Mexametric and cutometric assessment of the signs of aging of the skin area around the eyes after the use of non-ablative fractional laser, non-ablative radiofrequency and intense pulsed light

Abstract

The assessment of the signs of aging within eyes area in cutometric (skin elasticity) and mexametric (discoloration and severity of erythema) examination after the treatment with: non-ablative fractional laser, non-ablative radiofrequency (RF) and intense light source (IPL). This study included 71 patients, aged 33–63 years (the average age was 45.81) with Fitzpatrick skin type II and III. 24 patients received 5 successive treatment sessions with a 1,410-nm non-ablative fractional laser in two-week intervals, 23 patients received 5 successive treatment sessions with a non-ablative RF in one-week intervals and 24 patients received 5 successive treatment sessions with an IPL in two-week intervals. The treatment was performed for the skin in the eye area. The Cutometer and Mexameter (Courage + Khazaka electronic) reference test was used as an objective method for the assessment of skin properties: elasticity, skin pigmentation and erythema. Measurements of skin elasticity were made in three or four sites within eye area. The results of cutometric measurements for R7 showed the improvement in skin elasticity in case of all treatment methods. The largest statistically significant improvement (p < .0001) was observed in case of laser and RF, during treatment sessions, at sites at upper and lower eyelid. The smallest change in skin elasticity for the laser, RF and IPL – p = .017, p = .003 and p = .001, respectively—was observed in a site within the outer corner of the eye. In all sites of measurements and for all methods, the greatest improvement in skin elasticity was demonstrated between the first and second measurement (after 3rd procedures). The majority of the results of mexametric measurements—MEX (melanin level) and ERYT (the severity of erythema) are statistically insignificant. Fractional, non-ablative laser, non-ablation RF and intense light source can be considered as methods significantly affecting elasticity and to a lesser extent erythema and skin pigmentation around the eyes. Fractional non-ablative laser is a method which, in comparison to other methods, has the greatest impact on skin viscoelasticity. These procedures are well tolerated and are associated with a low risk of side effects.

http://ift.tt/2lBm3PR

The role of nicotinamide in acne treatment

Abstract

Safe and effective treatment options for acne vulgaris are needed to address side effects and increasing rates of antibiotic resistance from current treatments. Nicotinamide is a vitamin with potent anti-inflammatory properties that could offer a potential treatment option. We aim to summarize the relevant literature on the role of nicotinamide in acne vulgaris and discuss the next steps necessary to move this approach into clinical practice. We searched PubMed for clinical studies using nicotinamide for treatment of acne vulgaris. We summarized the 10 studies that met our search criteria. Six of eight studies using topical nicotinamide led to a significant reduction in acne compared with the patient's baseline or performed similarly to another standard-of-care acne treatment. Both studies using an oral supplement containing nicotinamide resulted in a significant reduction in acne compared with baseline. No major adverse side effects were noted. Our review suggests that topical and oral nicotinamide has an unclear effect on acne vulgaris due to the limited nature of the available literature. Additional studies are needed comparing nicotinamide to other first-line acne treatments and evaluating the efficacy and side effect profile of nicotinamide over an extended period of time.

http://ift.tt/2l2znd3

Commentary: Prostate cancer screening—A long run for a short slide

Publication date: Available online 20 February 2017
Source:Seminars in Oncology
Author(s): Howard L. Parnes




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Evaluation of RAG1 mutations in an adult with combined immunodeficiency and progressive multifocal leukoencephalopathy

Publication date: Available online 20 February 2017
Source:Clinical Immunology
Author(s): Claudia Schröder, Niklas Baerlecken, Ulrich Pannicke, Thilo Dörk, Torsten Witte, Roland Jacobs, Matthias Stoll, Klaus Schwarz, Bodo Grimbacher, Reinhold E. Schmidt, Faranaz Atschekzei
Here we describe novel mutations in recombination activation gene 1 (RAG1) in a compound heterozygous male patient with combined T and B cell immunodeficiency (CID). Clinical manifestations besides antibody deficiency included airway infections, granulomatosis and autoimmune features. He died at the age of 37 due to PML caused by JC virus infection.By targeted next-generation sequencing we detected post mortem in this patient three mutations in RAG1. One allele harbored two novel mutations (c.1123C>G, p.H375D and c.1430delC, p.F478Sfs*14), namely a missense variant and a frameshift deletion, of which the latter leads to a truncated RAG1 protein. The other allele revealed a previously described missense mutation (c.1420C>T, p.R474C, rs199474678). Functional analysis of the p.R474C variant in an in vitro V(D)J recombination assay exhibited reduced recombination activity compared to a wild-type control. Our findings suggest that mutations in RAG1, specifically the p.R474C variant, can be associated with relatively mild clinical symptoms or delayed occurrence of T cell and B cell deficiencies but may predispose to PML.



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Therapeutic antibody targeting of indoleamine-2,3-dioxygenase (IDO2) inhibits autoimmune arthritis

Publication date: Available online 20 February 2017
Source:Clinical Immunology
Author(s): Lauren M.F. Merlo, Samantha Grabler, James B. DuHadaway, Elizabeth Pigott, Kaylend Manley, George C. Prendergast, Lisa D. Laury-Kleintop, Laura Mandik-Nayak
Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2. Treatment with IDO2-specific mAb alleviated arthritis in two independent preclinical arthritis models, reducing autoreactive T and B cell activation and recapitulating the strong anti-arthritic effect of genetic IDO2 deficiency. Mechanistic investigations identified FcγRIIb as necessary for mAb internalization, allowing targeting of an intracellular antigen traditionally considered inaccessible to mAb therapy. Taken together, our results offer preclinical proof of concept for antibody-mediated targeting of IDO2 as a new therapeutic strategy to treat RA and other autoantibody-mediated diseases.

Graphical abstract

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Clogging development and hydraulic performance of the horizontal subsurface flow stormwater constructed wetlands: a laboratory study

Abstract

The horizontal subsurface constructed wetland (HSSF CW) is a highly effective technique for stormwater treatment. However, progressive clogging in HSSF CW is a widespread operational problem. The aim of this study was to understand the clogging development of HSSF CWs during stormwater treatment and to assess the influence of microorganisms and vegetation on the clogging. Moreover, the hydraulic performance of HSSF CWs in the process of clogging was evaluated in a tracer experiment. The results show that the HSSF CW can be divided into two sections, section I (circa 0–35 cm) and section II (circa 35–110 cm). The clogging is induced primarily by solid entrapment in section I and development of biofilm and vegetation roots in section II, respectively. The influence of vegetation and microorganisms on the clogging appears to differ in sections I and II. The tracer experiment shows that the hydraulic efficiency (λ) and the mean hydraulic retention time (t _mean) increase with the clogging development; although, the short-circuiting region (S) extends slightly. In addition, the presence of vegetation can influence the hydraulic performance of the CWs, and their impact depends on the characteristics of the roots.

http://ift.tt/2lGvUEF

Irisin in goldfish (Carassius auratus): effects of irisin injections on feeding behavior and expression of appetite regulators, uncoupling proteins and lipoprotein lipase, and fasting-induced changes in FNDC5 expression

Publication date: Available online 20 February 2017
Source:Peptides
Author(s): Zahndra Diann Butt, Jessica Dalton Hackett, Hélène Volkoff
Irisin is a peptide cleaved from the fibronectin type III domain containing protein 5 (FNDC5) gene that is secreted predominantly by muscle cells but also by other tissues including brain and intestine. In mammals, irisin has been shown to have thermogenic actions via the modulation of uncoupling proteins (UCPs) and to affect feeding and energy homeostasis via actions in brain, adipose tissue, liver, muscle and gastrointestinal tract. To examine the role of irisin on feeding and metabolism in fish, the effects of peripheral (intraperitoneal) injections of irisin on feeding behavior, glucose levels and the mRNA expressions of appetite regulators (cocaine and amphetamine regulated transcript CART, agouti related protein AgRP, orexin), UCPs and lipoprotein lipase LPL and brain factors (brain-derived neurotrophic factor , BDNF and tyrosine hydroxylase TH) were assessed in brain, white muscle and intestine. Irisin injections (100ng/g) induced a decrease in food intake and increases in brain orexin, CART1 and CART2, UCP2, BDNF, muscle UCP2 and intestine LPL mRNA expressions but did not affect blood glucose levels, brain AgRP, TH, UCP1, UCP3 and LPL or muscle UCP1, UCP3 and LPL expressions. A partial goldfish FNDC5 cDNA was isolated and the expressions of FDNC5, UCPs, LPL and BDNF were also compared between fed and fasted fish. Fasting induced decreases FNDC5 mRNA expression in the brain and intestine, but not in muscle. Fasting also induced increases in brain BDNF and LPL expressions and increases in UCP1, UCP2, UCP3 and LPL expressions in muscle. Our result suggest that irisin is an anorexigenic factor in fish and its actions might be in part mediated by appetite-regulating factors such as CART and orexins as well as UCP2 and brain factors such as BDNF.



