Frequency: Evidence From Pupillometry.

Author: Diede, Nathaniel T.; Bugg, Julie M.

DOI: 10.1037/xlm0000349

Publication Date: POST AUTHOR CORRECTIONS, 9 January 2017

http://ift.tt/2ih3DCa

Basic Composition and Enriched Integration in Idiom Processing: An EEG Study.

Author: Canal, Paolo; Pesciarelli, Francesca; Vespignani, Francesco; Molinaro, Nicola; Cacciari, Cristina

DOI: 10.1037/xlm0000351

Publication Date: POST AUTHOR CORRECTIONS, 9 January 2017

http://ift.tt/2jgZso6

Our Moral Choices Are Foreign to Us.

Author: Corey, Joanna D.; Hayakawa, Sayuri; Foucart, Alice; Aparici, Melina; Botella, Juan; Costa, Albert; Keysar, Boaz

DOI: 10.1037/xlm0000356

Publication Date: POST AUTHOR CORRECTIONS, 9 January 2017

http://ift.tt/2ih4ItG

The perfusion code of DIEP and ms-TRAM flaps is a hard nut to crack

We read with interest the article by Ludolph et al. entitled "Cracking the perfusion code?: Laser-assisted Indocyanine Green angiography and combined laser Doppler spectrophotometry for intraoperative evaluation of tissue perfusion in autologous breast reconstruction with DIEP or ms-TRAM flaps".1 We completely agree with the authors that intraoperative evaluation of flap perfusion can still be challenging. Such is especially true in those cases where flaps are composed of several angiosomes as is usually the case with the DIEP and ms-TRAM flaps.

http://ift.tt/2ibhifu

Kinetics of early stages of resorcinol-formaldehyde polymerization investigated by solution-phase nuclear magnetic resonance spectroscopy

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Katarzyna Z. Gaca, John A. Parkinson, Jan Sefcik
Resorcinol and formaldehyde reactions were quantitatively monitored by means of ¹H and ¹³C NMR spectroscopy at room temperature (293 K) before heat treatment leading to formation of organic gels. We found that resorcinol substitution with formaldehyde starts with an initial surprisingly rapid step followed by a more gradual depletion of the reactants. Substituted species with both monomeric and dimeric hydroxymethyl groups were observed immediately after mixing of the reagents with the proportion of formaldehyde-based solution species consumed between 30 and 50%. Substituted resorcinol species can be all accounted for by solution-phase NMR at ambient conditions before they form nanoscale clusters upon heating. It can therefore be expected that the final properties of resorcinol-formaldehyde gels depend not only on the composition of reaction mixtures and duration of the high temperature treatment but also on the manner and period of reagent mixing (a hitherto overlooked synthesis step), as different amounts of alternatively substituted resorcinol can be produced before heat treatment commences.

Graphical abstract

http://ift.tt/2j3ySBr

Synthesis of emulsion-templated macroporous materials via Diels-Alder polymerization

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Chenchen Xiao, Yun Zhu, Jianding Chen, Shengmiao Zhang
Emulsion-templated macroporous materials, known in the literature for many years as polyHIPEs, have found an increasing number of applications due to their well-defined structures. However, most of the emulsion-templated materials are synthesized using conventional radical polymerization, and most of the radical polymerization are thermally initiated. Expanding the polymerization mechanisms available for emulsion-templated material synthesis is still highly desired. In this work, macroporous polymers were firstly synthesized by Diels-Alder reaction of furan derivatives and bismaleimide within the continuous phase of particle-stabilized emulsions. These polymers have a well-defined controllable porous structure and good self-healing performance.

Graphical abstract

http://ift.tt/2j3JDUu

Facile fabrication of core-shell polyelectrolyte complexes nanofibers based on electric field induced phase separation

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Haoqin Ma, Guangkai Chen, Jingnan Zhang, Yong Liu, Jun Nie, Guiping Ma
The core-shell polyelectrolyte complexes chitosan (CS)/hyaluronic acid (HA) nanofibers could be produced from electric field inducing phase separation during the progress of electrospinning. The morphology of core-shell nanofibers was supported using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The presence of CS on the shell of the nanofibers was also verified by X-ray photoelectron spectroscopy (XPS) analysis as further evidence of core-shell formation. In the electrospinning process, the protonated CS molecules migrated in the direction of the electric field, whereas the ionized HA molecules migrated in the opposite direction. Methylthiazolydiphenyl-tetrazolium bromide (MTT) assay was employed to investigate the toxic and cytocompatibility with the possible application for tissue engineering scaffolds. The drug release from core–shell nanofiber in vitro was investigated by UV spectrophotometry. The release profiles for core–shell nanofibers showed more controlled and sustained release. while fibroblasts cells could still adhere to and proliferate on the drug-loaded core–shell nanofiber membranes. The results implied that core-shell polyelectrolyte complexes CS/HA nanofibers encapsulating drugs have great potential in tissue engineering scaffolds.

Graphical abstract

http://ift.tt/2jsPlMx

Synthesis and characterization of biodegradable multiblock poly(carbonate-co-esters) containing biobased monomer

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Cai Xiaodong, Yang Xiangui, Wang Gongying
Multiblock poly(carbonate-co-esters) (PBC-PBSe) containing poly(butylene carbonates) (PBC) and poly(butylene sebacate) (PBSe) were synthesized successfully via chain-extension of dihydroxyl terminated PBC (PBC-OH) and PBSe (PBSe-OH) using 1,6-hexmethylene diisocyanate (HDI) as chain extender. The chemical structures, molecular weights, crystallization behaviors, thermal, degradation as well as mechanical properties of the copolyesters were characterized by Proton nuclear magnetic resonance spectroscopy (¹H NMR), Fourier transform infrared spectroscopy (FT-IR), Gel permeation chromatography (GPC), Differential scanning calorimetry (DSC), Thermogravimetry analysis (TGA), hydrolytic degradation and mechanical testing, respectively. The results indicated that the introduction of PBSe segment not only significantly enhanced the crystallization rate of PBC, but also displayed the same crystallization mechanism within the investigated crystallization temperature range despite of the variation of the PBSe segment content. Furthermore, the thermal stability and hydrolytic degradation rate of PBC-PBSe multiblock copolymers increases with increasing PBSe content. The mechanical properties of copolymers can be adjusted by changing the feed composition.

Graphical abstract

http://ift.tt/2jsT3pm

Coil-helix-globule transition for self-attractive semiflexible ring chains

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Zhiyong Yang, Zheyu Deng, Linxi Zhang
An off-lattice dynamics Monte Carlo method is used to study the conformations of self-attractive semiflexible ring chains. The conformations depend mainly on the bending energy b and the self-attractive interaction ε of ring chains, and perfect helical structures are found in self-attractive semiflexible ring chains with the moderate attractive interaction ε. Some monomers of the semiflexible ring chains wrap around the linearly aligned monomers and the size of helix is independent of chain length of ring chains. Coil-helix-globule transition occurs when the self-attractive interaction increases within semiflexibe ring chains, and the phase transition is attributed to the competition among the configurational entropy, the bending energy, and the self-attractive interaction. This study can help us understand the effects of topological constraints on the conformations and dynamical behaviors of polymer chains, and the importance of chain stiffness in biological systems and in the dynamics of DNA and protein folding.

