The gating of the CFTR channel

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel expressed in the apical membrane of epithelia. Mutations in the CFTR gene are the cause of cystsic fibrosis. CFTR is the only ABC-protein that constitutes an ion channel pore forming subunit. CFTR gating is regulated in complex manner as phosphorylation is mandatory for channel activity and gating is directly regulated by binding of ATP to specific intracellular sites on the CFTR protein. This review covers our current understanding on the gating mechanism in CFTR and illustrates the relevance of alteration of these mechanisms in the onset of cystic fibrosis.

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The multifaceted role of extracellular vesicles in metastasis: Priming the soil for seeding

Abstract

Extracellular vesicles (EVs), including exosomes, play a key role in inter and intracellular communication, promoting the proliferation and invasion of recipient cells to support tumor growth and metastasis. Metastasis comprises multiple steps that first include the detachment of tumor cells through epithelial to mesenchymal transition (EMT), allowing the physical dissemination to distant organs. Thereafter, cancer-derived exosomes are still critical components for preparing the tumor microenvironment by (i) enabling tumor cells to escape from the immunological surveillance and (ii) arranging the pre-metastatic site for the engraftment of detached cancer cells. In this review, we discuss the multifaceted role of EVs in the multiple steps of metastasis. Future research directions draw attention to EVs as biological targets for cancer diagnosis, prognosis, and therapy. However, due to their significant role in cell communication, they may become a valuable drug delivery system. This article is protected by copyright. All rights reserved.

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Effects of NO Synthase Blocker L-NAME on Functional State of the Neuromotor System during Traumatic Disease of the Spinal Cord

Functional state of the neuromotor system after administration of a nonspecific NO synthase blocker L-NAME was studied on the model of experimental contusion of the spinal cord. Electron paramagnetic resonance measurements of NO production in the damaged segment of the spinal cord were performed for estimation of the dynamics of intensity of NO production during traumatic disease of the spinal cord and selection of optimal period for L-NAME administration. The status of the neuromotor system was evaluated by stimulation electromyography. Treatment with L-NAME during the acute period of traumatic injury to the spinal cord sharply reduced the intensity of evoked motor responses and more pronounced increase in excitability of peripheral motor structures. The results suggest that NO system is a factor of regulation of the stress-induced and adaptive responses of the body at the early stage of spinal cord injury.

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Effect of New Antiviral Agent Camphecin on Behavior of Mice

We studied the effect of camphecin (1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol) on mouse behavior in the open-field test. Camphecin possesses antiviral activity and inhibits viral replication, but its influence on the nervous system is poorly studied. Single camphecin injection produced no significant changes in behavioral patterns. Chronic camphecin administration (5 times over 2 weeks) to mice of different strains had no significant influence on open field behavior (motor, exploratory activity, anxiety, emotional state and vegetative functions). The findings are discussed in the context of neutral influence of camphecin on animal behavior.

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FDG-PET for Early Response Assessment in Lymphomas: Part 1 —Hodgkin Lymphoma

Here we critically analyze the role of PET/CT in the early assessment of Hodgkin lymphoma. (Source: CancerNetwork)

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FDG-PET for Early Response Assessment in Lymphomas: Part 2 —Diffuse Large B-Cell Lymphoma, Use of Quantitative PET Evaluation

Here we review the role of interim PET/CT in diffuse large B-cell lymphoma (DLBCL), and also explore the question of whether new approaches to quantitative assessment improve the prognostic value of interim PET scans in both Hodgkin lymphoma and DLBCL. (Source: CancerNetwork)

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Customized Cooking Methods Enhance Antioxidant, Antiglycemic, and Insulin-Like Properties of Momordica charantia and Moringa oleifera

The current study compares antioxidant activities, total phenolic content (TPC), vitamin C content, and antiglycemic properties of Momordica charantia (small bitter gourd) and Moringa oleifera (drumstick leaves) before and after subjecting to boiling and microwave heating for different durations. Both cooking methods enhanced the antioxidant activity and vitamin C content in the vegetables studied when cooked for five minutes and these properties declined when the cooking time was prolonged to 20 minutes. Cooking also retained or slightly improved the α-glucosidase enzyme inhibition activity of the vegetables; however, it reduced the ability of the vegetable extracts to inhibit α-amylase enzyme activity. The antioxidant activities were positively correlated with the TPC and vitamin C content in the vegetable extracts tested. The present study also evaluated the insulin-like properties (stimulation of adipogenesis) of selected vegetable extracts (five minutes microwaved). 3T3-L1 adipocytes treated with small bitter gourd extract significantly stimulated lipogenesis (in the absence of insulin) compared to drumstick leaves. Thus, the finding of this study negates the belief that cooking will reduce the nutritional value of the vegetables and also suggested that appropriate cooking method and duration for different vegetables could be selected to improve or preserve their nutritional value.

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Water Pollution Detection Based on Hypothesis Testing in Sensor Networks

Water pollution detection is of great importance in water conservation. In this paper, the water pollution detection problems of the network and of the node in sensor networks are discussed. The detection problems in both cases of the distribution of the monitoring noise being normal and nonnormal are considered. The pollution detection problems are analyzed based on hypothesis testing theory firstly; then, the specific detection algorithms are given. Finally, two implementation examples are given to illustrate how the proposed detection methods are used in the water pollution detection in sensor networks and prove the effectiveness of the proposed detection methods.

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An Adaptive Medium Access Parameter Prediction Scheme for IEEE 802.11 Real-Time Applications

Multimedia communications have experienced an unprecedented growth due mainly to the increase in the content quality and the emergence of smart devices. The demand for these contents is tending towards wireless technologies. However, these transmissions are quite sensitive to network delays. Therefore, ensuring an optimum QoS level becomes of great importance. The IEEE 802.11e amendment was released to address the lack of QoS capabilities in the original IEEE 802.11 standard. Accordingly, the Enhanced Distributed Channel Access (EDCA) function was introduced, allowing it to differentiate traffic streams through a group of Medium Access Control (MAC) parameters. Although EDCA recommends a default configuration for these parameters, it has been proved that it is not optimum in many scenarios. In this work a dynamic prediction scheme for these parameters is presented. This approach ensures an appropriate traffic differentiation while maintaining compatibility with the stations without QoS support. As the APs are the only devices that use this algorithm, no changes are required to current network cards. The results show improvements in both voice and video transmissions, as well as in the QoS level of the network that the proposal achieves with regard to EDCA.

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Simultaneous Determination of 5 Flavonoids and 7 Saponins for Quality Control of Traditional Chinese Medicine Preparation Xinnaoshutong Capsule Using HPLC-VWD-ELSD

Xinnaoshutong capsule (XC) is a traditional Chinese prescription derived from the ripe fruit of Tribulus terrestris L. (TT). Although XC has long been considered as an important herbal medicine, no analytical method of marker compounds for quality assessment is registered in the Chinese Pharmacopoeia. A simple analytical method of twelve marker components was developed and validated by HPLC-VWD-ELSD method. Chromatographic separation by HPLC was carried out on a Hedera ODS 2 column (4.6 × 250 mm, 5 μm) by gradient elution with acetonitrile-water (0.1% formic acid) as the mobile phase. Various extraction conditions were optimized to achieve twelve marker compounds with faster extraction and higher recovery. The analytical condition was then validated in terms of the linearity, accuracy and precision, repeatability, and stability. The twelve markers were successfully quantified in 30 batches of commercial samples. The developed HPLC-VWD-ELSD could be used as a rapid and reliable way in the assessment and quality control of XC and TT.

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Quality, Microstructure, and Technological Properties of Sheep Meat Marinated in Three Different Ways

The objective of this study was to explore the effect of 24 and 48 h alkaline (2% pentasodium tripolyphosphate), acid (2% sodium lactate), and water-oil marinating (water : sun flavor oil = 1 : 1 and 2% salt) as well as brine soaking (2% salt) on microstructure, changes in protein, and lipid fractions and technological properties of sheep (m. Longissimus dorsi). Strong myofibrillar fragmentation after 48 h alkaline marinating was observed. Significant swelling and increasing of spaces between myofibrils were found after 24 h brine soaking. Marinating in water-oil emulsions did not show a significant impact on the muscle microstructure. Alkaline and acid marinating as well as salt soaking promote the myofibrillar protein solubility and increased the free amino nitrogen content. After 24 h acid and 48 h alkaline marinating SDS-PAGE electrophoresis showed increasing of 25–30 kDa protein bands. The results obtained for the lipid and protein oxidation confirm prooxidant action of the sodium lactate (2%) and antioxidant effect of polyphosphates (2%) in marinated sheep.

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Upper Bound of the Generalized Value for the Population Variances of Lognormal Distributions with Known Coefficients of Variation

This paper presents an upper bound for each of the generalized values for testing the one population variance, the difference between two population variances, and the ratio of population variances for lognormal distribution when coefficients of variation are known. For each of the proposed generalized values, we derive a closed form expression of the upper bound of the generalized value. Numerical computations illustrate the theoretical results.