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Inhibitory effects of dynorphin 3-14 on the lipopolysaccharide-induced toll-like receptor 4 signalling pathway

Publication date: Available online 20 February 2017
Source:Peptides
Author(s): Siti Sarah Fazalul Rahiman, Michael Morgan, Paul Gray, Paul Nicholas Shaw, Peter John Cabot
Dynorphin 1-17 (DYN 1-17) is biotransformed rapidly to a range of fragments in rodent inflamed tissue with dynorphin 3-14 (DYN 3-14) being the most stable and prevalent. DYN 1-17 has been shown previously to be involved in the regulation of inflammatory response following tissue injury, in which the biotransformation fragments of DYN 1-17 may possess similar features. This study investigated the effects of DYN 3-14 on lipopolysaccharide (LPS)-induced nuclear factor-kappaB/p65 (NF-κB/p65) nuclear translocation and the release of pro-inflammatory cytokines interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in differentiated THP-1 cells. Treatment with DYN 3-14 (10nM) resulted in 35% inhibition of the LPS-induced nuclear translocation of NF-κB/p65. Furthermore, DYN 3-14 modulated both IL-1β and TNF-α release; inhibiting IL-1β and paradoxically augmenting TNF-α release in a concentration-independent manner. A number of opioids have been implicated in the modulation of the toll-like receptor 4 (TLR4), highlighting the complexity of their immunomodulatory effects. To determine whether DYN 3-14 modulates TLR4, HEK-Blue™⁻hTLR4 cells were stimulated with LPS in the presence of DYN 3-14. DYN 3-14 (10μM) inhibited TLR4 activation in a concentration-dependent fashion by suppressing the LPS signals around 300-fold lower than LPS-RS, a potent TLR4 antagonist. These findings indicate that DYN 3-14 is a potential TLR4 antagonist that alters cellular signaling in response to LPS and cytokine release, implicating a role for biotransformed endogenous opioid peptides in immunomodulation.



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Obestatin Improves Oxidative Brain Damage and Memory Dysfunction in Rats Induced with an Epileptic Seizure

Publication date: Available online 20 February 2017
Source:Peptides
Author(s): Türkan Koyuncuoğlu, Caner Vızdıklar, Doğan Üren, Hakan Yılmaz, Çağan Yıldırım, Sefa Semih Atal, Dilek Akakın, Elif Kervancıoğlu-Demirci, Meral Yüksel, Berrak Ç. Yeğen
Obestatin was shown to alleviate renal, gastrointestinal and haemorrhage-induced brain injury in rats. In order to investigate the neuroprotective effects of obestatin on seizure-induced oxidative brain injury, an epileptic seizure was induced with a single intraperitoneal (i.p.) dose of pentylenetetrazole (PTZ, 45mg/kg) in male Wistar rats. Thirty minutes before the PTZ injection, rats were treated with either saline or obestatin (1μg/kg, i.p.). Seizure was video-taped and then evaluated by using Racine's scoring (0-5). For the assessment of memory function, passive-avoidance test was performed before seizure induction, which was repeated on the 3rd day of seizure. The rats were decapitated at the 24th or 72nd hour of seizures and brain tissues were obtained for histopathological examination and for measuring levels of malondialdehyde (MDA), glutathione (GSH), reactive oxygen radicals and myeloperoxidase (MPO) activity. Obestatin treatment reduced the average seizure score, decreased the occurrence and duration of generalized tonic-clonic seizures, presenting with a shorter latency to their onset. Increased lipid peroxidation and enhanced generation of oxygen-derived radicals detected at the post-seizure 72nd h were suppressed by the consecutive treatments of obestatin, but no changes were observed by the single obestatin treatment in the 24-h seizure group. Neuronal damage and increased GFAP immunoreactivity, observed in the hippocampal areas and cortex of PTZ-induced rats were alleviated in 3-day obestatin-treated PTZ group. PTZ-induced memory dysfunction was significantly improved in obestatin-treated PTZ group as compared to saline-treated rats. The present data indicates that obestatin ameliorated the severity of PTZ-induced seizures, improved memory dysfunction and reduced neuronal damage by limiting oxidative damage.



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Association between circulating angiotensin-converting enzyme 2 and cardiac remodeling in hypertensive patients

Publication date: Available online 20 February 2017
Source:Peptides
Author(s): Shichao Li, Zhijun Wang, Xiuhong Yang, Bo Hu, Yuling Huang, Sujing Fan
BackgroundAngiotensin-converting enzyme 2 (ACE2) plays a vital role in the pathogenesis of hypertension-induced cardiac remodeling and exhibits cardioprotective properties in hypertensive animal models. Evidence that ACE2 is an important regulator of hypertensive cardiac remodeling in humans has not been addressed directly yet.MethodsA total of 161 patients with essential hypertension and 47 age- and sex-matched normotensive healthy subjects were consecutively recruited. Serum concentration levels of ACE2 were determined by enzyme-linked immunosorbent assay. Cardiac structural and functional parameters were measured by echocardiography.ResultsSerum ACE2 concentrations were higher in hypertensive patients compared to healthy subjects (170.31 [83.50–707.12] pg/ml in patients versus 59.28 [39.71–81.81] pg/ml in healthy subjects, P<0.001). After adjustment for confounders, including age, sex, body mass index, snoring, smoking, duration of hypertension, comorbidities, medication use, mean arterial pressure and N-terminal pro-brain natriuretic peptide, serum ACE2 concentrations were positively correlated with left atrial diameter, left ventricular end-diastolic diameter and left ventricular mass in hypertensive patients. Moreover, multiple regression analyses adjusting for covariates revealed that serum ACE2 concentrations were also independently associated with left ventricular ejection fraction and late diastolic filling velocities of the mitral inflow.ConclusionsThis study reveals an elevated serum concentration of ACE2 and independent associations between serum ACE2 and echocardiographic parameters in hypertensive patients.



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Editorial board

Publication date: 1 March 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 5





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New insights into highly potent tyrosinase inhibitors based on 3-heteroarylcoumarins: Anti-melanogenesis and antioxidant activities, and computational molecular modeling studies

Publication date: 1 March 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 5
Author(s): Francesca Pintus, Maria J. Matos, Santiago Vilar, George Hripcsak, Carla Varela, Eugenio Uriarte, Lourdes Santana, Fernanda Borges, Rosaria Medda, Amalia Di Petrillo, Benedetta Era, Antonella Fais
Melanogenesis is a physiological pathway for the formation of melanin. Tyrosinase catalyzes the first step of this process and down-regulation of its activity is responsible for the inhibition of melanogenesis. The search for molecules capable of controlling hyperpigmentation is a trend topic in health and cosmetics. A series of heteroarylcoumarins have been synthesized and evaluated. Compounds 4 and 8 exhibited higher tyrosinase inhibitory activities (IC50=0.15 and 0.38μM, respectively), than the reference compound, kojic acid (IC50=17.9μM). Compound 4 acts as competitive, while compound 8 as uncompetitive inhibitor of mushroom tyrosinase. Furthermore, compounds 2 and 8 inhibited tyrosinase activity and melanin production in B16F10 cells. In addition, compounds 2–4 and 8 proved to have an interesting antioxidant profile in both ABTS and DPPH radicals scavenging assays. Docking experiments were carried out in order to study the interactions between these heteroarylcoumarins and mushroom tyrosinase.

Graphical abstract

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Synthesis of bulky-tailed sulfonamides incorporating pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-1(5H)-yl) moieties and evaluation of their carbonic anhydrases I, II, IV and IX inhibitory effects

Publication date: Available online 21 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Mohamed Fares, Radwa A. Eladwy, Alessio Nocentini, Soha R. Abd El Hadi, Hazem A. Ghabbour, Ashraf Abdel-Megeed, Wagdy M. Eldehna, Hatem A. Abdel-Aziz, Claudiu T. Supuran
Using celecoxib as lead, two novel series of sulfonamides incorporating the pyridotriazolopyrimidine scaffold have been synthesized and evaluated in vitro as inhibitors against four relevant human (h) carbonic anhydrases (CAs, EC 4.2.1.1), the cytosolic and ubiquitous hCA I and II as well as the transmembrane hCA IV and hCA IX. Most of the reported sulfonamides acted as efficient, low micromolar inhibitors of hCAI, II and IV, whereas they displayed higher efficacy in inhibiting the tumor-associated isoform hCA IX. Many derivates herein reported showed better hCA IX versus hCA II selectivity ratios compared to celecoxib or acetazolamide. Considering isoform IX is a validated target for the diagnosis and treatment of hypoxic tumors, discovery of selective CA IX inhibitors represents a promising step to unveil more effective anticancer therapies.