Graphical abstract

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Novel shape memory behaviour in IPDI based polyurethanes: Influence of nanoparticle

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Satyam Srivastava, Arpan Biswas, Sudipta Senapati, Biswajit Ray, Dipak Rana, Vinod K. Aswal, Pralay Maiti
A diverse nanostructure, key to property alteration, has been observed by the insertion of two dimensional nanoparticles through in-situ polymerization. Self-assembly at the molecular level has been revealed starting from nanoscale to observable microscale in thermoplastic polyurethane using alicyclic diisocyanate and how the self-assembly behaviour changes in presence of nanoparticle. Varying dispersion of nanoparticles observed using two different fillers has been explained from the interactions point of view through spectroscopic techniques. Thermal stability and unique crystallization behaviour have been reported in presence of nanoparticles. Better dispersion of nanofillers within the matrix offers greater number of nucleating site which enhances the ordering of the polymer chains, also supported by the semi-empirical calculation. The effect of modulated nanostructure and self-assembly augmented the shape memory behaviour in polyurethanes having alicyclic diisocyanate. Enhanced shape recovery has been observed in presence of organically modified clay as opposed to layered double hydroxide. The reason for this improved shape memory behaviour in nanohybrid is explained from the exclusive crystallization of the soft segment domain leading to a proposed model for shape recovery. Finally, the recovery of different shapes (coil, spinal and straight strip) at physiological temperature (37 °C) has been demonstrated, added advantage of these materials to be used in the biomedical applications.

Graphical abstract

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One-step synthesis of PHEMA hydrogel films capable of generating highly ordered wrinkling patterns

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): Jianjun Gu, Xiaoyun Li, Hancheng Ma, Ying Guan, Yongjun Zhang
Poly(2-hydroxyethyl methacrylate) (PHEMA) films with gradient crosslinking density are the only hydrogel films capable of generating regular wrinkling patterns upon swelling, however, they were synthesized via a complicated two-stage photopolymerization. In an effort to develop a simple synthesis method, we found that one-step UV-curing of HEMA liquid always results in films with corrugated surface, which is a common issue when curing liquid prepolymers. We further found that the introduction of a physical network in the prepolymer solution could prevent the surface from corrugating during UV curing. For this purpose, linear PHEMA was added into the prepolymer solutions, and PHEMA films with a smooth surface were successfully synthesized by a simple one-step UV curing. The resulting films generate various swelling-induced wrinkling patterns, including random worms, peanuts and long-range ordered hexagons, depending on the contents of crosslinker and linear PHEMA in the prepolymer solution. Particularly, large area, highly ordered, honeycomb-like wrinkling patterns were obtained from films with proper content of crosslinker and linear PHEMA. These regular patterns are expected to find applications such as the fabrication of uniform multicellular spheroids.

Graphical abstract

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Preparation of stable poly(methacrylic acid)-b-polystyrene emulsion by emulsifier-free emulsion iodine transfer polymerization (emulsion ITP) with self-assembly nucleation

Publication date: 10 February 2017
Source:Polymer, Volume 110
Author(s): S. Sue-eng, T. Boonchuwong, P. Chaiyasat, M. Okubo, A. Chaiyasat
Emulsifier-free emulsion iodine transfer polymerization (emulsion ITP) of styrene with self-assembly nucleation was successfully carried out with some living features for the first time as follows. Firstly, poly(methacrylic acid) (PMAA; degree of polymerization, 37)-iodide (PMAA37-I) as a macro chain transfer agent was synthesized by solution reversible chain transfer catalyzed polymerization (solution RTCP) with 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) as an initiator, iodoform as a chain transfer agent and germanium iodide as a catalyst in dioxane at 40 °C. A dioxane solution of PMAA37-I and styrene were added stepwisely under stirring into an aqueous solution (pH∼9), and then emulsion ITP was initiated by adding 4,4′-azobis(4-cyanopentanoic acid) at 60 °C with stirring at 500 rpm. Stable polystyrene emulsion was obtained without coagulation. At 100% conversion, the number-average diameter was 223 nm. Number-average molecular weight (Mn) increased linearly with conversion, which were well closed to theoretical Mn and molecular weight distribution at 100% conversion was comparatively narrow (Mw/Mn∼2.1).

Graphical abstract

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In vitro oral bioaccessibility and total content of Cu, Fe, Mn and Zn from transgenic (through cp4 EPSPS gene) and nontransgenic precursor/successor soybean seeds

Publication date: 15 June 2017
Source:Food Chemistry, Volume 225
Author(s): Mónica A. Herrera-Agudelo, Manuel Miró, Marco A.Z. Arruda
In this paper, Cu, Fe, Mn and Zn contents in transgenic (T – MSOY7122RR) and non-transgenic (NT – MSOY8200) soybean seeds, sown at summer and winter cultivation periods are investigated using four microwave decomposition methods. Student's t tests demonstrate significant differences (p=0.05; n=4), for Cu, Mn and Zn (namely, 8, 9 and 26% higher concentrations in T compared to NT seeds, respectively). Through principal component analysis, precursor and successor soybean seeds are identified. Cu is demonstrated to play an important role in the differentiation of the cultivars, whereas Fe and Zn are of particular relevance in the classification of seeds cultivated in winter against those in summer. Using in vitro extraction based on the Unified Bioaccessibility Method, the bioaccessibility of the above nutrients is proven to differ in both the gastric and gastrointestinal phases on the basis of the transgenesis and the cultivation periods.



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Superplasticity of clad aluminium alloy

Publication date: May 2017
Source:Journal of Materials Processing Technology, Volume 243
Author(s): A.V. Mikhaylovskaya, A.G. Mochugovskiy, A.D. Kotov, O.A. Yakovtseva, M.V. Gorshenkov, V.K. Portnoy
Different Al-based alloys were evaluated as materials for cladding on a high-strength Al-Zn-Mg-Cu-Ni-Zr alloy with high-strain rate superplasticity. Clad sheets were fabricated by hot-roll bonding. Superplastic behaviour, mechanical properties at room temperature and corrosion properties of clad sheets were studied. The microstructure analysis and tensile results revealed that bonding was acceptable in the samples with cladding materials. The research revealed that the Al-Zn-Ca alloy provided good corrosion protection, superplasticity and a low decrease in the mechanical properties of cladded sheets.

Graphical abstract

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Safety and tolerability of pasireotide long-acting release in acromegaly—results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study

Abstract

Purpose

Pasireotide long-acting release is a somatostatin analog that is indicated for treatment of patients with acromegaly. This analysis documents the safety of pasireotide long-acting release in patients with acromegaly enrolled in the ACCESS trial (ClinicalTrials.gov identifier: NCT01995734).

Methods

ACCESS is an open-label, multicenter, single-arm, expanded-treatment protocol designed to provide patients access to pasireotide long-acting release pending regulatory approval. Patients received pasireotide long-acting release 40 mg administered intramuscularly every 28 days. The primary outcome was the proportion of patients having a treatment-emergent grade ≥3 or serious adverse event. Efficacy data were not collected.

Results

Forty-four adult patients with active acromegaly were enrolled in the study for an average of 37.6 weeks (range, 4–70 weeks). Twenty-five grade ≥3 treatment-emergent adverse events were reported in 11 patients (25.0 %), 3 of whom (27.3 %) experienced grade ≥3 hyperglycemia. In patients treated with pasireotide long-acting release for ≥3 months (n = 42), mean glycated hemoglobin and fasting plasma glucose levels increased significantly from 5.9 % and 100.4 mg/dL at baseline to 6.8 % and 135.9 mg/dL at 3 months, respectively. Ten patients (22.7 %) were treated with pasireotide long-acting release for ≥15 months, after which mean glycated hemoglobin and fasting plasma glucose levels were 6.3 % and 123 mg/dL, respectively. Twenty-one patients (48 %) initiated antidiabetic medication.