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Effects of a Novel Glucokinase Activator, HMS5552, on Glucose Metabolism in a Rat Model of Type 2 Diabetes Mellitus

Glucokinase (GK) plays a critical role in the control of whole-body glucose homeostasis. We investigated the possible effects of a novel glucokinase activator (GKA), HMS5552, to the GK in rats with type 2 diabetes mellitus (T2DM). Male Sprague-Dawley (SD) rats were divided into four groups: control group, diabetic group, low-dose (10 mg/kg) HMS5552-treated diabetic group (HMS-L), and high-dose (30 mg/kg) HMS5552-treated diabetic group (HMS-H). HMS5552 was administered intragastrically to the T2DM rats for one month. The levels of total cholesterol, triglyceride, fasting plasma insulin (FINS), and glucagon (FG) were determined, and an oral glucose tolerance test was performed. The expression patterns of proteins and genes associated with insulin resistance and GK activity were assayed. Compared with diabetic rats, the FINS level was significantly decreased in the HMS5552-treated diabetic rats. HMS5552 treatment significantly lowered the blood glucose levels and improved GK activity and insulin resistance. The immunohistochemistry, western blot, and semiquantitative RT-PCR results further demonstrated the effects of HMS5552 on the liver and pancreas. Our data suggest that the novel GKA, HMS5552, exerts antidiabetic effects on the liver and pancreas by improving GK activity and insulin resistance, which holds promise as a novel drug for the treatment of T2DM patients.

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Corrigendum to “Design and Implementation of a Vehicle Social Enabler Based on Social Internet of Things”

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New Operational Matrix via Genocchi Polynomials for Solving Fredholm-Volterra Fractional Integro-Differential Equations

It is known that Genocchi polynomials have some advantages over classical orthogonal polynomials in approximating function, such as lesser terms and smaller coefficients of individual terms. In this paper, we apply a new operational matrix via Genocchi polynomials to solve fractional integro-differential equations (FIDEs). We also derive the expressions for computing Genocchi coefficients of the integral kernel and for the integral of product of two Genocchi polynomials. Using the matrix approach, we further derive the operational matrix of fractional differentiation for Genocchi polynomial as well as the kernel matrix. We are able to solve the aforementioned class of FIDE for the unknown function . This is achieved by approximating the FIDE using Genocchi polynomials in matrix representation and using the collocation method at equally spaced points within interval . This reduces the FIDE into a system of algebraic equations to be solved for the Genocchi coefficients of the solution . A few numerical examples of FIDE are solved using those expressions derived for Genocchi polynomial approximation. Numerical results show that the Genocchi polynomial approximation adopting the operational matrix of fractional derivative achieves good accuracy comparable to some existing methods. In certain cases, Genocchi polynomial provides better accuracy than the aforementioned methods.

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A kind of rd1 mouse in C57BL/6J mice from crossing with a mutated Kunming mouse

Publication date: 5 April 2017
Source:Gene, Volume 607
Author(s): Weiming Yan, Lu Yao, Wei Liu, Kai Sun, ZuoMing Zhang, Lei Zhang
We occasionally discovered a mouse with spontaneous retinitis pigmentosa (RP) from Kunming (KM) mouse breeding colony, with no obvious waveforms in ERG recordings. The aim of this study is to cross the spontaneously hereditary retinal degeneration mice (temporarily designated as KM/rd mice) derived from KM mice with C57BL/6J mice to establish a congenic inbred strain (temporarily designated as the B6/rd mice), and study the ocular phenotype and genotype of the mice. Fundus photography, tissue morphology, electroretinography (ERG), qRT-PCR, western blot and DNA sequence analysis were performed to observe the ocular phenotype and genotype of KM/rd and B6/rd mice. The fundus photography showed progressive retinal vascular degeneration and depigmentation in KM/rd and B6/rd mice. Compared to wild-type mice, the histological analysis revealed that the outer nuclear layer of the mutated mice was significantly reduced at 14days post born (P14), and almost disappeared by P21. No obvious waveforms were detected at P14 and P21 in the ERG from KM/rd and B6/rd mice. qRT-PCR results showed that the expression quantities of mRNA of pde6b gene in KM/rd and B6/rd mice were significantly lower compared with those of wild-type controls at P21. Western blot results confirmed an abnormal protein expression of pde6b gene in KM/rd and B6/rd mice with no protein products, while there was an obvious protein expression in wild-type mice. The nonsense mutation in exon 7 (a mutation that changes the codon 347 from TAC to TAA) in the pde6b gene of KM/rd and B6/rd mice was identified by genomic DNA sequence analysis. All these findings revealed that the ocular phenotype and genotype of KM/rd and B6/rd mice were similar to those of rd1 mice, which indicates that KM/rd and B6/rd mice can be used as an RP mouse model.



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New Operational Matrix via Genocchi Polynomials for Solving Fredholm-Volterra Fractional Integro-Differential Equations

It is known that Genocchi polynomials have some advantages over classical orthogonal polynomials in approximating function, such as lesser terms and smaller coefficients of individual terms. In this paper, we apply a new operational matrix via Genocchi polynomials to solve fractional integro-differential equations (FIDEs). We also derive the expressions for computing Genocchi coefficients of the integral kernel and for the integral of product of two Genocchi polynomials. Using the matrix approach, we further derive the operational matrix of fractional differentiation for Genocchi polynomial as well as the kernel matrix. We are able to solve the aforementioned class of FIDE for the unknown function . This is achieved by approximating the FIDE using Genocchi polynomials in matrix representation and using the collocation method at equally spaced points within interval . This reduces the FIDE into a system of algebraic equations to be solved for the Genocchi coefficients of the solution . A few numerical examples of FIDE are solved using those expressions derived for Genocchi polynomial approximation. Numerical results show that the Genocchi polynomial approximation adopting the operational matrix of fractional derivative achieves good accuracy comparable to some existing methods. In certain cases, Genocchi polynomial provides better accuracy than the aforementioned methods.

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Analysis of Waterman’s Method in the Case of Layered Scatterers

The method suggested by Waterman has been widely used in the last years to solve various light scattering problems. We analyze the mathematical foundations of this method when it is applied to layered nonspherical (axisymmetric) particles in the electrostatic case. We formulate the conditions under which Waterman’s method is applicable, that is, when it gives an infinite system of linear algebraic equations relative to the unknown coefficients of the field expansions which is solvable (i.e., the inverse matrix exists) and solutions of the truncated systems used in calculations converge to the solution of the infinite system. The conditions obtained are shown to agree with results of numerical computations. Keeping in mind the strong similarity of the electrostatic and light scattering cases and the agreement of our conclusions with the numerical calculations available for homogeneous and layered scatterers, we suggest that our results are valid for light scattering as well.

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Corrigendum to “GIT1/PIX signaling proteins and PAK1 kinase regulate microtubule nucleation” [Biochim. Biophys. Acta 1863/6PA (2016) 1282–1297]

Publication date: Available online 15 January 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Markéta Černohorská, Vadym Sulimenko, Zuzana Hájková, Tetyana Sulimenko, Vladimíra Sládková, Stanislav Vinopal, Eduarda Dráberová, Pavel Dráber




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PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson's disease

Background

A number of early features can precede the diagnosis of Parkinson's disease (PD).

Objective

To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population.

Methods

Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations. Risk scores were calculated based on the results of a systematic review of risk factors and early features of PD, and individuals were grouped into higher (above 15th centile), medium, and lower risk groups (below 85th centile). Previously defined indicators of increased risk of PD (“intermediate markers”), including smell loss, rapid eye movement–sleep behavior disorder, and finger-tapping speed, and incident PD were used as outcomes. The correlation of risk scores with intermediate markers and movement of individuals between risk groups was assessed each year and prospectively. Exploratory Cox regression analyses with incident PD as the dependent variable were performed.

Results

A total of 1323 participants were recruited at baseline and >79% completed assessments each year. Annual risk scores were correlated with intermediate markers of PD each year and baseline scores were correlated with intermediate markers during follow-up (all P values < 0.001). Incident PD diagnoses during follow-up were significantly associated with baseline risk score (hazard ratio = 4.39, P = .045). GBA variants or G2019S LRRK2 mutations were found in 47 participants, and the predictive power for incident PD was improved by the addition of genetic variants to risk scores.