Graphical abstract

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A PEGylated analog of short-length neuromedin U with potent anorectic and anti-obesity effects

Publication date: Available online 21 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Hiroshi Inooka, Kotaro Sakamoto, Tokuyuki Shinohara, Yasushi Masuda, Michiko Terada, Satoshi Kumano, Kotaro Yokoyama, Jiro Noguchi, Naoki Nishizawa, Hidenori Kamiguchi, Hisashi Fujita, Taiji Asami, Shiro Takekawa, Tetsuya Ohtaki
Neuromedin U (NMU) is a neuropeptide known to regulate food intake and energy homeostasis that is widely distributed in the gastrointestinal tract, hypothalamus, and pituitary. A short form of NMU, porcine NMU-8 has potent agonist activity for the receptors NMUR1 and NMUR2; however, its short half-life precludes its effective use in vivo. To address this limitation, we designed and synthesized NMU-8 analogs modified by polyethyleneglycol (PEG) with a molecular weight of 30 kDa (PEG30k) via a variety of linkers (i.e., ω-amino- and ω-imino-carboxylic acid linker). Integrated evaluation of NMUR1 and NMUR2 binding affinities in vitro and anorectic activity in mice revealed that the introduction of a linker with a rigid ring group, e.g., 2-(piperazin-1-yl)acetic acid (PipAc), yielded a highly potent anorectic peptide, PEG30k-PipAc-NMU-8 (14), possessing improved receptor binding affinity. Subsequent optimization of the molecular weight of the PEG moiety led to the discovery of a PEG20k conjugate (15), which exhibited significant anti-obesity effect upon once-daily subcutaneous administration in diet-induced obese mice with 10% and 22% body weight loss at doses of 10 and 30 nmol/kg, respectively. In addition, 15 reduced the weights of the liver and adipose tissue in a dose-dependent manner and improved the plasma biochemical parameters, e.g., insulin, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and total cholesterol. Thus, our results suggest that 15, which showed potent and long-lasting biological profiles in vivo, represents a candidate peptide for investigating the central and peripheral actions of NMU and its potential for clinical use.

Graphical abstract

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Discovery of Selective ATP-competitive eIF4A3 Inhibitors

Publication date: Available online 20 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Masahiro Ito, Misa Iwatani, Yusuke Kamada, Satoshi Sogabe, Shoichi Nakao, Toshio Tanaka, Tomohiro Kawamoto, Samuel Aparicio, Atsushi Nakanishi, Yasuhiro Imaeda
Eukaryotic initiation factor 4A3 (eIF4A3), an ATP-dependent RNA helicase, is a core component of exon junction complex (EJC). EJC has a variety of roles in RNA metabolism such as translation, surveillance, and localization of spliced RNA. It is worthwhile to identify selective eIF4A3 inhibitors with a view to investigating the functions of eIF4A3 and EJC further to clarify the roles of the ATPase and helicase activities in cells. Our chemical optimization of hit compound 2 culminated in the discovery of ATP-competitive eIF4A3 inhibitor 18 with submicromolar ATPase inhibitory activity and excellent selectivity over other helicases. Hence, compound 18 could be a valuable chemical probe to elucidate the detailed function of eIF4A3 and EJC.

Graphical abstract

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Extraction of the 3D Local Orientation of Myocytes in Human Cardiac Tissue Using X-ray Phase-Contrast Micro-Tomography and Multi-Scale Analysis

Publication date: Available online 20 February 2017
Source:Medical Image Analysis
Author(s): François Varray, Iulia Mirea, Max Langer, Françoise Peyrin, Laurent Fanton, Isabelle E. Magnin
This paper presents a methodology to access the 3D local myocyte arrangements in fresh human post-mortem heart samples. We investigated the cardiac micro-structure at a high and isotropic resolution of 3.5 μm in three dimensions using X-ray phase micro-tomography at the European Synchrotron Radiation Facility. We then processed the reconstructed volumes to extract the 3D local orientation of the myocytes using a multi-scale approach with no segmentation. We created a simplified 3D model of tissue sample made of simulated myocytes with known size and orientations, to evaluate our orientation extraction method. Afterwards, we applied it to 2D histological cuts and to eight 3D left ventricular (LV) cardiac tissue samples. Then, the variation of the helix angles, from the endocardium to the epicardium, was computed at several spatial resolutions ranging from 3.6³ mm³ to 112³ μm³. We measure an increased range of 20°to 30°from the coarsest resolution level to the finest level in the experimental samples. This result is in line with the higher values measured from histology. The displayed tractography demonstrates a rather smooth evolution of the transmural helix angle in six LV samples and a sudden discontinuity of the helix angle in two septum samples. These measurements bring a new vision of the human heart architecture from macro- to micro-scale.

Graphical abstract

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Task FMRI data analysis based on supervised stochastic coordinate coding

Publication date: Available online 20 February 2017
Source:Medical Image Analysis
Author(s): Jinglei Lv, Binbin Lin, Qingyang Li, Wei Zhang, Yu Zhao, Xi Jiang, Lei Guo, Junwei Han, Xintao Hu, Christine Guo, Jieping Ye, Tianming Liu
Task functional magnetic resonance imaging (fMRI) has been widely employed for brain activation detection and brain network analysis. Modeling rich information from spatially-organized collection of fMRI time series is challenging because of the intrinsic complexity. Hypothesis-driven methods, such as the general linear model (GLM), which regress exterior stimulus from voxel-wise functional brain activity, are limited due to overlooking the complexity of brain activities and the diversity of concurrent brain networks. Recently, sparse representation and dictionary learning methods have attracted increasing interests in task fMRI data analysis. The major advantage of this methodology is its promise in reconstructing concurrent brain networks systematically. However, this data-driven strategy is, to some extent, arbitrary and does not sufficiently utilize the prior information of task design and neuroscience knowledge. To bridge this gap, we here propose a novel supervised sparse representation and dictionary learning framework based on stochastic coordinate coding (SCC) algorithm for task fMRI data analysis, in which certain brain networks are learned with known information such as pre-defined temporal patterns and spatial network patterns, and at the same time other networks are learned automatically from data. Our proposed method has been applied to two independent task fMRI datasets, and qualitative and quantitative evaluations have shown that our method provides a new and effective framework for task fMRI data analysis.

Graphical abstract

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Listening to public concerns on vaccinations in order to provide information in a timely manner

Publication date: 7 March 2017
Source:Vaccine, Volume 35, Issue 10
Author(s): Nobutoshi Nawa, Shigetoyo Kogaki, Keiichi Ozono




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Policy making for vaccine use as a driver of vaccine innovation and development in the developed world

Publication date: 7 March 2017
Source:Vaccine, Volume 35, Issue 10
Author(s): Katherine Seib, Andrew J. Pollard, Philippe de Wals, Ross M. Andrews, Fangjun Zhou, Richard J. Hatchett, Larry K. Pickering, Walter A. Orenstein
In the past 200years, vaccines have had unmistakable impacts on public health including declines in morbidity and mortality, most markedly in economically-developed countries. Highly engineered vaccines including vaccines for conditions other than infectious diseases are expected to dominate future vaccine development. We examine immunization vaccine policy as a driver of vaccine innovation and development. The pathways to recommendation for use of licensed vaccines in the US, UK, Canada and Australia have been similar, including: expert review of disease epidemiology, disease burden and severity; vaccine immunogenicity, efficacy and safety; programmatic feasibility; public demand; and increasingly cost-effectiveness. Other attributes particularly important in development of future vaccines are likely to include: duration of immunity for improved vaccines such as pertussis; a greater emphasis on optimizing community protection rather than direct protection only; programmatic implementation, feasibility, improvements (as in the case of development of a universal influenza vaccine); public concerns/confidence/fears related to outbreak pathogens like Ebola and Zika virus; and major societal burden for combating hard to treat diseases like HIV and antimicrobial resistant pathogens. Driving innovation and production of future vaccines faces enormous economic hurdles as available approaches, technologies and regulatory pathways become more complex. As such, cost-mitigating strategies and focused, aligned efforts (by governments, private organizations, and private-public partnerships) will likely be needed to continue to spur major advances in vaccine technologies and development.