Conclusions

Grade ≥3 adverse events (primary outcome) were reported in 25.0 % of acromegaly patients treated with pasireotide long-acting release in a clinical setting. Hyperglycemia-related adverse events were reported in 45.5 % of patients, but were typically manageable, supporting the role of pasireotide long-acting release as a safe treatment option for acromegaly patients.

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Vitamin D and primary hyperparathyroidism: more insights into a complex relationship

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Erratum to: Prospective, long-term study of the effect of cabergoline on valvular status in patients with prolactinoma and idiopathic hyperprolactinemia

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VideoEndocrinology™ High-Impact Videos

FREE ACCESS through January 24, 2017.

Thyroidectomy with Wu Gaosong's Procedure
Gaosong Wu, Deguang Kong

Transoral Endoscopic Thyroidectomy Vestibular Approach
Angkoon Anuwong, Thanyawat Sasanakietkul, Pornpeera Jitpratoom

Transoral Robotic Thyroidectomy
Jeremy D. Richmon, Ralph P. Tufano, Jon Russell, Andrew Day, Hamad M. Chaudhary, Salem I. Noureldine

Novel Experience with Neuromonitoring in Robotic Thyroidectomy Using a Gasless Transaxillary Approach
Eun Jeong Ban, Changro Lee, Seul Gi Lee, Cho Rok Lee, Min Jhi Kim, Jung Bum Choi, Taehyung Kim, Sang Wook Kang, Jandee Lee, Jong Ju Jeong, Kee-Hyun Nam, Woong Youn Chung

A New Method for Direct Evaluation of Incisional Swelling After Thyroidectomy
Jenny Y. Yoo, Kelly L. McCoy, Linwah Yip, Michael T. Stang, Sally E. Carty

Indocyanine Green Fluorescence to Enhance Visual Contrast During Robotic Transaxillary Total Thyroidectomy
Pinar Yazici, Ryaz Chagpar, Sara Sound, Alexis Okoh, Eren Berber

Identification of the External Branch of the Superior Laryngeal Nerve During Thyroidectomy
Jonathan M. Bernstein, Jeremy L. Freeman

Robotic Thyroidectomy: Facelift Approach
Jeremy Richmon, Jason Prescott, Ralph Tufano, Martha Zeiger, Alan Dackiw,Heather Starmer

The post VideoEndocrinology™ High-Impact Videos appeared first on American Thyroid Association.

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Hookah tobacco smoking in a large urban sample of adult cigarette smokers: Links with alcohol and poly-tobacco use

Publication date: May 2017
Source:Addictive Behaviors, Volume 68
Author(s): Amy M. Cohn, Sarah J. Ehlke, Caroline O. Cobb, Eric K. Soule
Hookah tobacco smoking (HTS) has been increasing, particularly among young adults and has similar health effects compared to cigarette smoking. The link between HTS and poly-tobacco use is well documented, but fewer show an association between HTS and alcohol use. It is essential to identify factors that increase the risk for or addictiveness and consequences of HTS, given its growing prevalence. This study examined whether the association between HTS and poly-tobacco use differed as a function of age and alcohol consumption within in a sample of 1223 adult cigarette smokers. Approximately 20% of participants reported HTS. Compared to non-users, hookah users were more likely to be male, highly educated, and to report drug and alcohol use, binge drinking, and poly-tobacco use but were less likely to be heavy smokers (≥10 cigarettes per day). Regression analyses predicting number of tobacco products used (excluding cigarettes and HTS) indicated a three-way interaction of HTS, frequency of alcohol use, and age such that the association between HTS and number of tobacco products used was strongest for younger respondents who consumed alcohol more frequently. As observed in previous studies, alcohol is an important risk factor in the relationship between HTS and poly-tobacco use, particularly among younger cigarette smokers. The links between alcohol, HTS, and poly-tobacco use should be considered when developing HTS education and prevention materials directed toward younger cigarette smokers. Findings provide information relevant to FDA's interest in the addiction potential of HTS and its link to poly-tobacco use.



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Bayesian MRI denoising in complex domain

Publication date: May 2017
Source:Magnetic Resonance Imaging, Volume 38
Author(s): Fabio Baselice, Giampaolo Ferraioli, Vito Pascazio, Antonietta Sorriso
In recent years, several efforts have been done for producing Magnetic Resonance Image scanner with higher magnetic field strength mainly for increasing the Signal to Noise Ratio and the Contrast to Noise Ratio of the acquired images. However, denoising methodologies still play an important role for achieving images neatness. Several denoising algorithms have been presented in literature. Some of them exploit the statistical characteristics of the involved noise, some others project the image in a transformed domain, some others look for geometrical properties of the image. However, the common denominator consists in working in the amplitude domain, i.e. on the gray scale, real valued image. Within this manuscript we propose the idea of performing the noise filtering in the complex domain, i.e. on the real and on the imaginary parts of the acquired images. The advantage of the proposed methodology is that the statistical model of the involved signals is greatly simplified and no approximations are required, together with the full exploitation of the whole acquired signal. More in detail, a Maximum A Posteriori estimator developed for the handling complex data, which adopts Markov Random Fields for modeling the images, is proposed. First results and comparison with other widely adopted denoising filters confirm the validity of the method.



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Conditional potency is a hallmark of viral protein-derived toxic peptides

Publication date: Available online 10 January 2017
Source:Medical Hypotheses
Author(s): Man Tang, Xiaoxia Li, Qizhang Li, Yanchao Zhou, Wen Pan, Jiayang Gao, Ziwei Ye, Shaoping Weng, Qiuyun Liu, Jianguo He, Zhumei He
Viral infections are major ongoing challenges to mankind. The theory of cytokine storm cannot fully account for the virulence of some highly infectious viruses with high mortality rates. Although numerous viruses are capable of lysing animal and human cells in vivo, viral protein-derived peptides are mostly mild in standard culture conditions in in vitro assays. A hypothesis is postulated that conditional potency of viral protein-derived toxic peptides could at least in part explain cell senescence upon viral infections. The hypothesis can be tested with full length viral proteins against microbial and mammalian cells in various media. Viral protein injections to live animals may reveal that they are critical factors underlying cell destructions when protein degradation pathways and cytokine levels are controlled. Stimulation of autophagy could enhance current viral therapies by recycling toxic viral proteins.



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Repair of 8-oxoG:A Mismatches by the MUTYH Glycosylase: Mechanism, Metals & Medicine

Publication date: Available online 10 January 2017
Source:Free Radical Biology and Medicine
Author(s): Douglas M. Banda, Nicole N. Nuñez, Michael A. Burnside, Katie M. Bradshaw, Sheila S. David
Reactive oxygen and nitrogen species (RONS) may infringe on the passing of pristine genetic information by inducing DNA inter- and intra-strand crosslinks, protein-DNA crosslinks, and chemical alterations to the sugar or base moieties of DNA. 8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the most prevalent DNA lesions formed by RONS and is repaired through the base excision repair (BER) pathway involving the DNA repair glycosylases OGG1 and MUTYH in eukaryotes. MUTYH removes adenine (A) from 8-oxoG:A mispairs, thus mitigating the potential of G:C to T:A transversion mutations from occurring in the genome. The paramount role of MUTYH in guarding the genome is well established in the etiology of a colorectal cancer predisposition syndrome involving variants of MUTYH, referred to as MUTYH-associated polyposis. In this review, we highlight recent advances in understanding how MUTYH structure and related function participate in the manifestation of human disease such as MAP. Here we focus on the importance of MUTYH's metal cofactor sites, including a recently discovered "Zinc linchpin" motif, as well as updates to the catalytic mechanism. Finally, we touch on the insight gleaned from studies with MAP-associated MUTYH variants and recent advances in understanding the multifaceted roles of MUTYH in the cell, both in the prevention of mutagenesis and tumorigenesis.