Conclusions

The online PREDICT-PD algorithm is a unique and simple method to identify indicators of PD risk. © 2017 International Parkinson and Movement Disorder Society

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The many faces of autonomic failure in multiple system atrophy

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Mutations in TMEM230 are not a common cause of Parkinson's disease

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The epileptic and nonepileptic spectrum of paroxysmal dyskinesias: Channelopathies, synaptopathies, and transportopathies

ABSTRACT

Historically, the syndrome of primary paroxysmal dyskinesias was considered a group of disorders as a result of ion channel dysfunction. This proposition was primarily based on the discovery of mutations in ion channels, which caused other episodic neurological disorders such as epilepsy and migraine and also supported by the frequent association between paroxysmal dyskinesias and epilepsy. However, the discovery of the genes responsible for the 3 classic forms of paroxysmal dyskinesias disproved this ion channel theory. On the other hand, novel gene mutations implicating ion channels have been recently reported to produce episodic movement disorders clinically similar to the classic paroxysmal dyskinesias. Here, we review the clinical and pathophysiological aspects of the paroxysmal dyskinesias, further proposing a pathophysiological framework according to which they can be classified as synaptopathies (proline-rich transmembrane protein 2 and myofibrillogenesis regulator gene), channelopathies (calcium-activated potassium channel subunit alpha-1 and voltage-gated sodium channel type 8), or transportopathies (solute carrier family 2 member 1). This proposal might serve to explain similarities and differences among the various paroxysmal dyskinesias in terms of clinical features, treatment response, and natural history. © 2017 International Parkinson and Movement Disorder Society

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Study on Prevalence of Helminthes of Local Backyard and Exotic Chickens in and Around Ambowest Shoa Zone, Oromia Regional State, Ethiopia

The post Study on Prevalence of Helminthes of Local Backyard and Exotic Chickens in and Around Ambowest Shoa Zone, Oromia Regional State, Ethiopia appeared first on Welcome to Avens.

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Head and neck cancer art exhibition unveils hidden experience ... - Edmonton Sun

Edmonton Sun

Head and neck cancer art exhibition unveils hidden experience ... Edmonton Sun FLUX: Responding to Head and Neck Cancer Cancer survivor Sharon Dixon poses for a photo with Edmonton artist Brad Necyk's mixed media piece titled ... and more »

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Quercetin and Quercetin-Rich Red Onion Extract Alter Pgc-1α Promoter Methylation and Splice Variant Expression

Pgc-1α and its various isoforms may play a role in determining skeletal muscle mitochondrial adaptations in response to diet. 8 wks of dietary supplementation with the flavonoid quercetin (Q) or red onion extract (ROE) in a high fat diet (HFD) ameliorates HFD-induced obesity and insulin resistance in C57BL/J mice while upregulating Pgc-1α and increasing skeletal muscle mitochondrial number and function. Here, mice were fed a low fat (LF), high fat (HF), high fat plus quercetin (HF + Q), or high fat plus red onion extract (HF + RO) diet for 9 wks and skeletal muscle Pgc-1α isoform expression and DNA methylation were determined. Quantification of various Pgc-1α isoforms, including isoforms Pgc-1α-a, Pgc-1α-b, Pgc-1α-c, Pgc-1α4, total NT-Pgc-1α, and FL-Pgc-1α, showed that only total NT-Pgc-1α expression was increased in LF, HF + Q, and HF + RO compared to HF. Furthermore, Q supplementation decreased Pgc-1α-a expression compared to LF and HF, and ROE decreased Pgc-1α-a expression compared to LF. FL-Pgc-1α was decreased in HF + Q and HF + RO compared to LF and HF. HF exhibited hypermethylation at the −260 nucleotide (nt) in the Pgc-1α promoter. Q and ROE prevented HFD-induced hypermethylation. −260 nt methylation levels were associated with NT-Pgc-1α expression only. Pgc-1α isoform expression may be epigenetically regulated by Q and ROE through DNA methylation.

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PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors

Purpose: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs.

Experimental Design: We analyzed tumor and matched blood samples from 85 patients with GISTs and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in Kit^V558/+ mice that develop GISTs.

Results: The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFN-induced upregulation of PD-L1 via STAT1 inhibition. In Kit^V558/+ mice, imatinib downregulated IFN-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.

Conclusions: PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GISTs. Collectively, our results provide the rationale to combine these agents in human GISTs. Clin Cancer Res; 23(2); 454–65. ©2016 AACR.

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Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target

Purpose: To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)-expressing ovarian cancer cells.

Experimental Design: FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic subtypes and 20 human healthy tissues. The effectiveness of human T cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T cells.

Results: FSHR is expressed in gynecologic malignancies of different histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo. In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T cells persisted as memory lymphocytes without noticeable PD-1–dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor–transduced T cells away from targeted tumor cells.

Conclusions: T cells redirected against FSHR⁺ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries. Clin Cancer Res; 23(2); 441–53. ©2016 AACR.

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Retraction: Effective Targeting of Triple-Negative Breast Cancer Cells by PF-4942847, a Novel Oral Inhibitor of Hsp 90

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Correction: The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer

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PI3K/Akt/mTOR Signaling and Plasma Membrane Proteins Are Implicated in Responsiveness to Adjuvant Dendritic Cell Vaccination for Metastatic Colorectal Cancer

Purpose: We have previously demonstrated that patients with metastatic colorectal cancer who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared with patients in whom responses do not occur. We sought to characterize the patterns of T-lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine.

Experimental Design: Cytotoxic, memory, and regulatory T cells in resected metastases and surrounding normal liver tissue from 22 patients (11 responders and 11 nonresponders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the combined multivariate and collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on gene products with cell membrane–related functions.

Results: There was no correlation between vaccine response and intratumor, peritumor, or hepatic densities of T-cell subpopulations. Associated genes were found to be enriched in the PI3K/Akt/mTOR signaling axis (P < 0.001). Applying a consistent prediction score cutoff over 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%).

Conclusions: Adjuvant DC vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as tumor surface proteins. Clin Cancer Res; 23(2); 399–406. ©2016 AACR.

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Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors

Purpose: Pancreatic neuroendocrine tumors (PanNET) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing has identified recurrent mutations in the genes DAXX and ATRX, which correlate with loss of protein expression and alternative lengthening of telomeres (ALT). Both ALT and DAXX/ATRX loss were initially reported to be associated with a favorable prognosis; however, recent studies suggest the contrary. Our aims were to assess the prevalence and prognostic significance of ALT and DAXX/ATRX in both primary and metastatic PanNETs.

Experimental Design: Telomere-specific FISH and DAXX/ATRX IHC was performed on a multi-institutional cohort of 321 patients with resected PanNET and 191 distant metastases from 52 patients. These results were correlated with clinicopathologic features, including disease-free survival (DFS) and disease-specific survival (DSS).

Results: The prevalence of ALT and DAXX/ATRX loss in resected PanNETs was 31% and 26%, respectively, and associated with larger tumor size, higher WHO grade, lymph node metastasis, and distant metastasis (P < 0.001). The 5-year DFS and 10-year DSS of patients with ALT-positive and DAXX/ATRX-negative PanNETs were 40% and 50%, respectively, as compared with 96% and 89%, respectively, for wild-type PanNETs. Among distant metastases, ALT and DAXX/ATRX loss was 67% and 52%, respectively, and only occurred in the setting of an ALT-positive and DAXX/ATRX-negative primary PanNET. By multivariate analysis, both ALT and DAXX/ATRX loss were negative, independent prognostic factors for DFS.

Conclusions: ALT and DAXX/ATRX loss in PanNETs was associated with shorter DFS and DSS and likely plays a significant role in driving metastatic disease. Clin Cancer Res; 23(2); 600–9. ©2016 AACR.

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A Pilot Trial of the Combination of Vemurafenib with Adoptive Cell Therapy in Patients with Metastatic Melanoma

Purpose: This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF^V600 mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma.

Experimental Design: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration. Vemurafenib was restarted at the time of TIL infusion and was continued for 2 years or until disease progression. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Metastases resected prior to and after 2 weeks of vemurafenib were compared using TCRB deep sequencing, immunohistochemistry, proliferation, and recognition of autologous tumor.

Results: The treatment was well tolerated and had a safety profile similar to that of TIL or vemurafenib alone. Seven of 11 patients (64%) experienced an objective clinical response, and 2 patients (18%) had a complete response for 3 years (one response is ongoing at 46 months). Proliferation and viability of infusion bag TILs and peripheral blood T cells were inhibited in vitro by research-grade vemurafenib (PLX4032) when approaching the maximum serum concentration of vemurafenib. TCRB repertoire (clonotypes numbers, clonality, and frequency) did not significantly change between pre- and post-vemurafenib lesions. Recognition of autologous tumor by T cells was similar between TILs grown from pre- and post-vemurafenib metastases.

Conclusions: Coadministration of vemurafenib and TILs was safe and feasible and generated objective clinical responses in this small pilot clinical trial. Clin Cancer Res; 23(2); 351–62. ©2016 AACR.

See related commentary by Cogdill et al., p. 327

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Evaluating Acetate Metabolism for Imaging and Targeting in Multiple Myeloma

Purpose: We hypothesized that in multiple myeloma cells (MMC), high membrane biosynthesis will induce acetate uptake in vitro and in vivo. Here, we studied acetate metabolism and targeting in MMC in vitro and tested the efficacy of ¹¹C-acetate–positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo.

Experimental design: Acetate fate tracking using ¹³C-edited-¹H NMR (nuclear magnetic resonance) was performed to study in vitro acetate uptake and metabolism in MMC. Effects of pharmacological modulation of acetate transport or acetate incorporation into lipids on MMC cell survival and viability were assessed. Preclinical mouse MM models of subcutaneous and bone tumors were evaluated using ¹¹C-acetate-PET/CT imaging and tissue biodistribution.