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Editorial Board/Aims and Scope

Publication date: 7 March 2017
Source:Vaccine, Volume 35, Issue 10





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Omp16-based vaccine encapsulated by alginate-chitosan microspheres provides significant protection against Haemophilus parasuis in mice

Publication date: 7 March 2017
Source:Vaccine, Volume 35, Issue 10
Author(s): Xintian Zheng, Xiaoyan Yang, Xiaohua Li, Guo-Hua Qiu, Ailing Dai, Qichun Huang, Cuiqin Huang, Xiaofeng Guo
Haemophilus parasuis (H. parasuis) is the etiological agent of swine Glässer's disease, which leads to significant economic loss in swine industry over the world. Subunit vaccine based on outer membrane protein is one of the promising choices to protect pigs against H. parasuis infection despite low immunity efficiency. In this paper, outer membrane protein 16 (Omp16) of H. parasuis encapsulated by alginate-chitosan microspheres as antigen carriers was explored for the first time in a mouse model. Our results showed that the microspheres with Omp16 induced significant higher H. parasuis-specific antibodies, and higher titers of IL-2, IL-4, and IFN-γ than those by Omp16-FIA in treated mice (p<0.05). Moreover, H. parasuis load in the tissues from liver, spleen, and lung of mice immunized with microspheres containing Omp16 was significantly decreased (p<0.05) than that in the same counterpart tissues of control groups. In addition, 80% mice treated with Omp16 and 70% mice with Omp16-FIA were survived after challenged with H. parasuis virulent strain LY02 (serovar 5). Therefore, Omp16-based microsphere vaccine induces both humoral and cellular immune responses and provides promising protection against H. parasuis infection in mice.



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Immunogenicity and safety of an AS03-adjuvanted H7N1 vaccine in healthy adults: A phase I/II, observer-blind, randomized, controlled trial

Publication date: 7 March 2017
Source:Vaccine, Volume 35, Issue 10
Author(s): Anuradha Madan, Murdo Ferguson, Eric Sheldon, Nathan Segall, Laurence Chu, Azhar Toma, Paul Rheault, Damien Friel, Jyoti Soni, Ping Li, Bruce L. Innis, Anne Schuind
BackgroundH7 influenza strains have pandemic potential. AS03-adjuvanted H7N1 A/mallard/Netherlands/12/2000 split-virion vaccine formulations were evaluated as model H7-subtype vaccine and tested after H7N9 emerged in China, and caused severe human disease with high mortality.MethodsIn this phase I/II, observer-blind, randomized trial in US and Canada, 420 healthy adults (21–64years) were randomized to receive 1 of 4 H7N1 vaccine formulations (3.75 or 7.5μg hemagglutinin adjuvanted with either AS03A or AS03B), 15μg unadjuvanted H7N1 hemagglutinin, or saline placebo, given as 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays, at day 42 (21days post-dose 2), month 6, and month 12 (HI only) for the per-protocol cohorts (398, 379 and 368 participants, respectively). Safety is reported up to month 12.ResultsBeneficial AS03 adjuvant effect was demonstrated. Committee for Medical Products for Human Use, and Center for Biologics Evaluation and Research (CBER) criteria were met for all adjuvanted formulations at day 42 (H7N1 HI assay); seroprotection (SPR) and seroconversion rates (SCR) were 88.5–94.8%, mean geometric increase (MGI) 19.2–34.9, and geometric mean titers (GMT) 98.3–180.7. Unadjuvanted H7N1 vaccine did not meet CBER criteria. In adjuvanted groups, antibody titers decreased over time; month 12 SPRs and GMTs were low (2.0–18.8% and 8.1–12.2). MN antibodies showed similar kinetics, with titers persisting at higher range than HI at month 6. All adjuvanted groups showed cross-reactivity against H7N9, with HI responses similar to H7N1.The most frequent solicited symptom in adjuvanted groups was injection site pain (71.2–86.7%); grade 3 solicited symptoms were infrequent. Nine participants reported 17 serious adverse events; none were considered causally related to vaccination.ConclusionsAdjuvanted H7N1 vaccine formulations had an acceptable safety profile and induced an antibody response after 2 doses with cross-reactivity to H7N9.ClinicalTrials.gov: NCT01934127



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Spatial distribution of resting-state BOLD regional homogeneity as a predictor of brain glucose uptake: A study in healthy aging

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Michaël Bernier, Etienne Croteau, Christian-Alexandre Castellano, Stephen C. Cunnane, Kevin Whittingstall
Positron emission tomography using [18F]-fluorodeoxyglucose (PET-FDG) is the primary imaging modality used to measure glucose metabolism in the brain (CMRGlu). CMRGlu has been used as a biomarker of brain aging and neurodegenerative diseases, but the complexity and invasive nature of PET often limits its use in research. There is therefore great interest in developing non-invasive metrics for estimating brain CMRGlu. We therefore investigated resting state fMRI metrics such as regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF) and regional global connectivity (Closeness) with multiple analytical approaches to determine their relationship to CMRGlu. We investigated this relation in two distinct cognitively healthy populations separated by age (27 young adults and 35 older adults). Overall, we found that both regionally and across participants, ReHo strongly correlated with CMRGlu in healthy young and older adults. Moreover, ReHo demonstrated the same age-related differences as CMRGlu throughout all cortical regions, particularly in the default network and frontal areas.



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Predictive modelling using neuroimaging data in the presence of confounds

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Anil Rao, Joao M. Monteiro, Janaina Mourao-Miranda
When training predictive models from neuroimaging data, we typically have available non-imaging variables such as age and gender that affect the imaging data but which we may be uninterested in from a clinical perspective. Such variables are commonly referred to as 'confounds'. In this work, we firstly give a working definition for confound in the context of training predictive models from samples of neuroimaging data. We define a confound as a variable which affects the imaging data and has an association with the target variable in the sample that differs from that in the population-of-interest, i.e., the population over which we intend to apply the estimated predictive model. The focus of this paper is the scenario in which the confound and target variable are independent in the population-of-interest, but the training sample is biased due to a sample association between the target and confound. We then discuss standard approaches for dealing with confounds in predictive modelling such as image adjustment and including the confound as a predictor, before deriving and motivating an Instance Weighting scheme that attempts to account for confounds by focusing model training so that it is optimal for the population-of-interest. We evaluate the standard approaches and Instance Weighting in two regression problems with neuroimaging data in which we train models in the presence of confounding, and predict samples that are representative of the population-of-interest. For comparison, these models are also evaluated when there is no confounding present. In the first experiment we predict the MMSE score using structural MRI from the ADNI database with gender as the confound, while in the second we predict age using structural MRI from the IXI database with acquisition site as the confound. Considered over both datasets we find that none of the methods for dealing with confounding gives more accurate predictions than a baseline model which ignores confounding, although including the confound as a predictor gives models that are less accurate than the baseline model. We do find, however, that different methods appear to focus their predictions on specific subsets of the population-of-interest, and that predictive accuracy is greater when there is no confounding present. We conclude with a discussion comparing the advantages and disadvantages of each approach, and the implications of our evaluation for building predictive models that can be used in clinical practice.



http://ift.tt/2m6F3no

Effects of sex hormone treatment on white matter microstructure in individuals with gender dysphoria

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Georg S. Kranz, Rene Seiger, Ulrike Kaufmann, Allan Hummer, Andreas Hahn, Sebastian Ganger, Martin Tik, Christian Windischberger, Siegfried Kasper, Rupert Lanzenberger
Sex steroid hormones such as estradiol and testosterone are known to have organizing, as well as activating effects on neural tissue in animals and humans. This study investigated the effects of transgender hormone replacement therapy on white matter microstructure using diffusion tensor imaging. Female-to-male and male-to-female transgender participants were measured at baseline, four weeks and four months past treatment start and compared to female and male controls. We observed androgenization-related reductions in mean diffusivity and increases in fractional anisotropy. We also observed feminization-related increases in mean diffusivity and reductions in fractional anisotropy. In both transgender participants and controls, hormonal fluctuations were correlated with changes in white matter microstructure. Although the present study does not preclude regression to the mean as a potential contributing factor, the results indicate that sex hormones are – at least in part – responsible for white matter variability in the human brain. Studies investigating the effects of sex hormones on adult human brain structure may be an important route for greater understanding of the psychological differences between females and males.



http://ift.tt/2lh0tzJ

Impaired visual short-term memory capacity is distinctively associated with structural connectivity of the posterior thalamic radiation and the splenium of the corpus callosum in preterm-born adults