Graphical abstract

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Thioredoxin a novel biomarker of post-injury sepsis

Publication date: Available online 10 January 2017
Source:Free Radical Biology and Medicine
Author(s): Jesper Eriksson, Andreas Gidlöf, Mikael Eriksson, Emma Larsson, Olof Brattström, Anders Oldner
BackgroundThioredoxin (TRX), an endogenous anti-oxidant protein induced in inflammatory conditions, has been shown to increase in plasma and to be associated with outcome in septic patients. This biomarker has never been studied in a trauma setting. We hypothesized that TRX would be increased after trauma and associated with post-injury sepsis.MethodsSingle-centre prospective observational study conducted at the intensive care unit (ICU) at the Karolinska University Hospital, Stockholm, Sweden, a level-1 trauma centre. Eighty-three severely injured trauma patients, 18 years or older, with an ICU stay of three days or more were included. Plasma samples were obtained on day 1 and 3 after informed consent. Clinical, physiological and outcome data were retrieved from the trauma and ICU research registries. Plasma samples were also obtained from 15 healthy subjects. In addition, a standardized porcine trauma model was conducted where a femur fracture followed by a controlled hemorrhage period were inflicted in four pigs.ResultsIn pigs, however not significant, there was a continuing increase in plasma-TRX after femur fracture and sequential hemorrhage despite near normalisation of cardiac index and lactate levels. In patients, median injury severity score was 29 and 48 patients developed sepsis during their ICU stay. A three-fold increase in initial TRX was seen in trauma patients when compared to healthy volunteers. Thioredoxin was significantly higher in patients in shock on admission, those subject to massive transfusion and in the most severely injured patients. No difference was seen between survivors and non-survivors. Plasma-TRX on day 1 was significantly increased in patients who later developed post-injury sepsis. In a logistic regression analysis including TRX, C-reactive protein, injury severity, massive transfusion, and admission blood pressure, TRX was the only variable independently associated with post-injury sepsis.ConclusionsThis study demonstrates that TRX is released into plasma in response to severe trauma and independently associated with post-injury sepsis. The use of TRX as a biomarker in trauma patients needs further evaluation in larger studies.Level of evidenceRetrospective cohort study, level III.

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Hypothyroidism in Cancer Patients on Immune Checkpoint Inhibitors with anti-PD1 Agents: Insights on Underlying Mechanisms

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-119528

Background: Immune therapy using monoclonal antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD-1) for various cancers have been reported to cause thyroid dysfunction. Little is known, however, about the underlying pathogenic mechanisms and the course of hypothyroidism that subsequently develops. In this report, we use the change in thyroglobulin and thyroid antibody levels in patients on immune therapy who develop hypothyroidism to better understand its pathogenesis as well as examine the status of hypothyroidism in the long term. Methods: We report a case series of 10 patients who developed hypothyroidism after initiation of immune therapy (either anti-PD-1 alone or in combination with anti-CTLA-4). Available thyroid antibodies including anti-thyroglobulin (anti-Tg), anti-thyroid peroxidase (anti-TPO), and thyroid stimulating immunoglobulin (TSI) were noted during the initial thyroiditis phase as well as the hypothyroid phase. Persistence or remission of hypothyroidism was noted at 6 months. Summary: During the thyroiditis phase, 50% of the patients had elevated Tg titers, 40% had elevated anti-Tg, and 40% had elevated TSI. All of these titers decreased during the hypothyroid phase. Permanent hypothyroidism was noted in 80% of the cases. Conclusion: Hypothyroidism following initiation of immune therapy has immunologic and non-immunologic mediated mechanisms and is likely to be persistent.
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Alternative Treatment Strategies in Women Poorly Tolerating Moderate Doses of Bromocriptine

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-123041

Background: Metformin as well as dopaminergic agents exert a beneficial effect on glucose and lipid metabolism, often impaired in patients with hyperprolactinemia. Objective: The aim of this study was to compare metabolic- and prolactin-lowering effects of low-dose bromocriptine/metformin combination therapy and cabergoline in patients with elevated prolactin levels. Methods: The study included 27 women with hyperprolactinemia and impaired glucose tolerance who were treated with moderate doses of bromocriptine but experienced adverse effects of this treatment. In 12 of these patients bromocriptine was replaced with cabergoline (group A), while the remaining ones continued treatment with bromocriptine, the dose of which was halved, and administered together with metformin (group B). Plasma lipids, glucose homeostasis markers, as well as serum levels of prolactin, thyrotropin and insulin-like growth factor-1 (IGF-1) were assessed before and after 4 months of metformin treatment. Results: Both groups did not differ in baseline levels of plasma glucose and lipids, in insulin sensitivity, as well as in circulating levels of all measured hormones. All patients from group A and 12 patients from group B completed the study. Cabergoline reduced prolactin levels, while no effect on plasma prolactin was found in group B. Neither cabergoline nor bromocriptine plus metformin affected circulating levels of thyrotropin and IGF-1. Both treatment options, particularly low-dose bromocriptine plus metformin, improved glucose and lipid homeostasis. Conclusions: Low-dose bromocriptine combined with metformin may be an interesting alternative to cabergoline in patients with mild hyperprolactinemia and early glucose metabolism abnormalities, in whom moderate doses of bromocriptine are poorly tolerated.
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Long-term Consequences of Congenital Adrenal Hyperplasia due to Classic 21-hydroxylase Deficiency in Adolescents and Adults

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-123037

Background The management of congenital adrenal hyperplasia (CAH) from pediatric to adulthood is challenging to achieve optimal growth and puberty. This study characterizes the clinical outcomes of 21-hydroxylase deficiency. Methods 53 CAH patients were included (33 females, 15 and 18 patients with the salt-wasting [SW] and simple-virilizing [SV] forms; and 20 males, 16 and 4 patients with the SW and SV forms). We reviewed growth parameters, pubertal status, and long-term morbidities. Results In females, the age at pubertal onset and pubarche was 9.6±0.9 and 10.5±1.9 years, respectively, which was significantly earlier in the SV form (p=0.005). In males, the ages at pubertal onset and pubarche were 10.1±2.0 and 10.7±2.5 years, respectively, which were not significantly different between the groups. Forty patients reached adult height: −2.1±1.6 SDS in males and −1.5±1.1 SDS in females. Obesity and overweight was significantly common in adult patients. Testicular adrenal rest tumors were found in 4 SW males. 5 patients had adrenal tumor including adenoma, adenocarcinoma, or myelolipoma. Conclusions Reduced adult height and obesity/overweight are prevalent in adulthood. Adolescents and adults with 21-hydroxylase deficiency should be monitored for long-term consequences.
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The Effects of Blood Glucose Regulation in Omentin-1 Levels among Diabetic Patients