Results: In vitro, NMR showed significant uptake of acetate by MMC and acetate incorporation into intracellular metabolites and membrane lipids. Inhibition of lipid synthesis and acetate transport was toxic to MMC, while sparing resident bone cells or normal B cells. In vivo, ¹¹C-acetate uptake by PET imaging was significantly enhanced in subcutaneous and bone MMC tumors compared with unaffected bone or muscle tissue. Likewise, ¹¹C-acetate uptake was significantly reduced in MM tumors after treatment.

Conclusions: Uptake of acetate from the extracellular environment was enhanced in MMC and was critical to cellular viability. ¹¹C-Acetate–PET detected the presence of myeloma cells in vivo, including uptake in intramedullary bone disease. ¹¹C-Acetate–PET also detected response to therapy in vivo. Our data suggested that acetate metabolism and incorporation into lipids was crucial to MM cell biology and that ¹¹C-acetate–PET is a promising imaging modality for MM. Clin Cancer Res; 23(2); 416–29. ©2016 AACR.

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Branched Chain RNA In Situ Hybridization for Androgen Receptor Splice Variant AR-V7 as a Prognostic Biomarker for Metastatic Castration-Sensitive Prostate Cancer

Purpose: The androgen receptor (AR) mRNA splice variant AR-V7 has emerged as a predictive biomarker for response to AR-targeted therapies. There are currently no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues.

Experimental design: We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes. This automated ISH assay was applied to tumor tissue from two distinct clinical cohorts that we hypothesized would differ in AR-V7 status.

Results: We detected AR-V7 in all tumor samples from men with metastatic castration-resistant prostate cancer with tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide; n = 12). We detected AR-V7 in just one tumor from men who had undergone prostatectomy for localized adenocarcinoma (n = 30; Gleason 4 + 5 = 9 in the AR-V7–positive sample). Given the apparent distinction between the above groups by AR-V7 signal, we analyzed pretreatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naïve metastatic disease. Patients with metastases but without detectable AR-V7 RNA at baseline had significantly longer overall survival (log-rank P = 0.044) and a trend toward superior progression-free survival (log-rank P = 0.055).

Conclusions: Within an institutional cohort, the RNA ISH assay identified AR-V7 within FFPE tissue and may have prognostic value in metastatic castration-sensitive prostate cancer. These preliminary findings warrant further study in larger cohorts. Clin Cancer Res; 23(2); 363–9. ©2016 AACR.

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Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry

Purpose: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high-quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles toward widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular colorectal cancer subtyping in a multicenter study.

Experimental Design: Tissue microarrays from 1,076 patients with colorectal cancer from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1, and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semiquantitative pathologist scoring of the cores as input and applied to three independent clinical cohorts.

Results: This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular colorectal cancer subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild-type metastatic cancers of the canonical epithelial-like subtypes.

Conclusions: This study shows that a practical and robust immunohistochemical assay can be employed to identify molecular colorectal cancer subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of colorectal cancer samples, both in the format of an automated image analysis pipeline to score tumor core staining, and as a classifier based on semiquantitative pathology scoring. Clin Cancer Res; 23(2); 387–98. ©2016 AACR.

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Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer

Purpose: To determine the expression level, associations, and biological role of PD-L1, IDO-1, and B7-H4 in non–small cell lung cancer (NSCLC).

Experimental Design: Using multiplexed quantitative immunofluorescence (QIF), we measured the levels of PD-L1, IDO-1, B7-H4, and different tumor-infiltrating lymphoycte (TIL) subsets in 552 stages I–IV lung carcinomas from two independent populations. Associations between the marker levels, TILs, and major clinicopathologic variables were determined. Validation of findings was performed using mRNA expression data from The Cancer Genome Atlas (TCGA) and in vitro stimulation of lung adenocarcinoma A549 cells with IFN and IL10.

Results: PD-L1 was detected in 16.9% and 21.8% of cases in each population. IDO-1 was expressed in 42.6% and 49.8%; and B7-H4 in 12.8% and 22.6% of cases, respectively. Elevated PD-L1 and IDO-1 were consistently associated with prominent B- and T-cell infiltrates, but B7-H4 was not. Coexpression of the three protein markers was infrequent, and comparable results were seen in the lung cancer TCGA dataset. Levels of PD-L1 and IDO-1 (but not B7-H4) were increased by IFN stimulation in A549 cells. Treatment with IL10 upregulated B7-H4 but did not affect PD-L1 and IDO-1 levels.

Conclusions: PD-L1, IDO-1, and B7-H4 are differentially expressed in human lung carcinomas and show limited co-expression. While PD-L1 and IDO-1 are associated with increased TILs and IFN stimulation, B7-H4 is not. The preferential expression of discrete immune evasion pathways in lung cancer could participate in therapeutic resistance and support design of optimal clinical trials. Clin Cancer Res; 23(2); 370–8. ©2016 AACR.

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Estrogen Receptor Binding (18F-FES PET) and Glycolytic Activity (18F-FDG PET) Predict Progression-Free Survival on Endocrine Therapy in Patients with ER+ Breast Cancer

Purpose:¹⁸F-fluoroestradiol (FES) PET scans measure regional estrogen binding, and ¹⁸F-fluorodeoxyglucose (FDG) PET measures tumor glycolytic activity. We examined quantitative and qualitative imaging biomarkers of progression-free survival (PFS) in breast cancer patients receiving endocrine therapy.

Experimental Design: Ninety patients with breast cancer from an estrogen receptor–positive (ER⁺), HER2^– primary tumor underwent FES PET and FDG PET scans prior to endocrine therapy (63% aromatase inhibitor, 22% aromatase inhibitor and fulvestrant, 15% other). Eighty-four had evaluable data for PFS prediction.

Results: Recursive partitioning with 5-fold internal cross-validation used both FES PET and FDG PET measures to classify patients into three distinct response groups. FDG PET identified 24 patients (29%) with low FDG uptake, suggesting indolent tumors. These patients had a median PFS of 26.1 months (95% confidence interval, 11.2–49.7). Of patients with more FDG-avid tumors, 50 (59%) had high average FES uptake, and 10 (12%) had low average FES uptake. These groups had median PFS of 7.9 (5.6–11.8) and 3.3 months (1.4–not evaluable), respectively. Patient and tumor features did not replace or improve the PET measures' prediction of PFS. Prespecified endocrine resistance classifiers identified in smaller cohorts did not individually predict PFS.

Conclusions: A wide range of therapy regimens are available for treatment of ER⁺ metastatic breast cancer, but no guidelines are established for sequencing these therapies. FDG PET and FES PET may help guide the timing of endocrine therapy and selection of targeted and/or cytotoxic chemotherapy. A multicenter trial is ongoing for external validation. Clin Cancer Res; 23(2); 407–15. ©2016 AACR.

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Individualized Molecular Analyses Guide Efforts (IMAGE): A Prospective Study of Molecular Profiling of Tissue and Blood in Metastatic Triple-Negative Breast Cancer

Purpose: The clinical utility of next-generation sequencing (NGS) in breast cancer has not been demonstrated. We hypothesized that we could perform NGS of a new biopsy from patients with metastatic triple-negative breast cancer (TNBC) in a clinically actionable timeframe.

Experimental Design: We planned to enroll 40 patients onto a prospective study, Individualized Molecular Analyses Guide Efforts (IMAGE), to evaluate the feasibility of obtaining a new biopsy of a metastatic site, perform NGS (FoundationOne), and convene a molecular tumor board to formulate treatment recommendations within 28 days. We collected blood at baseline and at time of restaging to assess cell-free circulating plasma tumor DNA (ptDNA).

Results: We enrolled 26 women with metastatic TNBC who had received ≥1 line of prior chemotherapy, and 20 (77%) underwent NGS of a metastatic site biopsy. Twelve (60%) evaluable patients received treatment recommendations within 28 days of consent. The study closed after 20 patients underwent NGS, based on protocol-specified interim futility analysis. Three patients went on to receive genomically directed therapies. Twenty-four of 26 patients had genetic alterations successfully detected in ptDNA. Among 5 patients, 4 mutations found in tumor tissues were not identified in blood, and 4 mutations found in blood were not found in corresponding tumors. In 9 patients, NGS of follow-up blood samples showed 100% concordance with baseline blood samples.

Conclusions: This study demonstrates challenges of performing NGS on prospective tissue biopsies in patients with metastatic TNBC within 28 days, while also highlighting the potential use of blood as a more time-efficient and less invasive method of mutational assessment. Clin Cancer Res; 23(2); 379–86. ©2016 AACR.

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Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model

Purpose: New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the Thrb^PV/PVKras^G12D mouse, a model of anaplastic thyroid cancer.

Experimental Design: We treated Thrb^PV/PVKras^G12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression.

Results: JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1–CDK4–Rb–E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation.