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Aurore Menegaux, Chun Meng, Julia Neitzel, Josef G. Bäuml, Hermann J. Müller, Peter Bartmann, Dieter Wolke, Afra M. Wohlschläger, Kathrin Finke, Christian Sorg
Preterm birth is associated with an increased risk for lasting changes in both the cortico-thalamic system and attention; however, the link between cortico-thalamic and attention changes is as yet little understood. In preterm newborns, cortico-cortical and cortico-thalamic structural connectivity are distinctively altered, with increased local clustering for cortico-cortical and decreased integrity for cortico-thalamic connectivity. In preterm-born adults, among the various attention functions, visual short-term memory (vSTM) capacity is selectively impaired. We hypothesized distinct associations between vSTM capacity and the structural integrity of cortico-thalamic and cortico-cortical connections, respectively, in preterm-born adults.A whole-report paradigm of briefly presented letter arrays based on the computationally formalized Theory of Visual Attention (TVA) was used to quantify parameter vSTM capacity in 26 preterm- and 21 full-term-born adults. Fractional anisotropy (FA) of posterior thalamic radiations and the splenium of the corpus callosum obtained by diffusion tensor imaging were analyzed by tract-based spatial statistics and used as proxies for cortico-thalamic and cortico-cortical structural connectivity.The relationship between vSTM capacity and cortico-thalamic and cortico-cortical connectivity, respectively, was significantly modified by prematurity. In full-term-born adults, the higher FA in the right posterior thalamic radiation the higher vSTM capacity; in preterm-born adults this FA-vSTM-relationship was inversed. In the splenium, higher FA was correlated with higher vSTM capacity in preterm-born adults, whereas no significant relationship was evident in full-term-born adults.These results indicate distinct associations between cortico-thalamic and cortico-cortical integrity and vSTM capacity in preterm-and full-term-born adults. Data suggest compensatory cortico-cortical fiber re-organization for attention deficits after preterm delivery.



http://ift.tt/2m6Wu7i

Magnetic resonance fingerprinting based on realistic vasculature in mice

Publication date: 1 April 2017
Source:NeuroImage, Volume 149
Author(s): Philippe Pouliot, Louis Gagnon, Tina Lam, Pramod K. Avti, Chris Bowen, Michèle Desjardins, Ashok K. Kakkar, Eric Thorin, Sava Sakadzic, David A. Boas, Frédéric Lesage
Magnetic resonance fingerprinting (MRF) was recently proposed as a novel strategy for MR data acquisition and analysis. A variant of MRF called vascular MRF (vMRF) followed, that extracted maps of three parameters of physiological importance: cerebral oxygen saturation (SatO2), mean vessel radius and cerebral blood volume (CBV). However, this estimation was based on idealized 2-dimensional simulations of vascular networks using random cylinders and the empirical Bloch equations convolved with a diffusion kernel. Here we focus on studying the vascular MR fingerprint using real mouse angiograms and physiological values as the substrate for the MR simulations. The MR signal is calculated ab initio with a Monte Carlo approximation, by tracking the accumulated phase from a large number of protons diffusing within the angiogram. We first study the identifiability of parameters in simulations, showing that parameters are fully estimable at realistically high signal-to-noise ratios (SNR) when the same angiogram is used for dictionary generation and parameter estimation, but that large biases in the estimates persist when the angiograms are different. Despite these biases, simulations show that differences in parameters remain estimable. We then applied this methodology to data acquired using the GESFIDE sequence with SPIONs injected into 9 young wild type and 9 old atherosclerotic mice. Both the pre injection signal and the ratio of post-to-pre injection signals were modeled, using 5-dimensional dictionaries. The vMRF methodology extracted significant differences in SatO2, mean vessel radius and CBV between the two groups, consistent across brain regions and dictionaries. Further validation work is essential before vMRF can gain wider application.



http://ift.tt/2lgOMJj

Functional and oxygen-metabolic photoacoustic microscopy of the awake mouse brain

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Rui Cao, Jun Li, Bo Ning, Naidi Sun, Tianxiong Wang, Zhiyi Zuo, Song Hu
A long-standing challenge in optical neuroimaging has been the assessment of hemodynamics and oxygen metabolism in the awake rodent brain at the microscopic level. Here, we report first-of-a-kind head-restrained photoacoustic microscopy (PAM), which enables simultaneous imaging of the cerebrovascular anatomy, total concentration and oxygen saturation of hemoglobin, and blood flow in awake mice. Combining these hemodynamic measurements allows us to derive two key metabolic parameters—oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2). This enabling technology offers the first opportunity to comprehensively and quantitatively characterize the hemodynamic and oxygen-metabolic responses of the mouse brain to isoflurane, a general anesthetic widely used in preclinical research and clinical practice. Side-by-side comparison of the awake and anesthetized brains reveals that isoflurane induces diameter-dependent arterial dilation, elevated blood flow, and reduced OEF in a dose-dependent manner. As a result of the combined effects, CMRO2 is significantly reduced in the anesthetized brain under both normoxia and hypoxia, which suggests a mechanism for anesthetic neuroprotection. The head-restrained functional and metabolic PAM opens a new avenue for basic and translational research on neurovascular coupling without the strong influence of anesthesia and on the neuroprotective effects of various interventions, including but not limited to volatile anesthetics, against cerebral hypoxia and ischemia.



http://ift.tt/2m6y0uO

Macroanatomy and 3D probabilistic atlas of the human insula

Publication date: 15 April 2017
Source:NeuroImage, Volume 150
Author(s): Isabelle Faillenot, Rolf A. Heckemann, Maud Frot, Alexander Hammers
The human insula is implicated in numerous functions. More and more neuroimaging studies focus on this region, however no atlas offers a complete subdivision of the insula in a reference space. The aims of this study were to define a protocol to subdivide insula, to create probability maps in the MNI152 stereotaxic space, and to provide normative reference volume measurements for these subdivisions.Six regions were manually delineated bilaterally on 3D T1 MR images of 30 healthy subjects: the three short gyri, the anterior inferior cortex, and the two long gyri.The volume of the insular grey matter was 7.7 ± 0.9cm³ in native space and 9.9 ± 0.6cm³ in MNI152 space. These volumes expressed as a percentage of the ipsilateral grey matter volume were minimally larger in women (2.7±0.2%) than in men (2.6±0.2%). After spatial normalization, a stereotactic probabilistic atlas of each subregion was produced, as well as a maximum-probability atlas taking into account surrounding structures.Automatically labelling insular subregions via a multi-atlas propagation and label fusion strategy (MAPER) in a leave-one-out experiment showed high spatial overlaps of such automatically defined insular subregions with the manually derived ones (mean Jaccard index 0.65, corresponding to a mean Dice index of 0.79), with an average mean volume error of 2.6%.Probabilistic and maximum probability atlases and the original delineations are available on the web under free academic licences.

Graphical abstract

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Metacognitive ability correlates with hippocampal and prefrontal microstructure

Publication date: 1 April 2017
Source:NeuroImage, Volume 149
Author(s): Micah Allen, James C. Glen, Daniel Müllensiefen, Dietrich Samuel Schwarzkopf, Francesca Fardo, Darya Frank, Martina F. Callaghan, Geraint Rees
The ability to introspectively evaluate our experiences to form accurate metacognitive beliefs, or insight, is an essential component of decision-making. Previous research suggests individuals vary substantially in their level of insight, and that this variation is related to brain volume and function, particularly in the anterior prefrontal cortex (aPFC). However, the neurobiological mechanisms underlying these effects are unclear, as qualitative, macroscopic measures such as brain volume can be related to a variety of microstructural features. Here we leverage a high-resolution (800µm isotropic) multi-parameter mapping technique in 48 healthy individuals to delineate quantitative markers of in vivo histological features underlying metacognitive ability. Specifically, we examined how neuroimaging markers of local grey matter myelination and iron content relate to insight as measured by a signal-theoretic model of subjective confidence. Our results revealed a pattern of microstructural correlates of perceptual metacognition in the aPFC, precuneus, hippocampus, and visual cortices. In particular, we extend previous volumetric findings to show that right aPFC myeloarchitecture positively relates to metacognitive insight. In contrast, decreased myelination in the left hippocampus correlated with better metacognitive insight. These results highlight the ability of quantitative neuroimaging to reveal novel brain-behaviour correlates and may motivate future research on their environmental and developmental underpinnings.