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-118862

Objectives: Omentin-1, an adipocytokine that increases the insulin sensitivity, has been determined to be reduced in patients with insulin resistance, impaired glucose tolerance, and Type-2 diabetes mellitus. In this study, we have investigated the alterations in Omentin-1 levels with the blood glucose regulation in diabetic patients having poor glycemic control. By this way, we aimed to determine the role of Omentin-1 as a marker in follow-up and monitoring progression of diabetes. Methods: Totally 58 patients with type 2 diabetes mellitus, older than 18 years of age who were having poor glycemic control (HbA1c≥9) were included in this study. In the first visit, all clinical and biochemical parameters of patients were recorded. After baseline evaluation, the patients were advised life style changes, and their medical treatment was determined individually according to the recommendations of the American Diabetes Association guidelines. At the end of the third month patients were re-evaluated. Serum Omentin-1 levels were measured with ELISA. Results: In patients using only oral antidiabetic agents, after exchanging the treatment with insulin, on 3rd month of treatment, there was a significant decrease in serum C-peptide and Omentin-1 levels compared with the initial results (p=0.034, p=0.048, respectively). On the other hand, in patients using insulin treatment from the beginning of the study, there was not any significant alterations in serum C-peptide or Omentin-1 levels compared with the initial results (p>0.05). Conclusions: Serum Omentin-1 levels may change with insulin and metformin treatments in Type-2 diabetic patients. In patients with poor glycemic control, Omentin-1 levels do not change with the regulation of blood glucose levels. A decrease in Omentin-1 and C-peptide levels has been determined after the initiation of insulin therapy. This suggests that, Omentin-1 levels are closely associated with the endogenous insulin reserve and may be used in follow-up of patients.
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Evaluation of Glutathione Peroxidase and KCNJ11 Gene Polymorphisms in Patients with New Onset Diabetes Mellitus After Renal Transplantation

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-123040

Introduction Genetic mutations such as C599T polymorphism in glutathione peroxidase [GPX1] gene and polymorphisms in potassium channel (KCNJ11) genes have recently been proposed in the etiopathogenesis of new onset diabetes mellitus after renal transplantation (NODAT). We aimed to examine the association of GPX1 and KCNJ11 polymorphisms in NODAT. Materials and Methods This is a monocenter case-control study with a total of 118 renal transplant recipients who were divided into 2 groups; NODAT and normal glucose tolerance. Relation of GPX1 and KCNJ11 polymorphisms were investigated between these groups. PCR-RFLP method was used for genotyping of polymorphisms in the GPX1 (rs1050450) and KCNJ11 (rs1805127) genes. Two alleles were visualized for each gene (C/T for GPX1 and A/G for KCNJ11). Results NODAT was correlated with age at transplantation (p<0.001, r=0.380), post-transplant systolic blood pressure (BP) (p=0.02, r=0.211), post-transplant non-HDL cholesterol levels (p=0.01, r=0.803), degree of weight change at the end of the first year (p=0.01, r=0.471), presence of pre-transplant hypertension (HT) (p=0.02, r=0.201), family history of diabetes (p=0.01, r=0.29) and dyslipidemia (p=0.012, r=0.362). GPX1 polymorphism of TT (mutant) allele was significantly more frequent in patients with NODAT (p<0.001, r=0.396) independent from other diabetogenic risk factors. KCNJ11 polymorphisms were similar in both groups and did not show any significant association with NODAT (p=0.10). Conclusions In addition to several diabetogenic risk factors, C599T polymorphisms in GPX1 gene might also contribute to the development of NODAT. Further studies on larger patient series are necessary in order to reach definitive suggestions.
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Osteocalcin Improves Metabolic Profiles, Body Composition and Arterial Stiffening in an Induced Diabetic Rat Model

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-122138

Recent studies have demonstrated the benefits of osteocalcin (OCN) on glucose homeostasis and metabolic dysregulation. However, its role in body composition and vascular function remains unknown. This study was designed to examine changes in metabolic parameters and body composition as well as arterial stiffness after OCN treatment in type 2 diabetic rats. Adult male Sprague Dawley (SD) rats were fed chow or high fat diet (HFD) for 8 weeks, and then diabetes was induced with an injection of low-dose streptozotocin (STZ) and treated daily with intraperitoneal injections of OCN for 12 weeks. Our data showed that OCN treatment improved glucose homeostasis and lipid metabolism. Further analysis revealed that OCN treatment resulted in increased insulin sensitivity. In addition, untreated diabetic rats experienced significant weight loss, whereas OCN-treated rats better maintained body weight (300.75±38.14 g vs. 335.50±23.70, p=0.005). OCN also changed body composition, as evidenced by reduced body fat mass, specifically abdominal fat mass. OCN-treated diabetic rats also demonstrated decreased pulse-wave velocity, indicating of improved arterial stiffness. Taken together, our findings in the current study revealed that OCN therapy prevents arteriosclerosis in an induced diabetic rat model by exerting beneficial effects on glucose levels, insulin sensitivity, lipid metabolites, and body composition changes.
[...]

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The Effect of Vitamin D on Thyroid Autoimmunity in Levothyroxine-Treated Women with Hashimoto’s Thyroiditis and Normal Vitamin D Status

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-123038

Background: Low vitamin D status is associated with autoimmune thyroid disease. Oral vitamin D supplementation was found to reduce titers of thyroid antibodies in levothyroxine-treated women with postpartum thyroiditis and low vitamin D status. Methods: The study included 34 women with Hashimoto's thyroiditis and normal vitamin D status (serum 25-hydroxyvitamin D levels above 30 ng/mL) who had been treated for at least 6 months with levothyroxine. On the basis of patient preference, women were divided into 2 groups, receiving (n=18) or not receiving (n=16) oral vitamin D preparations (2000 IU daily). Serum levels of thyrotropin, free thyroxine, free triiodothyronine and 25-hydroxyvitamin D, as well as titers of thyroid peroxidase and thyroglobulin antibodies were measured at the beginning of the study and 6 months later. Results: There were no significant differences in baseline values between both study groups. 25-hydroxyvitamin D levels inversely correlated with titers of thyroid antibodies. No changes in hypothalamic-pituitary-thyroid axis activity and thyroid antibody titers were observed in vitamin-naïve patients. Vitamin D increased serum levels of 25-hydroxyvitamin D, as well as reduced titers of thyroid antibodies. This effect was more pronounced for thyroid peroxidase than for thyroglobulin antibodies and correlated with their baseline titers. Conclusions: Vitamin D preparations may reduce thyroid autoimmunity in levothyroxine-treated women with Hashimoto's thyroiditis and normal vitamin D status.
[...]