Conclusions: These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430–40. ©2016 AACR.

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Correction: Genomic EWSR1 Fusion Sequence as Highly Sensitive and Dynamic Plasma Tumor Marker in Ewing Sarcoma

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Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer

Purpose: The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide–MHC complexes can be targets for CAR T-cell therapy against solid tumors.

Experimental Design: We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP_158–166 peptide complexed with human leukocyte antigen (HLA)-A*02:01.

Results: We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01⁺/AFP⁺ while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP₁₅₈-expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6).

Conclusions: This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. Clin Cancer Res; 23(2); 478–88. ©2016 AACR.

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Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

Purpose: Cisplatin (CDDP) is frequently used in combination chemotherapy with paclitaxel for treating urothelial carcinoma of the urinary bladder (UCUB). CDDP cross-resistance has been suggested to develop with paclitaxel, thus hindering successful UCUB treatment. Therefore, elucidating the mechanisms underlying CDDP-induced anticancer drug resistance is imperative and may provide an insight in developing novel therapeutic strategy.

Experimental Design: Loss-of-function assays were performed to elucidate the role of the EGFR and STAT3 in CDDP-induced CCAAT/enhancer-binding protein delta (CEBPD) expression in UCUB cells. Reporter and in vivo DNA-binding assays were employed to determine whether CEBPD directly regulates ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily C member 2 (ABCC2) activation. Finally, a xenograft animal assay was used to examine the abilities of gefitinib and S3I-201 (a STAT3 inhibitor) to reverse CDDP and paclitaxel sensitivity.

Results: CEBPD expression was maintained in postoperative chemotherapy patients, and this expression was induced by CDDP even in CDDP-resistant UCUB cells. Upon CDDP treatment, CEBPD activated ABCB1 and ABCC2. Furthermore, the EGFR/STAT3 pathway contributed to CDDP-induced CEBPD expression in UCUB cells. Gefitinib and S3I-201 treatment significantly reduced the expression of CEBPD and enhanced the sensitivity of CDDP-resistant UCUB cells to CDDP and paclitaxel.

Conclusions: Our results revealed the risk of CEBPD activation in CDDP-resistant UCUB cells and suggested a therapeutic strategy for patients with UCUB or UCUB resisted to CDDP and paclitaxel by combination with either gefitinib or S3I-201. Clin Cancer Res; 23(2); 503–13. ©2016 AACR.

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Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma: CE7 Epitope Target Safety and Product Manufacturing Feasibility

Purpose: The identification and vetting of cell surface tumor-restricted epitopes for chimeric antigen receptor (CAR)–redirected T-cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation-dependent tumor-specific epitope recognized by the CE7 monoclonal antibody.

Experimental Design: CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays. The safety of targeting the CE7 epitope of CD171 with CE7-CAR T cells was evaluated in a preclinical rhesus macaque trial on the basis of CD171 homology and CE7 cross reactivity. The feasibility of generating bioactive CAR T cells from heavily pretreated pediatric patients with recurrent/refractory disease was assessed.

Results: CD171 is uniformly and abundantly expressed by neuroblastoma tumor specimens obtained at diagnoses and relapse independent of patient clinical risk group. CD171 expression in normal tissues is similar in humans and rhesus macaques. Infusion of up to 1 x 10⁸/kg CE7-CAR⁺ CTLs in rhesus macaques revealed no signs of specific on-target off-tumor toxicity. Manufacturing of lentivirally transduced CD4⁺ and CD8⁺ CE7-CAR T-cell products under GMP was successful in 4 out of 5 consecutively enrolled neuroblastoma patients in a phase I study. All four CE7-CAR T-cell products demonstrated in vitro and in vivo antitumor activity.

Conclusions: Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T-cell target for neuroblastoma immunotherapy. Clin Cancer Res; 23(2); 466–77. ©2016 AACR.

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IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells

Purpose: Alternative strategies to EGFR blockage by mAbs is necessary to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status.

Experimental Design: NK cells from normal donors or donors with pancreatic cancer were used to assess ADCC, IFN- release, and T-cell chemotaxis toward human pancreatic cancer cell lines. The in vivo efficacy of IL-21 in combination with cetuximab was evaluated in a subcutaneous and intraperitoneal model of pancreatic cancer.

Results: NK cell lysis of cetuximab-coated wild-type and mutant kras pancreatic cancer cell lines were significantly higher following NK cell IL-21 treatment. In response to cetuximab-coated pancreatic tumor cells, IL-21–treated NK cells secreted significantly higher levels of IFN- and chemokines, increased chemotaxis of T cells, and enhanced NK cell signal transduction via activation of ERK and STAT1. Treatment of mice bearing subcutaneous or intraperitoneal EGFR-positive pancreatic tumor xenografts with mIL-21 and cetuximab led to significant inhibition of tumor growth, a result further enhanced by the addition of gemcitabine.

Conclusions: These results suggest that cetuximab treatment in combination with IL-21 adjuvant therapy in patients with EGFR-positive pancreatic cancer results in significant NK cell activation, irrespective of KRAS mutation status, and may be a potential therapeutic strategy. Clin Cancer Res; 23(2); 489–502. ©2016 AACR.

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RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer

Introduction: PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)–deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display "cancer stem cell" properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence. The sensitivity of breast cancer stem cells (CSC) to PARPi is unknown.

Experimental Design: We determined the sensitivity of breast CSCs to PARP inhibition in BRCA1-mutant and -wild-type TNBC cell lines and tumor xenografts. We also investigated the role of RAD51 in mediating CSC resistance to PARPi in these in vitro and in vivo models.

Results: We demonstrated that the CSCs in BRCA1-mutant TNBCs were resistant to PARP inhibition, and that these cells had both elevated RAD51 protein levels and activity. Downregulation of RAD51 by shRNA sensitized CSCs to PARP inhibition and reduced tumor growth. BRCA1–wild-type cells were relatively resistant to PARP inhibition alone, but reduction of RAD51 sensitized both CSC and bulk cells in these tumors to PARPi treatment.

Conclusions: Our data suggest that in both BRCA1-mutant and BRCA1–wild-type TNBCs, CSCs are relatively resistant to PARP inhibition. This resistance is mediated by RAD51, suggesting that strategies aimed at targeting RAD51 may increase the therapeutic efficacy of PARPi. Clin Cancer Res; 23(2); 514–22. ©2016 AACR.

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ARDS

ARDS: Acronym that stands for a disorder known as or Acute Respiratory Distress Syndrome.

In ARDS there is respiratory failure of sudden (acute) onset due to the rapid accumulation of fluid in the lungs (pulmonary edema) following an abrupt increase in the permeability of the normal barrier between the capillaries and the air sacs in the lungs. ARDS is the most serious response to acute lung injury.

The types of acute lung injury that may lead to ARDS are very diverse. They include (but are by no means limited to) aspiration (swallowing fluid or food down the windpipe), inhalation of a toxic substance, widespread (diffuse) infection of the lungs, sepsis (blood infection) and near drowning.

ARDS forces the muscles of the lungs to work harder causing labored breathing (huffing and puffing). Despite the effort, breathing is inefficient. There is hypoxemia (an abnormally low level of oxygen in the blood), a characteristic feature of ARDS.

The treatment of ARDS frequently involves the transient use of a mechanical ventilator to help breathing.

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Exfoliation and supramolecular functionalization of graphene with an electron donor perylenediimide derivative

Photochem. Photobiol. Sci., 2017, Accepted Manuscript
DOI: 10.1039/C6PP00351F, Paper

Luis Martin-Gomis, Nikolaos Karousis, Fernando Fernandez-Lazaro, Ioannis D Petsalakis, Kei Ohkubo, Shunichi Fukuzumi, Nikos Tagmatarchis, Angela Sastre-Santos
The liquid exfoliation of graphite to few layered graphene sheets together with the non-covalent supramolecular functionalization of exfoliated graphene by the synthesized N,N'-di(2-ethylhexyl)-1-(N''''-methylpiperazin-N'''-yl)perylene-3,4,9,10-tetracarboxydiimide (Pip-PDI) is reported. The aromatic Pip-PDI has...
The content of this RSS Feed (c) The Royal Society of Chemistry

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Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression

The physical properties of the extracellular matrix (ECM), such as stiffness, are involved in the determination of the characteristics of cancer cells, including chemotherapy sensitivity. Resistance to chemotherapy is often linked to dysfunction of tumor suppressor p53; however, it remains elusive whether the ECM microenvironment interferes with p53 activation in cancer cells. Here, we show that, in MCF-7 breast cancer cells, extracellular stiffness influences p53 activation induced by the antitumor drug doxorubicin. Cell growth inhibition by doxorubicin was increased in response to ECM rigidity in a p53-dependent manner. The expression of Rho-associated coiled coil-containing protein kinase (ROCK) 2, which induces the activation of myosin II, was significantly higher when cells were cultured on stiffer ECM substrates. Knockdown of ROCK2 expression or pharmacological inhibition of ROCK decreased doxorubicin-induced p53 activation. Our results suggest that a soft ECM causes downregulation of ROCK2 expression, which drives resistance to chemotherapy by repressing p53 activation.