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Heterogeneous fractionation profiles of meta-analytic coactivation networks

Publication date: 1 April 2017
Source:NeuroImage, Volume 149
Author(s): Angela R. Laird, Michael C. Riedel, Mershack Okoe, Radu Jianu, Kimberly L. Ray, Simon B. Eickhoff, Stephen M. Smith, Peter T. Fox, Matthew T. Sutherland
Computational cognitive neuroimaging approaches can be leveraged to characterize the hierarchical organization of distributed, functionally specialized networks in the human brain. To this end, we performed large-scale mining across the BrainMap database of coordinate-based activation locations from over 10,000 task-based experiments. Meta-analytic coactivation networks were identified by jointly applying independent component analysis (ICA) and meta-analytic connectivity modeling (MACM) across a wide range of model orders (i.e., d=20–300). We then iteratively computed pairwise correlation coefficients for consecutive model orders to compare spatial network topologies, ultimately yielding fractionation profiles delineating how "parent" functional brain systems decompose into constituent "child" sub-networks. Fractionation profiles differed dramatically across canonical networks: some exhibited complex and extensive fractionation into a large number of sub-networks across the full range of model orders, whereas others exhibited little to no decomposition as model order increased. Hierarchical clustering was applied to evaluate this heterogeneity, yielding three distinct groups of network fractionation profiles: high, moderate, and low fractionation. BrainMap-based functional decoding of resultant coactivation networks revealed a multi-domain association regardless of fractionation complexity. Rather than emphasize a cognitive-motor-perceptual gradient, these outcomes suggest the importance of inter-lobar connectivity in functional brain organization. We conclude that high fractionation networks are complex and comprised of many constituent sub-networks reflecting long-range, inter-lobar connectivity, particularly in fronto-parietal regions. In contrast, low fractionation networks may reflect persistent and stable networks that are more internally coherent and exhibit reduced inter-lobar communication.



http://ift.tt/2m6SS5p

Frequency-specific electrophysiologic correlates of resting state fMRI networks

Publication date: 1 April 2017
Source:NeuroImage, Volume 149
Author(s): Carl D. Hacker, Abraham Z. Snyder, Mrinal Pahwa, Maurizio Corbetta, Eric C. Leuthardt
Resting state functional MRI (R-fMRI) studies have shown that slow (<0.1Hz), intrinsic fluctuations of the blood oxygen level dependent (BOLD) signal are temporally correlated within hierarchically organized functional systems known as resting state networks (RSNs) (Doucet et al., 2011). Most broadly, this hierarchy exhibits a dichotomy between two opposed systems (Fox et al., 2005). One system engages with the environment and includes the visual, auditory, and sensorimotor (SMN) networks as well as the dorsal attention network (DAN), which controls spatial attention. The other system includes the default mode network (DMN) and the fronto-parietal control system (FPC), RSNs that instantiate episodic memory and executive control, respectively. Here, we test the hypothesis, based on the spectral specificity of electrophysiologic responses to perceptual vs. memory tasks (Klimesch, 1999; Pfurtscheller and Lopes da Silva, 1999), that these two large-scale neural systems also manifest frequency specificity in the resting state. We measured the spatial correspondence between electrocorticographic (ECoG) band-limited power (BLP) and R-fMRI correlation patterns in awake, resting, human subjects. Our results show that, while gamma BLP correspondence was common throughout the brain, theta (4–8Hz) BLP correspondence was stronger in the DMN and FPC, whereas alpha (8–12Hz) correspondence was stronger in the SMN and DAN. Thus, the human brain, at rest, exhibits frequency specific electrophysiology, respecting both the spectral structure of task responses and the hierarchical organization of RSNs.



http://ift.tt/2m6Jcrz

Group B streptococcal carriage, antimicrobial susceptibility, and virulence related genes among pregnant women in Alexandria, Egypt

Publication date: Available online 21 February 2017
Source:Alexandria Journal of Medicine
Author(s): Salama Mohamed Sadaka, Hala Abdelsalam Aly, Marwa Ahmed Meheissen, Yasser Ibrahim Orief, Basma Mohamed Arafa
Background and aimGroup B Streptococcus (GBS) has emerged as a leading cause of illness and death among neonates. The study was conducted to estimate the prevalence of recto-vaginal carriage of GBS among pregnant women at 35–37weeks, gestation, to describe GBS antimicrobial susceptibility profile and to investigate selected virulence genes by PCR.Subjects and methodsTwo-hundred pregnant women at 35–37weeks of gestation attending antenatal clinic at Al-Shatby University Hospital were enrolled in the study. Both vaginal and rectal swabs were collected from each subject. Swabs were inoculated onto CHROMagar™ StrepB and sheep blood agar plates. All GBS isolates were subjected to antimicrobial susceptibility testing using disc diffusion. Disc approximation test was performed to detect erythromycin resistance phenotype (MLSB). GBS virulence genes scpB, bac, bca, and rib were identified by PCR.ResultsAmong the 200 pregnant women, 53 (26.5%) were identified as GBS carriers. All carriers had vaginal colonization (100%), four (7.5%) had combined recto-vaginal colonization. None of the carriers had rectal colonization alone. All isolates (100%) were susceptible to penicillin, ampicillin, ceftriaxone, cefotaxime, cefepime, vancomycin, and linezolid. On the other hand, 43.4%, 28.3%, 22.6%, and 15% of isolates were resistant to levofloxacin, azithromycin, erythromycin, and clindamycin respectively. Out of 12 erythromycin resistant isolates, six isolates had constitutive while two had inducible MLSB resistance. scpB was identified in 100%, rib in 79.2%, and bac in 35.8% of GBS isolates. None of the isolates possessed the bca gene.ConclusionIntroduction of GBS screening in Egyptian pregnant women is recommended. Penicillin or ampicillin is still the antibiotic of choice for intrapartum prophylaxis.



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The developmental relationship between central dopaminergic level and response inhibition from late childhood to young adulthood

Publication date: Available online 20 February 2017
Source:International Journal of Psychophysiology
Author(s): Ting Zhang, Qin Zhang, Cuicui Wang, Antao Chen
Dopamine (DA) is known to modulate response inhibition (RI). In contrast to the abundant adult studies, only few developmental studies have focused on this topic. Moreover, the mechanism underlying the modulation of RI by the DA system from childhood to adulthood remains unclear. We aimed to assess whether the relationship between DA and RI during late childhood and young adulthood is similar. Accordingly, DA function was measured using the spontaneous eye blink rate (EBR), whereas RI ability was tested using the Go/Nogo task. Experiment 1 included 149 adults (age range, 18–25years) who completed the EBR test and the Go/Nogo task; the results showed that higher EBR was associated with lower commission error in the Nogo trials. Experiment 2 included 45 children (age range, 10–12years) and 37 adults (age range, 18–19years) who completed the EBR test and Go/Nogo tasks (similar to experiment 1); in both the child and adult groups, higher EBR was related to better RI ability. As EBR is closely related to central DA function, these findings suggest that DA plays a similar role in the processing of RI in late childhood and young adulthood.



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Renaud Mazeron, 1977-2016

Publication date: Available online 21 February 2017
Source:Brachytherapy





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Immunoprofiling as a predictor of patient’s response to cancer therapy—promises and challenges

Publication date: April 2017
Source:Current Opinion in Immunology, Volume 45
Author(s): Daniel Bethmann, Zipei Feng, Bernard A Fox
Immune cell infiltration is common to many tumors and has been recognized by pathologists for more than 100 years. The application of digital imaging and objective assessment software allowed a concise determination of the type and quantity of immune cells and their location relative to the tumor and, in the case of colon cancer, characterized overall survival better than AJCC TNM staging. Subsequently, expression of PD-L1, by 50% or more tumor cells, identified NSCLC patients with double the response rate to anti-PD-1. Soon, automated staining methods will improve reproducibility of multiplex staining and allow for CLIA standards so that multiplex staining can be used to make clinical decisions. Ultimately, machine-learning algorithms will help interpret data from tissue images and lead to improved delivery of precision medicine.



http://ift.tt/2m5JGhE

Computed Tomography Angiography in Head and Neck Emergencies

Publication date: Available online 20 February 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Nikhil Madhuripan, Oliver David Atar, Richard Zheng, Mary Tenenbaum
Computed tomography angiography offers a rapid means of evaluating the vasculature of the head and neck in patients presenting with acute neurological symptoms and blunt trauma to the head and neck. CTA is noninvasive, easy to acquire, and offers excellent detail in identifying site and nature of the lesion. The learning objectives of this review article are to review normal anatomy and variants, recognize CTA appearance of vascular pathologies, describe typical parameters utilized for acquiring the study and recognize common pitfalls.



http://ift.tt/2kTpi13

Ultrasound Emergencies of the Male Pelvis

Publication date: Available online 20 February 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Kimberly Weatherspoon, Stanley Polansky, Tara Catanzano
Male pelvic emergencies are uncommon, and symptoms typically include scrotal pain, scrotal enlargement and/or a palpable scrotal mass. Ultrasound is often the first line modality for evaluation of male pelvic emergencies, which may be stratified into vascular, infectious or traumatic causes. Entities like testicular torsion; Fournier′s gangrene and testicular dislocation are surgical emergencies and should not be missed or misdiagnosed, as this may cause a significant delay in urgently necessary treatment. Radiologists need to be familiar with the role of imaging as well as the key characteristic imaging findings of these injuries in order to direct the appropriate management.