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Brown and White Adipose Tissue Expression of IL6, UCP1 and SIRT1 are Associated with Alterations in Clinical, Metabolic and Anthropometric Parameters in Obese Humans

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-119525

Aim: The present study aimed to analyze the expression of IL6, UCP1 and SIRT1 in adipose tissue (WAT and BAT) in association to clinical, metabolic and anthropometric parameters in obese humans. Methods: WAT and BAT samples from obese patients (n=27) were collected. IL6, UCP1 and SIRT1 markers were measured by qRT-PCR. The association between IL6, UCP1 and SIRT1 mRNA expression and anthropometric and clinical parameters were evaluated, using appropriate statistical tests. Results: Our results demonstrated that high levels of IL6 are associated with altered glucose levels in the WAT (p=0.01). In contrast, high levels of IL6 in the BAT were associated with decreased % fat (p=0.01) and fat weight (p=0.02) and increased mVO2 (p=0.02) and VO2 (p=0.02). For UCP1, a higher expression in the BAT was observed when compared to the WAT (p=0.0001). This gene expression was associated with lower values of BMI (p=0.03), % fat (P=0.02) and fat weight (P=0.02) and increased mVO2 (p=0.041) and VO2 (p=0.001). In the WAT, decreased levels of SIRT1 were associated with increased fat weight (p=0.02); in the BAT, associations were found for % fat (p=0.018) and mVO2 (p=0.03). Conclusion: These results reveal different characteristics in the biological actions between WAT and BAT in obese humans. Increased levels of IL6, UCP1 and SIRT1 in the BAT were associated with metabolic parameters improvements.
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© Georg Thieme Verlag KG Stuttgart · New York

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Testosterone Plasma Concentration is Associated with Insulin Resistance in Male Hypertensive Patients

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-121492

Background: Low testosterone levels are a common finding among men with Type 2 Diabetes Mellitus (T2DM) and are inversely related to insulin resistance. Whether this relationship holds true in patients with hypertension, but normal glucose tolerance or prediabetes, is unclear. Methods: We recruited 87 male outpatients with essential arterial hypertension, aged 35–70 years. Anthropometric data were collected, an Oral Glucose Tolerance Test (OGTT) performed, and the homeostasis model assessment of insulin resistance (HOMA-IR) score calculated. Follicle-Stimulating Hormone, Luteinizing Hormone, testosterone, Sex Hormone-Binding-Globulin and free-testosterone were measured. The concentrations of sex hormones were compared between normoglucotolerant, prediabetic and diabetic patients. Non-parametric tests were applied as appropriate to verify differences among groups, while multiple linear regression was used to predict the variability of testosterone and free-testosterone. Results: Total serum testosterone concentration was significantly lower in T2DM in comparison to normoglucotolerant subjects (p<0.01) and was inversely related to body mass index (r=− 0.25, p<0.01), waist circumference (r=− 0.27, p<0.01), pre and post-OGTT plasma glucose (r=− 0.4, p<0.0001 and r=− 0.29, p<0.01, respectively), pre and post-OGTT plasma insulin (r=− 0.42, p<0.0001 and r=− 0.42, p<0.0001) and HOMA-IR (r=− 0.46, p<0.0001). Similar associations were observed for free testosterone; HOMA-IR was related to testosterone and free-testosterone even in patients with normal glucose tolerance (r=− 0.47, p<0.01 and r=− 0.34, p<0.05, respectively). At multivariate analysis HOMA-IR was the only variable associated to testosterone (p<0.001) and free-testosterone (p<0.05) plasma concentration. Conclusions: In males with hypertension, the link between insulin sensitivity and hypothalamic-pituitary-gonadal axis is maintained along the entire spectrum of glucose tolerance.
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© Georg Thieme Verlag KG Stuttgart · New York

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Diabetes Mellitus and Bone Metabolism

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0042-123036

Diabetes mellitus and bone metabolism affect mesenchymal tissues and have numerous epidemiological and pathophysiological associations in common. Diabetes mellitus affects bone metabolism and increases fracture risk. The pathophysiological mechanims how type 1 and type 2 diabetes impair bone metabolism and bone strength may differ which is outlined in this review. Direct metabolic effects in additon to centrally controlled endocrine loops exert suppressive effects on bone formation and may also stimulate bone Resorption. Decreased bone formation in combination with increased bone resorption strongly increases fracture risk.
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© Georg Thieme Verlag KG Stuttgart · New York

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Salvianolic Acids for Injection (SAFI) Suppresses Inflammatory Responses in Activated Microglia to Attenuate Brain Damage in Focal Cerebral Ischemia

Publication date: Available online 10 January 2017
Source:Journal of Ethnopharmacology
Author(s): Pengwei Zhuang, Yanjun Wan, Shihan Geng, Ying He, Bo Feng, Zhengliang Ye, Dazheng Zhou, Dekun Li, Hongjun Wei, Hongyan Li, Yanjun Zhang, Aichun Ju
BackgroundInflammatory reactions induced by microglia in the brain play crucial roles in ischemia/reperfusion (I/R) cerebral injuries. Microglia activation has been shown to be closely related to TLR4/NF-κB signal pathways. Salvianolic acids for injection (SAFI) have been used in clinical practice to treat ischemic stroke with reported neuroprotective effects; however, the underlying mechanisms are still uncertain.Objective and MethodsFirst, we studied the effect of SAFI on inflammatory responses in LPS-stimulated BV-2 microglia. Then, to discover whether the beneficial in vitro effects of SAFI lead to in vivo therapeutic effects, an MCAO (Middle cerebral artery occlusion) rat model was further employed to elucidate the probable mechanism of SAFI in treating ischemic stroke. Rats in the SAFI group were given SAFI (23 or 46mg/kg) before I/R injury.ResultsThe results showed that SAFI treatment significantly decreased neuroinflammation and the infarction volume compared with the vehicle group. Activation of microglia cells was reduced, and TLR4/NF-κB signals, which were markedly inhibited by SAFI treatment in ischemic hemisphere, were accompanied by reduced expression and release of cytokines IL-1β and IL-6.ConclusionThis study provides evidence that SAFI effectively protects the brain after cerebral ischemia, which may be caused by attenuating inflammation in microglia.

Graphical abstract

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Extract of Clinopodium bolivianum protects against E. coli invasion of uroepithelial cells

Publication date: Available online 10 January 2017
Source:Journal of Ethnopharmacology
Author(s): Soumitra Mohanty, Witchuda Kamolvit, Silvia Zambrana, Corine Sandström, Eduardo Gonzales, Claes-Göran Östenson, Annelie Braunerf
Ethnopharmacological relevanceClinopodium bolivianum is a South American plant with anti-inflammatory and anti-infective activities. The increasing antibiotic resistance urges for alternative therapy. Based on its use in traditional medicine, we investigated the effect of C. bolivianum on the ability to defend bladder epithelial cells from E. coli infection.Materials and MethodsThe extract was analysed by LC-MS. Bladder epithelial cell lines T24 and 5637 and uropathogenic E. coli No. 12, its isogenic mutant WE16 csgBA bscA::Cm and CFT073 were used to investigate the effect of C. bolivianum on uroepithelial infection. Bacterial adherence and invasion to cells treated with C. bolivianum were analyzed. Expression of uroplakin 1a, β1 integrin, caveolin-1, IL-8 and antimicrobial peptides in response to C. bolivianum treatment was assessed using RT-PCR. Protein expression was confirmed by Western blot analysis or ELISA. The antimicrobial effects of C. bolivianum on bacteria and fungus were investigated using minimum inhibitory concentration. Furthermore, the formation of biofilm was investigated with crystal violet assay.ResultsC. bolivianum extract consisted of more than 70 different types of phytochemicals including sugars and phenolic compounds. The extract decreased the uroplakin 1a expression and E. coli adhesion and invasion of uroepithelial cells while up-regulated caveolin-1. In uninfected C. bolivianum treated cells, IL-8 was lower than in non-treated cells. In infected cells, however, no difference was observed between treated and non-treated cells. Further, C. bolivianum treatment reduced uropathogenic E. coli (UPEC) biofilms but did not inhibit bacterial growth.ConclusionsOur results show that C. bolivianum has a protective role on bladder epithelial cells against UPEC infection by decreasing the bacterial adhesion, invasion and biofilm formation.

Graphical abstract

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FOLFOXIRI plus bevacizumab as conversion-therapy for liver metastases in colorectal cancer: A necessity?