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Threshold Dynamics in Stochastic SIRS Epidemic Models with Nonlinear Incidence and Vaccination

In this paper, the dynamical behaviors for a stochastic SIRS epidemic model with nonlinear incidence and vaccination are investigated. In the models, the disease transmission coefficient and the removal rates are all affected by noise. Some new basic properties of the models are found. Applying these properties, we establish a series of new threshold conditions on the stochastically exponential extinction, stochastic persistence, and permanence in the mean of the disease with probability one for the models. Furthermore, we obtain a sufficient condition on the existence of unique stationary distribution for the model. Finally, a series of numerical examples are introduced to illustrate our main theoretical results and some conjectures are further proposed.

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Epidermal Growth Factor Signaling towards Proliferation: Modeling and Logic Inference Using Forward and Backward Search

In biological systems, pathways define complex interaction networks where multiple molecular elements are involved in a series of controlled reactions producing responses to specific biomolecular signals. These biosystems are dynamic and there is a need for mathematical and computational methods able to analyze the symbolic elements and the interactions between them and produce adequate readouts of such systems. In this work, we use rewriting logic to analyze the cellular signaling of epidermal growth factor (EGF) and its cell surface receptor (EGFR) in order to induce cellular proliferation. Signaling is initiated by binding the ligand protein EGF to the membrane-bound receptor EGFR so as to trigger a reactions path which have several linked elements through the cell from the membrane till the nucleus. We present two different types of search for analyzing the EGF/proliferation system with the help of Pathway Logic tool, which provides a knowledge-based development environment to carry out the modeling of the signaling. The first one is a standard (forward) search. The second one is a novel approach based on narrowing, which allows us to trace backwards the causes of a given final state. The analysis allows the identification of critical elements that have to be activated to provoke proliferation.

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Psychological Distress in Healthy Low-Risk First-Time Mothers during the Postpartum Period: An Exploratory Study

Psychological distress, defined as depression, anxiety, and insomnia in this study, can occur following the birth of a baby as new mothers, in addition to marked physiological changes, are faced with adapting to new roles and responsibilities. We investigated the cooccurrence of stress, depression, anxiety, and insomnia in mothers during the postpartum period; tested the feasibility of study methods and procedures for use in this population; and identified new mothers interest in using cranial electrotherapy stimulation (CES) as an intervention for reducing psychological distress. We recruited healthy, low-risk, English speaking first-time mothers, ages 18–32 years, with healthy babies (), within 12 months of an uncomplicated birth. Participants completed the PSS, HAM-D14, HAM-A17, and PSQI19. No problems were encountered with study procedures. Mothers reported a high interest (4.9) in the potential use of CES to treat or prevent the occurrence of psychological distress. All participants () reported moderate levels of depression and anxiety, while 75.8% () reported insomnia. PSS scores were within the norms for healthy women. Further research is recommended to investigate if our findings can be replicated or if different patterns of associations emerge. Implications for clinical practice are addressed.

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Hybrid Assistive Neuromuscular Dynamic Stimulation Therapy: A New Strategy for Improving Upper Extremity Function in Patients with Hemiparesis following Stroke

Hybrid Assistive Neuromuscular Dynamic Stimulation (HANDS) therapy is one of the neurorehabilitation therapeutic approaches that facilitates the use of the paretic upper extremity (UE) in daily life by combining closed-loop electromyography- (EMG-) controlled neuromuscular electrical stimulation (NMES) with a wrist-hand splint. This closed-loop EMG-controlled NMES can change its stimulation intensity in direct proportion to the changes in voluntary generated EMG amplitudes recorded with surface electrodes placed on the target muscle. The stimulation was applied to the paretic finger extensors. Patients wore a wrist-hand splint and carried a portable stimulator in an arm holder for 8 hours during the daytime. The system was active for 8 hours, and patients were instructed to use their paretic hand as much as possible. HANDS therapy was conducted for 3 weeks. The patients were also instructed to practice bimanual activities in their daily lives. Paretic upper extremity motor function improved after 3 weeks of HANDS therapy. Functional improvement of upper extremity motor function and spasticity with HANDS therapy is based on the disinhibition of the affected hemisphere and modulation of reciprocal inhibition. HANDS therapy may offer a promising option for the management of the paretic UE in patients with stroke.

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Effect of Mahuang Gancao Ganjiang Decoction on Fusion and Fission of Mitochondria and Apoptosis of Lymphocytes in Mice under Cold Stress

Mahuang Gancao Ganjiang Decoction (MGGD) can effectively alleviate the symptoms of the patients suffering from exogenous cold stress. However, the curative mechanism has not been fully clarified. This study was designed to investigate the effect of MGGD on the apoptosis of lymphocytes induced by cold stress in mice. The model mice were randomly divided into four groups: the normal control group (no handling mice), cold stress group, MGGD + cold stress group, and MGGD group. Lymphocytes of the mice were isolated from the peripheral blood. Electron microscopy analysis revealed cold stress resulted in mitochondrial fragmentation. Accompanied with the change of morphology of mitochondria, ATP production and the activity of respiratory chain complex decreased in these cells. Western blot analysis showed that these cells expressed decreased fusion-related proteins Mitofusin 1 (Mfn1), Mitofusin 2 (Mfn2), and optic atrophy protein-1 (Opa-1) and increased fission-related proteins dynamin-related protein 1 (Drp1) and fission 1 (Fis-1); our results also show that decreased mitochondrial fusion induces cell apoptosis during cold stress. Meanwhile, we found MGGD can inhibit cell apoptosis induced by cold stress through regulating expression level of Mfn1, Mfn2, Drp1, Fis-1, and Opa-1. These findings are very significant for understanding how MGGD regulates cold-stress-induced cell apoptosis.

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Mismatch Based Diagnosis of PV Fields Relying on Monitored String Currents

This paper presents a DC side oriented diagnostic method for photovoltaic fields which operates on string currents previously supplied by an appropriate monitoring system. The relevance of the work relies on the definition of an effective and reliable day-by-day target for the power that every string of the field should have produced. The procedure is carried out by comparing the instantaneous power produced by all solar strings having the same orientation and by attributing, as producible power for all of them, the maximum value. As figure of merit, the difference between the maximum allowed energy production (evaluated as the integral of the power during a defined time interval) and the energy actually produced by the strings is defined. Such a definition accounts for both weather and irradiance conditions, without needing additional sensors. The reliability of the approach was experimentally verified by analyzing the performance of two medium size solar fields that were monitored over a period of four years. Results allowed quantifying energy losses attributable to underperforming solar strings and precisely locating their position in the field.

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Performance of NiFe2O4-SiO2-TiO2 Magnetic Photocatalyst for the Effective Photocatalytic Reduction of Cr(VI) in Aqueous Solutions

Investigation into the reduction of Cr(VI) in aqueous solution was carried out through some batch photocatalytic studies. The photocatalysts used were silica coated nickel ferrite nanoparticles (NiFe2O4-SiO2), nickel ferrite titanium dioxide (NiFe2O4-TiO2), nickel ferrite silica titanium dioxide (NiFe2O4-SiO2-TiO2), and titanium dioxide (TiO2). The characterization of the materials prepared via stepwise synthesis using coprecipitation and sol-gel methods were carried out with the aid of X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, thermal gravimetric analysis (TGA), and vibrating sample magnetometry (VSM). The reduction efficiency was studied as a function of pH, photocatalyst dose, and contact time. The effects of silica interlayer between the magnetic photocatalyst materials reveal that reduction efficiency of NiFe2O4-SiO2-TiO2 towards Cr(VI) was higher than that of NiFe2O4-TiO2. However, TiO2 was observed to have the highest reduction efficiency at all batch photocatalytic experiments. Kinetics study shows that photocatalytic reduction of Cr(VI) obeyed Langmuir-Hinshelwood model and first-order rate kinetics. Regenerability study also suggested that the photocatalyst materials can be reused.

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Patient-Centered Robot-Aided Passive Neurorehabilitation Exercise Based on Safety-Motion Decision-Making Mechanism

Safety is one of the crucial issues for robot-aided neurorehabilitation exercise. When it comes to the passive rehabilitation training for stroke patients, the existing control strategies are usually just based on position control to carry out the training, and the patient is out of the controller. However, to some extent, the patient should be taken as a “cooperator” of the training activity, and the movement speed and range of the training movement should be dynamically regulated according to the internal or external state of the subject, just as what the therapist does in clinical therapy. This research presents a novel motion control strategy for patient-centered robot-aided passive neurorehabilitation exercise from the point of the safety. The safety-motion decision-making mechanism is developed to online observe and assess the physical state of training impaired-limb and motion performances and regulate the training parameters (motion speed and training rage), ensuring the safety of the supplied rehabilitation exercise. Meanwhile, position-based impedance control is employed to realize the trajectory tracking motion with interactive compliance. Functional experiments and clinical experiments are investigated with a healthy adult and four recruited stroke patients, respectively. The two types of experimental results demonstrate that the suggested control strategy not only serves with safety-motion training but also presents rehabilitation efficacy.