http://ift.tt/2l23iSR

Recognition and Appropriate Use of MRI for Emergent Neuroradiology

Publication date: Available online 20 February 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Joseph M. Rozell, Shan Li
The use of magnetic resonance imaging (MRI) for the diagnosis of emergent life threatening neurological conditions and what are considered "do not miss" pathologies has dramatically risen over the last ten years due to its increasing importance in the Emergency Department (ED). Although Computed Tomography is likely to remain the more significantly utilized imaging modality due to lower cost and faster speeds, continuing technological advances in MRI have made its use more mainstream. Knowledge of specific clinical signs and symptoms as well as the technical limitations of MRI should help to guide ED clinicians with both the recognition and the appropriate use of emergent MRI.



http://ift.tt/2l2djza

Neurologic Emergencies on Computed Tomography of the Head

Publication date: Available online 20 February 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Jed Hollingsworth, Mae Mae Mirabelli
The purpose of this manuscript is to provide the reader, either a seasoned radiologist, a budding resident, or a curious practitioner, the background necessary to accurately and swiftly interpret a head CT in the emergency setting. At the very least, being able to generate a reasonable differential diagnosis is the aim and will be accomplished by describing not only features of classic neurologic emergencies, but the possible traps to which one may fall prey. Images will be used to illustrate cases and the reader will be instructed when other imaging modalities may be required to clarify diagnoses.



http://ift.tt/2lARH03

The Four Quadrants: Acute Pathology in the Abdomen and Current Imaging Guidelines

Publication date: Available online 20 February 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Bradley Mattson, Kal Dulaimy
With several different imaging options available, it′s not surprising that healthcare providers are unsure which imaging study is most appropriate for evaluating patients who present to the emergency department with abdominal pain. The American College of Radiology currently has appropriateness criteria for patients presenting with right upper, right lower, and left lower quadrant pain and there are different variants for each of these quadrants. Clinicians should be aware of the ACR appropriateness criteria and, whenever possible, should be using the criteria as guide to help them order the most appropriate imaging study.



http://ift.tt/2lG18Mi

Imaging of Female Pelvic Emergencies

Publication date: Available online 20 February 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Daniel P. Thut, Michael S. Morrow, Christopher C. Moore
Pelvic pain is a common complaint in female patients who present to the Emergency Department. Although encountered frequently, the path to a definitive diagnosis is not always a straightforward one, and imaging offers a valuable tool to aid in this diagnostic challenge. Radiologists must be familiar with the most common etiologies of female pelvic pain in the emergency setting, their imaging characteristics, and the best way to further evaluate challenging clinical presentations. This will allow the radiologist to serve as a valuable asset to the treating physician, aiding in accurate diagnosis and in guiding the course of treatment, all while ensuring the "Image Wisely" principle. A sonographic approach to female patients presenting to the emergency setting with pelvic pain has been presented in this article and some example entities along with their imaging findings have also been reviewed.



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Adenosine A2 receptor activation ameliorates mitochondrial oxidative stress upon reperfusion through the posttranslational modification of NDUFV2 subunit of complex I in the heart

Publication date: Available online 20 February 2017
Source:Free Radical Biology and Medicine
Author(s): Jingman Xu, Xiyun Bian, Yuan Liu, Lan Hong, Tianming Teng, Yuemin Sun, Zhelong Xu
While it is well known that adenosine receptor activation protects the heart from ischemia/reperfusion injury, the precise mitochondrial mechanism responsible for the action remains unknown. This study probed the mitochondrial events associated with the cardioprotective effect of 5'-(N-ethylcarboxamido) adenosine (NECA), an adenosine A2 receptor agonist. Isolated rat hearts were subjected to 30min ischemia followed by 10min of reperfusion, whereas H9c2 cells experienced 20min ischemia and 10min reperfusion. NECA prevented mitochondrial structural damage, decreases in respiratory control ratio (RCR), and collapse of mitochondrial membrane potential (ΔΨm). Both the adenosine A2A receptor antagonist SCH58261 and A2B receptor antagonist MRS1706 inhibited the action of NECA. NECA reduced mitochondrial proteins carbonylation, H2O2, and superoxide generation at reperfusion, but did not change superoxide dismutase (SOD) activity. In support, the protective effects of NECA and Peg-SOD on ΔΨm upon reperfusion were additive, implying that NECA's protection is attributable to the reduced superoxide generation but not to the enhancement of the superoxide-scavenging capacity. NECA increased the mitochondrial Src tyrosine kinase activity and suppressed complex I activity at reperfusion in a Src-dependent manner. NECA also reduced mitochondrial superoxide through Src tyrosine kinase. Studies with liquid chromatography-mass spectrometer (LC-MS) identified Tyr118 of the NDUFV2 subunit of complex 1 as a likely site of the tyrosine phosphorylation. Furthermore, the complex I activity of cells transfected with the Y118F mutant was increased, suggesting that this site might be a negative regulator of complex I activity. In support, NECA failed to suppress complex I activity at reperfusion in cells transfected with the Y118F mutant of NDUFV2. In conclusion, NECA prevents mitochondrial oxidative stress by decreasing mitochondrial superoxide generation through inhibition of complex I via the mitochondrial Src tyrosine kinase. Phosphorylation of Tyr¹¹⁸ residue in NDUFV2 subunit may account for the inhibitory effect of NECA on complex I.

Graphical abstract

http://ift.tt/2lgJmy8

Conversion to purpurogallin, a key step in the mechanism of the potent xanthine oxidase inhibitory activity of pyrogallol

Publication date: Available online 20 February 2017
Source:Free Radical Biology and Medicine
Author(s): Sari Honda, Yuya Fukuyama, Hisashi Nishiwaki, Akiko Masuda, Toshiya Masuda
In this study, the mechanism of the xanthine oxidase (XO) inhibitory activity of pyrogallol, the main inhibitor found in roasted coffee, was investigated. Pyrogallol was unstable and readily converted to purpurogallin in a pH 7.4 solution, a physiological model of human body fluids. The XO inhibitory activity of the produced purpurogallin was higher than that of pyrogallol, as evidenced by comparing their IC50 values (0.2 µmol L⁻¹ for purpurogallin, 1.6 µmol L⁻¹ for pyrogallol). The XO activity of pyrogallol was enhanced by pre-incubation in pH 7.4 solution. Although the initial XO inhibitory activity of 4-methylpyrogallol was weak (IC50 33.3 µmol L⁻¹), its XO inhibitory activity was also enhanced by pre-incubation in the pH 7.4 solution. In contrast, 5-methylpyrogallol, which could not be transformed into corresponding purpurogallin derivatives, did not show XO inhibitory activity before or after incubation in pH 7.4 solution. Molecular docking simulations clarified that purpurogallins have stronger affinities for XO than corresponding pyrogallols. These results revealed that the potent XO inhibitory activity seemingly observed in pyrogallol is actually derived from its chemical conversion, under alkaline conditions, into purpurogallin.

Graphical abstract

http://ift.tt/2lgBUmm

Muscle Response to Complete Peripheral Nerve Injury: Changes of Acetylcholine Receptor and Creatine Kinase Activity over Time

J reconstr Microsurg
DOI: 10.1055/s-0037-1598619

Background This study was designed to assess the changes of acetylcholine receptor (AChR) and creatine kinase (CK) levels, which are important biochemical markers for muscle viability in cases of long-term muscle denervation. Scientists and peripheral nerve surgeons may find these data important regarding maximal range of muscle viability applicable for timing of effective peripheral nerve reconstructive surgery. Methods The study was conducted on 48 rats (96 gastrocnemius muscles), whose right legs were denervated by removing a 10-mm segment of sciatic nerve, while their left legs remained intact. Under general anesthesia, the rats were euthanized at seven points in time, on days 7, 14, 21, 30, 60, 120, and 210. In both legs, AChR was quantified by 125I-α-bungarotoxin, whereas CK activity was measured using a spectrophotometric method. Results CK levels in the denervated limb reached a minimal level of 34% on day 30 in comparison to the intact limb and remained at this level up to 210 days after operation. AChR levels in the denervated limb reached a minimal level of 38% on day 120 in comparison to the intact limb and remained at this level up to 210 days after operation. Conclusion The present study shows that AChR and CK levels in rat denervated muscles remain constant at about third of its intact condition for a period of at least a third of rat's lifetime postinjury.
[...]