Publication date: Available online 9 January 2017
Source:European Journal of Cancer
Author(s): D.P. Modest, U.P. Neumann, J. Pratschke




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Pharmacokinetic and exposure–response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer

Abstract

Purpose

The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancers, (2) to further evaluate PK drug–drug interactions (DDIs) when given in combination with trastuzumab, and (3) to assess the relationship between exposure and efficacy to assess the clinical dosing regimen in the EBC patients.

Methods

Pertuzumab serum concentration data from 180 patients in NeoSphere were compared to historical observations and potential DDI was assessed, by applying simulation techniques using a population PK model. The impact of pertuzumab exposure on pCR rate was evaluated using a logit response model (n = 88).

Results

The observed PK matched the population PK model simulations, confirming that the PK in neoadjuvant EBC appear to be in agreement with the historical observations. No evidence of a DDI effect of trastuzumab or docetaxel on pertuzumab was observed supporting the doses when given in combination. In NeoSphere >90% of EBC patients achieved the non-clinical target serum concentration. There was no association between the pertuzumab serum concentration and pCR within the range observed in this study (20–100 μg/mL) supporting no dose adjustments needed for patients with lower exposure.

Conclusions

This analysis further supports the lack of DDI between the two therapeutic proteins and the appropriateness of the approved fixed non-body-weight-adjusted pertuzumab dose in the treatment of neoadjuvant EBC with pertuzumab in combination with trastuzumab and docetaxel.

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Successful afatinib treatment of advanced non-small-cell lung cancer patients undergoing hemodialysis

Abstract

The treatment for patients with lung cancer undergoing hemodialysis, who are frequently elderly and have poor performance status, becomes a more important subject. However, the feasibility of afatinib in patients with chronic renal failure undergoing hemodialysis has not, so far, been reported. Here, afatinib was administered to three patients with NSCLC harboring EGFR mutation and chronic renal failure undergoing hemodialysis. Pharmacokinetic (PK) data of afatinib supported the safety of afatinib treatment. After receiving their written informed consent from all patients, they were administered 30 mg afatinib daily with HD three times a week. We performed PK analyses of afatinib on days 1, 2, 10, and 11 after initial administration of afatinib. All three patients exhibited a partial response without any serious adverse events during the administration of afatinib. These PK data were similar to those of patients with normal organ function, which were previously reported. Our findings may be particularly useful given the current opportunity to use afatinib as a first-line treatment for EGFR-mutated NSCLC patients, providing an additional option for patients with impaired renal function.

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Long noncoding RNA GAS5 inhibits malignant proliferation and chemotherapy resistance to doxorubicin in bladder transitional cell carcinoma

Abstract

Purpose

Bladder cancer is the most general malignant cancer in genitourinary system, more than 90% of BCs are bladder transitional cell carcinomas (BTCC). This study aimed to investigate the clinical significance of growth arrest-specific 5 (GAS5) gene and its regulatory effects of malignant proliferation and chemotherapy resistance to doxorubicin in BTCC cells.

Methods

The expression of GAS5 was detected by quantitative real-time PCR. Statistical analysis was used to determine the relationship between GAS5 expression and clinical features and the prognostic value of GAS5 for disease free survival. MTT assay was used to detect cell proliferation ability and chemosensitivity. Dual-color flow cytometric method was used to detect cell apoptosis. The expression of Bcl-2 protein was examined by western blot.

Results

In this study, we found that GAS5 low-expressed in BTCC tissues and cells, and its low expression level had positive correlation with higher pathological grades of BTCC. Moreover, GAS5 was a prognostic biomarker of disease free survival for BTCC patients. GAS5 over-expression could inhibit cell proliferation of BTCC J82 and T24 cells significantly. The IC50 to doxorubicin in T24/DOX cells (resistance to doxorubicin) presented a conspicuous depression, GAS5 enhancement reduced the chemotherapy resistance to doxorubicin. GAS5 over-expression promoted apoptosis induced by doxorubicin in T24/DOX cells, and depressed the expression of anti-apoptosis protein Bcl-2. The results indicated that GAS5 regulated the chemotherapy resistance to doxorubicin via Bcl2 partly.

Conclusions

In summary, lncRNA GAS5 was a prognostic biomarker of disease free survival in BTCC patients, and acted as a tumor-suppressing gene to inhibit malignant proliferation and resistance to doxorubicin in BTCC cells. LncRNA GAS5 might be a novel potential therapeutic target for BTCC.

http://ift.tt/2jpG47N

Randomized phase II study of cetuximab versus irinotecan and cetuximab in patients with chemo-refractory KRAS codon G13D metastatic colorectal cancer (G13D-study)

Abstract

Purpose

This study investigated the efficacy and safety of cetuximab-based treatment in patients with chemotherapy-resistant refractory mCRC with KRAS G13D mutation.

Patients and methods

An assessment of the efficacy and safety of cetuximab-based treatment was performed in an observation-enriched randomized controlled study comparing the cetuximab alone group (Cet group) and the combination of cetuximab and irinotecan group (CetI group) for KRAS G13D-mutated mCRC in Japan. In this study, the patients received a biweekly (500 mg/m² on day 1) or weekly (250 mg/m²) intravenous infusion of cetuximab in Cet group, or a biweekly (500 mg/m² on day 1) or weekly (250 mg/m²) intravenous infusion of cetuximab followed by irinotecan (150 mg/m²) in CetI group. Propensity score adjustment was used to achieve balance in the observational arm.

Results

Data from a total of 29 patients (10 in Cet group, 19 in CetI group) were analyzed. Crude median progression-free survival time was 2.9 months in the Cet group and 2.5 months in the CetI group. Crude disease control rates were 55.6% in the Cet group and 47.4% in the CetI group. After a median follow-up of 43 months, the crude median overall survival was 8.0 months in the Cet group and 7.6 months in the CetI group. Cetuximab-based treatment did not markedly increase any characteristic toxicity and was generally well tolerated. Propensity score analyses adjusted for performance status and number of metastases showed comparable results with the crude results.

Conclusion

Cetuximab-based treatment seemed to benefit patients with chemotherapy-resistant, refractory KRAS G13D-mutated mCRC. Our results might support the administration of cetuximab-based treatment for KRAS-mutant mCRC and would be able to provide treatment flexibility in this setting.

http://ift.tt/2jpO34U

Survival impact of neoadjuvant gemcitabine plus S-1 chemotherapy for patients with borderline resectable pancreatic carcinoma with arterial contact

Abstract

Purpose

The aim of this study was to evaluate the efficacy of neoadjuvant gemcitabine plus S-1 (GS) chemotherapy as measured by overall survival for patients with pancreatic carcinoma with arterial contact.

Methods

Medical records of 77 patients with pancreatic carcinoma with arterial contact who intended to undergo tumor resection were analyzed retrospectively. These patients were divided into two groups: patients who underwent upfront surgery and patients who underwent tumor resection after neoadjuvant GS chemotherapy. Clinicopathological factors were compared between the two groups.

Results

Of the 77 patients, 25 patients underwent upfront surgery while the remaining 52 patients received neoadjuvant GS chemotherapy. Seven patients did not undergo tumor resection due to distant metastasis. No serious adverse effects associated with neoadjuvant GS chemotherapy were observed. The R0 resection rate of patients who received neoadjuvant GS chemotherapy was significantly higher than that of patients who did not (P < 0.001). Overall survival of patients who received neoadjuvant GS chemotherapy was significantly longer than that of patients who did not among all 77 patients (P = 0.003, median survival time, 27.1 vs. 11.6 months) as well as among the 70 patients who underwent tumor resection (P = 0.001, median survival time, 27.2 vs. 11.6 months). Multivariate analysis demonstrated that neoadjuvant GS chemotherapy was an independent prognostic factor of overall survival for patients who underwent tumor resection (P = 0.019).