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Developing Intervention Strategies to Optimise Body Composition in Early Childhood in South Africa

Purpose. The purpose of this research was to collect data to inform intervention strategies to optimise body composition in South African preschool children. Methods. Data were collected in urban and rural settings. Weight status, physical activity, and gross motor skill assessments were conducted with 341 3–6-year-old children, and 55 teachers and parents/caregivers participated in focus groups. Results. Overweight and obesity were a concern in low-income urban settings (14%), but levels of physical activity and gross motor skills were adequate across all settings. Focus group findings from urban and rural settings indicated that teachers would welcome input on leading activities to promote physical activity and gross motor skill development. Teachers and parents/caregivers were also positive about young children being physically active. Recommendations for potential intervention strategies include a teacher-training component, parent/child activity mornings, and a home-based component for parents/caregivers. Conclusion. The findings suggest that an intervention focussed on increasing physical activity and improving gross motor skills per se is largely not required but that contextually relevant physical activity and gross motor skills may still be useful for promoting healthy weight and a vehicle for engaging with teachers and parents/caregivers for promoting other child outcomes, such as cognitive development.

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Particle Collision Near 1 + 1-Dimensional Horava-Lifshitz Black Hole and Naked Singularity

The unbounded center-of-mass (CM) energy of oppositely moving colliding particles near horizon emerges also in -dimensional Horava-Lifshitz gravity. This theory has imprints of renormalizable quantum gravity characteristics in accordance with the method of simple power counting. Surprisingly the result obtained is not valid for a 1-dimensional Compton-like process between an outgoing photon and an infalling massless/massive particle. It is possible to achieve unbounded CM energy due to collision between infalling photons and particles. The source of outgoing particles may be attributed to an explosive process just outside the horizon for a black hole and the naturally repulsive character for the case of a naked singularity. It is found that absence of angular momenta in -dimension does not yield unbounded energy for collisions in the vicinity of naked singularities.

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Incidence and Molecular Characterization of Hepatitis E Virus from Swine in Eastern Cape, South Africa

Hepatitis E virus-mediated infection is a serious public health concern in economically developing nations of the world. Globally, four major genotypes of HEV have been documented. Hepatitis E has been suggested to be zoonotic owing to the increase of evidence through various studies. Thus far, this paper reports on prevalence of hepatitis E virus among swine herd in selected communal and commercial farms in the Eastern Cape Province of South Africa. A total of 160 faecal samples were collected from swine herds in Amathole and Chris Hani District Municipalities of Eastern Cape Province for the presence of HEV. Of the 160 faecal samples screened, only seven were positive (4.4%) for HEV. The nucleotide sequences analyses revealed the isolates as sharing 82% to 99% identities with other strains (KX896664, KX896665, KX896666, KX896667, KX896668, KX896669, and KX896670) from different regions of the world. We conclude that HEV is present among swine in the Eastern Cape Province, albeit in low incidence, and this does have public health implications. There is a need for maintenance of high hygienic standards in order to prevent human infections through swine faecal materials and appropriate cooking of pork is highly advised.

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Internet of Things (IoT) Platform for Structure Health Monitoring

Increase in the demand for reliable structural health information led to the development of Structural Health Monitoring (SHM). Prediction of upcoming accidents and estimation of useful life span of a structure are facilitated through SHM. While data sensing is the core of any SHM, tracking the data anytime anywhere is a prevailing challenge. With the advancement in information technology, the concept of Internet of Things (IoT) has made it possible to integrate SHM with Internet to track data anytime anywhere. In this paper, a SHM platform embedded with IoT is proposed to detect the size and location of damage in structures. The proposed platform consists of a Wi-Fi module, a Raspberry Pi, an Analog to Digital Converter (ADC), a Digital to Analog Converter (DAC), a buffer, and piezoelectric (PZT) sensors. The piezoelectric sensors are mounted as a pair in the structure. Data collected from the piezoelectric sensors will be used to detect the size and location of damage using a proposed mathematical model. Implemented on a Raspberry Pi, the proposed mathematical model will estimate the size and location of structural damage, if any, and upload the data to Internet. This data will be stored and can be checked remotely from any mobile device. The system has been validated using a real test bed in the lab.

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Associated Factors and Standard Percentiles of Blood Pressure among the Adolescents of Jahrom City of Iran, 2014

Background. High blood pressure in adults is directly correlated with increased risk of cardiovascular diseases. Hypertension in childhood and adolescence could be considered among the major causes of this problem in adults. This study aimed to investigate the factors associated with hypertension among the adolescents of Jahrom city in Iran and also standard percentiles of blood pressure were estimated for this group. Methods. In this community-based cross-sectional study 983 high school students from different areas of the city were included using a multistage random cluster sampling method in 2014. Blood pressure, weight, and height of each student measured using standard methods. Data were analyzed by statistical software SPSS 16. Results. In total, 498 male and 454 female students were included in this study. Average systolic blood pressure of students was 110.27 mmHg with a variation range of 80.6–151.3. Average diastolic blood pressure was 71.76 mmHg with the variation range of 49.3–105. Results of this study indicated that there was a significant relationship between gender, body mass index, and parental education level with systolic and diastolic blood pressure of the students (). Conclusions. Body mass index was one of the most important changeable factors associated with blood pressure in adolescents. Paying attention to this factor in adolescence could be effective in prevention of cardiovascular diseases in adulthood.

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Pathway-Driven Approaches of Interaction between Oxidative Balance and Genetic Polymorphism on Metabolic Syndrome

Despite evidences of association between basic redox biology and metabolic syndrome (MetS), few studies have evaluated indices that account for multiple oxidative effectors for MetS. Oxidative balance score (OBS) has indicated the role of oxidative stress in chronic disease pathophysiology. In this study, we evaluated OBS as an oxidative balance indicator for estimating risk of MetS with 6414 study participants. OBS is a multiple exogenous factor score for development of disease; therefore, we investigated interplay between oxidative balance and genetic variation for development of MetS focusing on biological pathways by using gene-set-enrichment analysis. As a result, participants in the highest quartile of OBS were less likely to be at risk for MetS than those in the lowest quartile. In addition, persons in the highest quartile of OBS had the lowest level of inflammatory markers including C-reactive protein and WBC. With GWAS-based pathway analysis, we found that VEGF signaling pathway, glutathione metabolism, and Rac-1 pathway were significantly enriched biological pathways involved with OBS on MetS. These findings suggested that mechanism of angiogenesis, oxidative stress, and inflammation can be involved in interaction between OBS and genetic variation on risk of MetS.

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Pediatric Posttraumatic Endophthalmitis in China for Twenty Years

Pediatric posttraumatic endophthalmitis (PTE) is a rare but serious disease that frequently has a poor visual prognosis. To date, only a few English studies have focused on this disease. We perform a systematic review of the Chinese literature on pediatric PTE and describe the epidemiology, management, causative organisms, and visual acuity outcomes of reported cases in twenty years. We found that Staphylococcus epidermidis was the most common isolated organism and the use of a disposable syringe needle was the most common cause of ocular injuries in pediatric PTE in China. In the last ten years, the time from injury to first presentation for treatment has shortened, the proportion of cases resulting from a disposable syringe needle has decreased, the use of intravitreal antibiotics as the initial treatment has increased, and the use of palliative treatment has decreased. Although these favorable changes have occurred in the last ten years, the visual prognosis of pediatric PTE is still poor.

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The Impact of Perception toward the Built Environment in Airport Access Mode Choice Using Hybrid Choice Modeling

Built environment (BE), as an objective variable, plays a substantial role in urban residents’ behavior. However, the perception toward a BE, as a subjective variable, varies among people. To identify the role of perception toward BE, we used a stated preference (SP) survey conducted in January–February 2015 at the Imam Khomeini International Airport (IKIA), Tehran, Iran. The data was drawn from 641 individuals; 359 of them were residents of Tehran. For the estimation of the model, a hybrid discrete choice model was used to capture the latent variable, in addition to mode attributes and trip conditions, with 1795 SP observations. Psychometric questions concerned the perception of ease in access to main streets or highways and good traffic conditions within their residential areas. The results showed that the latent variable (positive perception toward built environment or PBE) had a significant positive effect on people’s willingness to park at the airport. Moreover, the gender, age, marital status, level of education, experience living in a foreign country, and income level also influenced the formation of perception toward the BE and airport transportation mode choice.