Conclusions

Neoadjuvant GS chemotherapy may provide a survival benefit to patients with pancreatic carcinoma with arterial contact.

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Efficacy and safety of nab -paclitaxel in patients with previously treated metastatic colorectal cancer: a phase II COLO-001 trial

Abstract

Purpose

This single-arm, phase II trial evaluated nab-paclitaxel monotherapy in pretreated patients with metastatic colorectal cancer (mCRC).

Methods

Patients with mCRC (RAS wild-type and RAS mutant cohorts) received nab-paclitaxel 125 mg/m² days 1, 8, and 15 (28-day cycle). The primary endpoint was investigator-assessed progression-free survival (PFS) rate at week 8; secondary endpoints included overall survival, overall response rate, and safety. Stage 1 planned enrollment was 15 patients per cohort per Simon 2-stage design. Stage 2 enrollment was to continue unless ≤8 of the first 15 patients per cohort achieved PFS at 8 weeks.

Results

Stage 1 enrolled 41 patients (RAS wild type: n = 18; RAS mutant: n = 23). In both RAS cohorts, 3 of 15 patients initially enrolled were progression-free at week 8 (20%; 95% CI 4.0–48.0). Median PFS was 8.1 weeks (95% CI 7.7–8.6) and 7.9 weeks (95% CI 7.6–8.0) for RAS wild-type and RAS mutant cohorts, respectively. There were no complete or partial responses. The overall disease control rate was 16% (95% CI 6.0–32.0), and rates were similar in the RAS wild-type and RAS mutant cohorts (18 and 15%, respectively). No new safety signals were reported; the most common grade ≥3 adverse events included neutropenia, asthenia, and peripheral neuropathy. This study did not progress to stage 2 per the preplanned statistical stopping rule.

Conclusions

In patients with heavily pretreated mCRC, nab-paclitaxel did not demonstrate promising antitumor activity; further assessment of nab-paclitaxel monotherapy in this population of patients is not supported.

Trial registration

NCT02103062.

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Phase I trial of daily triapine in combination with cisplatin chemotherapy for advanced-stage malignancies

Abstract

Purpose

Advanced-stage malignancies have increased deoxyribonucleotide demands in DNA replication and repair, making deoxyribonucleotide supply a potential exploitable target for therapy based on ribonucleotide reductase (RNR) inhibition.

Methods

A dose-finding phase I trial was conducted of intravenous (i.v.) triapine, a small-molecule RNR inhibitor, and cisplatin chemotherapy in patients with advanced-stage solid tumor malignancies. Patients received dose-finding levels of i.v. triapine (48–96 mg/m²) and i.v. cisplatin (20–75 mg/m²) on 1 of 3 different schedules. The primary endpoint was to identify the maximum tolerated dose of a triapine–cisplatin combination. Secondary endpoints included the rate of triapine–cisplatin objective response and the pharmacokinetics and bioavailability of a single oral triapine dose. (Clinicaltrials.gov number, NCT00024323).

Results

The MTD was 96 mg/m² triapine daily days 1–4 and 75 mg/m² cisplatin split over day 2 and day 3. Frequent grade 3 or 4 adverse events included fatigue, dyspnea, leukopenia, thrombocytopenia, and electrolyte abnormalities. No objective responses were observed; 5 (50%) of 10 patients treated at the MTD had stable disease. Pharmacokinetics indicated an oral triapine bioavailability of 88%.

Conclusions

The triapine–cisplatin combination may be given safely in patients with advanced-stage solid tumor malignancies. On the basis of these results, a phase I trial adequately powered to evaluate oral triapine bioavailability in women with advanced-stage uterine cervix or vulvar cancers is underway.

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Burkitt’s lymphoma of nasal cavity and bilateral maxillary sinuses

Publication date: Available online 10 January 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): H. Nurul Atikah, I. Hashimah, M.N. Rosli, S. Zulkiflee, S.A.H. Suzina
Burkitt's lymphoma is a malignant, highly aggressive B-cell type of non-Hodgkin's lymphoma. Prolonged fever followed by bilateral cheek swelling and nasal obstruction was the first symptoms of a 2-year-old boy with Burkitt's lymphoma. When the chemotherapy was started, the facial swelling reduced within few weeks. This case report highlights a rare case of Burkitt's lymphoma in the nasal cavity and bilateral maxillary sinuses and the need of high index of suspicious for early diagnosis and treatment.



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Angiomatous antrochoanal polyps: Challenge in diagnosis

Publication date: Available online 9 January 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): Anuar Idwan Idris, Ramiza Ramza Ramli, Ida Sadja'ah Sachlin
Epistaxis is a common complaint seen in the younger population. Its etiology is typically from the anterior nares, although we present a case of epistaxis from an uncommon source. Diagnosis of bleeding nasal mass is varied from benign to malignant lesions. Angiomatous antrochoanal polyps (AAP) are one of the causes but it is rare and the diagnosis is challenging as it mimic other nasal mass especially nasopharyngeal angiofibroma (NA). There are a lot of similarities of clinical presentations, between imaging and histopathological findings between these two which made the diagnosis even more difficult. A correct diagnosis is extremely important as although they have similar clinical presentations, the management is different. Here we report a case of a young lady with significant epistaxis which was initially diagnosed as NA but with a final revised diagnosis of AAP.



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An unusual presentation of nasofacial NK/T-cell lymphoma – A case report

Publication date: Available online 10 January 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): Santosh Kumar Swain, Mahesh Chandra Sahu
Nasofacial NK/T-cell lymphoma is a rare clinical entity characterized by destruction and mutilation of the nasofacial area. It has unknown etiology, often affect face, nose, paranasal sinuses, palate, oral cavity and surrounding structures. As the clinical manifestations are often variable and non-specific, it may obscure the exact diagnosis, so it may delay the treatment. We present a case report of nasofacial NK/T-cell lymphoma in a 56years old male who gave a 3months history of clinical manifestation with destruction of nasofacial area. After confirmed diagnosis, a combined chemotherapy and radiotherapy were offered to the patient who responded well to combination therapy.



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Epigenetic sampling effects: nephrectomy modifies the clear cell renal cell cancer methylome

Abstract

Purpose

Currently, it is unclear to what extent sampling procedures affect the epigenome. Here, this phenomenon was evaluated by studying the impact of artery ligation on DNA methylation in clear cell renal cancer.

Methods

DNA methylation profiles between vascularised tumour biopsy samples and devascularised nephrectomy samples from two individuals were compared. The relevance of significantly altered methylation profiles was validated in an independent clinical trial cohort.

Results

We found that six genes were differentially methylated in the test samples, of which four were linked to ischaemia or hypoxia (REXO1L1, TLR4, hsa-mir-1299, ANKRD2). Three of these genes were also found to be significantly differentially methylated in the validation cohort, indicating that the observed effects are genuine.

Conclusion

Tissue ischaemia during normal surgical removal of tumour can cause epigenetic changes. Based on these results, we conclude that the impact of sampling procedures in clinical epigenetic studies should be considered and discussed, particularly after inducing hypoxia/ischaemia, which occurs in most oncological surgery procedures through which tissues are collected for translational research.

http://ift.tt/2jrYaGa