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Self-Medication Pattern among Social Science University Students in Northwest Ethiopia

Background. Inappropriate self-medication causes wastage of resources among others. Method. This survey study was conducted to determine self-medication pattern of 404 social science university students in Northwest Ethiopia, who were selected through stratified random sampling technique. Data were collected using self-administered questionnaire and analyzed with SPSS version 20 statistical software. Binary Logistic Regression analysis was employed with value

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A Case of Nonuremic Calciphylaxis in a Caucasian Woman

We report a case of nonuremic calcific arteriolopathy (NUCA) in an 82-year-old Caucasian woman from rural Australia. The patient had no history of kidney disease or dialysis. NUCA is rare disease suspected on cutaneous and clinical features and diagnosed by characteristic findings on skin biopsy and vasculature imaging. Calcification induced microvascular occlusion in the absence of renal failure may not be immediately apparent. Clinical suspicion and appropriate investigations are essential for making a diagnosis. A diagnosis of NUCA may be missed given the rarity of the disease, and dermatologists and patients alike would benefit from a greater awareness of this disease.

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Periorbital and Intraorbital Studies of the Terminal Branches of the Ophthalmic Artery for Periorbital and Glabellar Filler Placements

Abstract

Background

Filler injections for sunken upper eyelid correction and glabellar augmentation at the orbitoglabellar region need to be performed correctly. Precise knowledge of the emerging sites of all terminal branches of the ophthalmic artery is essential for these procedures to be conducted safely.

Methods

The terminal branches of the ophthalmic artery were studied in both periorbital and intraorbital dissections. The aim of this study was to verify the critical positions of the emerging sites at the orbital septum that may act as potential retrograde channels for filler emboli.

Results

In the 40 eyes examined, the branches of the ophthalmic artery were found to emerge from four different sites. Two substantial emerging sites were situated on both sides of the trochlea of the superior oblique muscle. These sites were located at the superior part of the medial orbital rim (SMOR) and are alternatively named as the epitrochlear and the subtrochlear emerging sites. The other two sites can be regarded as accessory emerging sites due to the comparably smaller artery. Dissection of the intraorbital region revealed small periosteal branches of the infraorbital artery which coursed anteriorly on the orbital floor to form anastomoses with the lacrimal artery. In other areas of the orbital floor, no branches extended from the infraorbital artery. In front of the lacrimal gland, very minute branches descended and coursed along both margins of the superior tarsus but did not course outside the lateral orbital rim.

Conclusion

A danger zone was located at the SMOR, where the ophthalmic branches emerge to form anastomotic channels. Compression at the trochlea guarantees safe injection of filler, reducing the risk of complication.

No Level Assigned

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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An Alternative Posterosuperior Auricular Fascia Flap for Ear Elevation During Microtia Reconstruction

Abstract

Background

Advances in staged total auricular reconstruction have resulted in improved anterior auricular appearance; however, satisfactory postreconstruction esthetics of the retroauricular fold remain challenging. The postauricular appearance of the reconstructed ear depends largely upon optimizing the covering material. When used as the covering soft tissue for ear elevation, a flap containing primarily the upper portion of the retroauricular fascia has potential advantages over the conventional book cover-type retroauricular fascia flap.

Methods

We developed a geometrically designed, posterosuperior auricular fascia flap to replace the conventional retroauricular fascia flap for ear elevation. During the second-stage operation, the posterosuperior auricular fascia flap is rotated downward and turned over to wrap around the inner strut and entire posterior auricular surface.

Results

Compared to the conventional book cover-type retroauricular fascia flap, the novel posterosuperior auricular fascia flap was easier to harvest and the operative time significantly decreased (110.3 vs. 121.5 min, p < 0.01). The modified flap produced a thin and natural contour of the postauricular surface, as well as reduced the incidence of postauricular hypertrophic scarring (from 24.7 to 13.2%, p = 0.03) and partial skin graft necrosis (from 43.4 to 31.2%, p = 0.01).

Conclusion

The geometrically designed posterosuperior auricular fascia flap improves ear elevation. Compared to the conventional book cover-type retroauricular fascia flap, this covering tissue is easier to perform so the surgical time is decreased. It was highly vascularized, well defined, thinner, and yields reliable results. Thus, favorable postauricular surface results can be achieved during auricular reconstruction by using the modified fascia flap.

No Level Assigned

This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj

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Discussion: A New Method of Salvaging Breast Reconstruction After Breast Implant Using Negative-Pressure Wound Therapy and Instillation

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Acute rheumatic fever outbreak in southern central European country

Abstract

A decline in the incidence of acute rheumatic fever (ARF) in developed countries over the past century can be attributed to the improved public hygiene and to widespread use of antibiotics. ARF seemed to be a rare disease in southern central European country, Slovenia, up to 2010 when we noticed an increase in the number of patients with ARF. In order to assess the current incidence of ARF, we performed a retrospective study of all patients with ARF treated at the University Children’s Hospital Ljubljana from January 2008 until the end of December 2014. In a period of 7 years, 19 patients with ARF were identified. The estimated annual incidence of ARF during the study period was 1.25 cases per 100,000 children. Carditis was present in all patients, arthritis in 37 % and Sydenham chorea in 32 %.

Conclusion: Recent ARF outbreak in Slovenia revealed that this disease is still present in southern central Europe with an estimated annual incidence of 1.25 cases per 100,000 children. Unrecognized or inadequately treated ARF could be the cause of acquired heart disease and must be even nowadays included among the differential diagnoses in a febrile child with arthritis, heart murmur or movement disorder.

What is Known: • Acute rheumatic fever (ARF) is diagnosed based on the major and minor Jones Criteria. • A decline in the incidence of ARF in developed countries over the past century can be attributed to the improved public hygiene and to widespread use of antibiotics. What is New: • In the last decade, an increase in the incidence of ARF was observed in Slovenia which has a central European geographic position. • Our paper highlights the importance of including ARF in the differential diagnosis of a febrile child with arthritis/arthralgia and/or heart murmur and/or acute chorea.

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Anti-diabetic activity of Garcinia xanthochymus seeds

Abstract

In the present study, extracts of Garcinia xanthochymus seeds were used to determine anti-diabetic, anti-oxidant, and biochemical activities in alloxan-induced diabetic mice. Of the petroleum ether (G. xanthochymus petroleum ether extract (GXSPE)) and methanol (G. xanthochymus methanol extract (GXSME)) seed extracts, 100 and 200 mg/kg were used and compared with normal, diabetic, and glibenclamide groups for various activities. The parameters like blood glucose, body weight, serum biochemicals, serum enzymes, and anti-oxidative enzymes in different groups were monitored at regular intervals. The extracts produced a dose-dependent response for blood glucose levels and associated serum biochemicals, serum enzymes, and anti-oxidative enzymes compared to the diabetic control groups. The high-pressure liquid chromatography (HPLC) analysis revealed the presence of phenolic compounds especially gallic acid, 4-hydroxybenzoic acid, and tannic acid, which have an important role in anti-diabetic action. Thus, this study points out the strong anti-diabetic, anti-oxidant, and biochemical activity of G. xanthochymus seeds. Hence, it can be used for the development of an effective herbal pharmaceutical drug for curing diabetes.

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Flexor pollicis longus reconstruction using the “demi-tendon” technique

Abstract

We report the case of a delayed flexor pollicis longus tendon rupture post distal radius fracture and its reconstruction using the “demi-tendon” technique. This technique has been well described in relation to delayed closed flexor digitorum profundus injuries as a method to facilitate primary repair. In this instance, it is a novel application of the technique which, to date, has not been described as a method of primary tennorrhaphy for a closed rupture of the flexor pollicis longus tendon.

Level of Evidence: Level V, therapeutic study.

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The association between sclerostin and incident type 2 diabetes risk: a cohort study

Abstract

Objective

To determine whether sclerostin is associated with fasting glucose, insulin levels, insulin resistance or increased risk of incident type 2 diabetes.

Background

Type 2 diabetic patients have a higher risk of fractures. Recent studies suggest sclerostin, a regulator of osteoblast activity, is associated with diabetes.

Materials and Methods

Sclerostin levels were obtained from 1,778 individuals with no history of type 2 diabetes participating in the population-based Canadian Multicentre Osteoporosis Study (CaMos) cohort. Participants were followed until diagnosis of type 2 diabetes, death, or end of the study period (December 31, 2013). The relationship of sclerostin with fasting glucose, insulin levels and homeostatic model assessment-insulin resistance (HOMA-IR) was studied in linear regression models. Cox proportional hazards models were used to determine the association of sclerostin levels and the risk of incident type 2 diabetes during a mean 7.5 years of follow-up.

Results

Fasting glucose, fasting insulin levels and HOMA-IR were weakly correlated with sclerostin levels (Spearman's correlation coefficient: 0.11, p<0.05; -0.09, p<0.05; and -0.07, p=0.02 respectively). Multiple linear regression analyses confirmed a significant association between sclerostin and fasting insulin and HOMA-IR but no significant association with fasting glucose levels. Sclerostin levels were not found to be significantly associated with the risk of incident type 2 diabetes (HR: 1.30; 95% CI: 0.37-4.57).

Conclusions

We observed an association between sclerostin levels with fasting insulin levels and HOMA-IR, but there was no clear association with type 2 diabetes risk. Further studies are needed to understand the role of sclerostin in type 2 diabetes.

This article is protected by copyright. All rights reserved.

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