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Article in Thieme eJournals:
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Forehead flaps for nasal reconstruction: A single-center experience

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Management of Cancer in the Older Age Person: An Approach to Complex Medical Decisions

The management of cancer in older aged people is becoming a common problem due to the aging of the population. There are many variables determining the complex situation that are interconnected. Some of them can be assessed, such as risk of mortality and risk of treatment complications, but many others are still unknown, such as the course of disease, the host-related factors that influence cancer aggressiveness, and the phenotype heralding risk of permanent treatment-related damage.

This article presents a dynamic and personalized approach to older people with cancer based on our experience on aging, cancer, and their biological interactions. Also, novel treatments and management approaches to older individuals, based on their functional age and their social and emotional needs, are thoughtfully explored here. The Oncologist 2017;22:1–8

Implications for Practice: The goal of this article is to suggest a practical approach to complexity, a clinical situation becoming increasingly common with the aging of the population. Beginning with the analysis of two clinical cases, the authors offer an algorithm for approaching cancer in the older person that involves the assessment of life expectancy without cancer, the risk that cancer might compromise a patient's survival, function, or quality of life, and the potential benefits and risks of the treatments based on a clinical evaluation. The authors then review possible laboratory assessment of functional age and the importance of rapid-learning databases in the study of cancer and age.

http://ift.tt/2mgNmMB

Early Palliative Care Reduces End-of-Life Intensive Care Unit (ICU) Use but Not ICU Course in Patients with Advanced Cancer

Background.

Early palliative care for advanced cancer patients improves quality of life and survival, but less is known about its effect on intensive care unit (ICU) use at the end of life. This analysis assessed the effect of a comprehensive early palliative care program on ICU use and other outcomes among patients with advanced cancer.

Patients and Methods.

A retrospective cohort of patients with advanced cancer enrolled in an early palliative care program (n = 275) was compared with a concurrent control group of patients receiving standard care (n = 195) during the same time period by using multivariable logistic regression analysis. The multidisciplinary outpatient palliative care program used early end-of-life care planning, weekly interdisciplinary meetings to discuss patient status, and patient-reported outcomes assessment integrated within the electronic health record.

Results.

Patients in the control group had statistically significantly higher likelihood of ICU admission at the end of life (odds ratios [ORs]: last 6 months, 3.07; last month, 3.59; terminal admission, 4.69), higher likelihood of death in the hospital (OR, 4.14) or ICU (OR, 5.57), and lower likelihood of hospice enrollment (OR, 0.13). Use of chemotherapy or radiation did not significantly differ between groups, nor did length of ICU stay, code status, ICU procedures (other than cardiopulmonary resuscitation), disposition location, and outcomes after ICU admission.

Conclusion.

Early palliative care significantly reduced ICU use at the end of life but did not change ICU events. This study supports early initiation of palliative care for advanced cancer patients before hospitalizations and intensive care. The Oncologist 2017;22:1–6

Implications for Practice: Palliative care has shown clear benefit in quality of life and survival in advanced cancer patients, but less is known about its effect on intensive care. This retrospective cohort study at a university hospital showed that in the last 6 months of life, palliative care significantly reduced intensive care unit (ICU) and hospital admissions, reduced deaths in the hospital, and increased hospice enrollment. It did not, however, change patients' experiences within the ICU, such as number of procedures, code status, length of stay, or disposition. The findings further support that palliative care exerts its benefit before, rather than during, the ICU setting.

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Population-Level Differences in Rectal Cancer Survival in Uninsured Patients Are Partially Explained by Differences in Treatment

Background.

Rectal cancer (RC) is a common malignancy with a substantial mortality but good survival for patients with optimally treated nonmetastatic disease. Lack of insurance may compromise access to care and therefore compromise survival. Here, we examine RC survival by insurance type.

Methods.

Data from the Surveillance, Epidemiology, and End Results database were used to determine 1- to 3-year survival for patients with RC by insurance type (Medicaid, uninsured, other insurance).

Results.

Patients with Medicaid or no insurance presented at later stages and were less likely to receive definitive surgery. Overall 3-year survival was higher for patients with other insurance compared with Medicaid-insured (+22.2% units) and uninsured (+18.8% units) patients. Major differences in survival were still observed after adjustment for stage. When patients with stage II and III RC were considered, 3-year survival was higher for patients with other insurance versus those with Medicaid (+16.2% units) and uninsured patients (+12.2% units). However, when the analysis was limited to patients with stage II and III disease who received radiation therapy followed by definitive surgery, the difference decreased to +11.8% units and +7.3% units, respectively, for Medicaid and no insurance.

Conclusion.

For patients with stage II and III RC, much of the difference in survival between uninsured patients and those with insurance other than Medicaid can be explained by differences in treatment. Further efforts to determine the cause of residual differences as well as efforts to improve access to standard-of-care treatment for uninsured patients may improve population-level survival for RC. The Oncologist 2017;22:1–8

Implications for Practice: Insurance status affects survival for patients with rectal cancer, but a substantial proportion of the difference in survival can be corrected if standard-of-care treatment is given. Every effort should be made to ensure that uninsured or publically insured patients receive standard-of-care treatment with as little delay as possible to improve patient outcomes.

Implications for Practice: Insurance status affects survival for patients with rectal cancer, but a substantial proportion of the difference in survival can be corrected if standard-of-care treatment is given. Every effort should be made to ensure that uninsured or publically insured patients receive standard-of-care treatment with as little delay as possible to improve patient outcomes.

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Molecular Subtypes Improve Prognostic Value of International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Model

Introduction.

Gene-expression signatures for prognosis have been reported in localized renal cell carcinoma (RCC). The aim of this study was to test the predictive power of two different signatures, ClearCode34, a 34-gene signature model [Eur Urol 2014;66:77–84], and an 8-gene signature model [Eur Urol 2015;67:17–20], in the setting of systemic therapy for metastatic disease.

Materials and Methods

Metastatic RCC (mRCC) patients from five institutions who were part of TCGA were identified and clinical data were retrieved. We trained and implemented each gene model as described by the original study. The latter was demonstrated by faithful regeneration of a figure and results from the original study. mRCC patients were dichotomized to good or poor prognostic risk groups using each gene model. Cox proportional hazard regression and concordance index (C-Index) analysis were used to investigate an association between each prognostic risk model and overall survival (OS) from first-line therapy.

Results.

Overall, 54 patients were included in the final analysis. The primary endpoint was OS. Applying the ClearCode34 model, median survival for the low-risk—ccA (n = 17)—and the high-risk—ccB (n = 37)—subtypes were 27.6 and 22.3 months (hazard ratio (HR): 2.33; p = .039), respectively. ClearCode34 ccA/ccB and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classifications appear to represent distinct risk criteria in mRCC, and we observed no significant overlap in classification (p > .05, chi-square test). On multivariable analyses and adjusting for IMDC groups, ccB remained independently associated with a worse OS (p = .044); the joint model of ccA/ccB and IMDC was significantly more accurate in predicting OS than a model with IMDC alone (p = .045, F-test). This was also observed in C-Index analysis; a model with both ccA and ccB subtypes had higher accuracy (C-Index 0.63, 95% confidence interval [CI] = 0.51–0.75) and 95% CIs of the C-Index that did not include the null value of 0.5 in contrast to a model with IMDC alone (0.60, CI = 0.47–0.72). The 8-gene signature molecular subtype model was a weak but insignificant predictor of survival in this cohort (p = .13). A model that included both the 8-gene signature and IMDC (C-Index 0.62, CI = 0.49–0.76) was more prognostic than IMDC alone but did not reach significance, as the 95% CI included the null value of 0.5. These two genomic signatures share no genes in common and are enriched in different biological pathways. The ClearCode34 included genes ARNT and EPAS1 (also known as HIF2a), which are involved in regulation of gene expression by hypoxia-inducible factor.

Conclusion.

The ClearCode34 but not the 8-gene molecular model improved the prognostic predictive power of the IMDC model in this cohort of 54 patients with metastatic clear cell RCC. The Oncologist 2017;22:1–7

Implications for Practice: The clinical and laboratory factors included in the International Metastatic Renal Cell Carcinoma Database Consortium model provide prognostic information in metastatic renal cell carcinoma (mRCC). The present study shows that genomic signatures, originally validated in localized RCC, may add further complementary prognostic information in the metastatic setting. This study may provide new insights into the molecular basis of certain mRCC subgroups. The integration of clinical and molecular data has the potential to redefine mRCC classification, enhance the understanding of mRCC biology, and potentially predict response to treatment in the future.

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Using Metaphors to Explain Molecular Testing to Cancer Patients

Background.

Molecular testing to identify targetable molecular alterations is routine practice for several types of cancer. Explaining the underlying molecular concepts can be difficult, and metaphors historically have been used in medicine to provide a common language between physicians and patients. Although previous studies have highlighted the use and effectiveness of metaphors to help explain germline genetic concepts to the general public, this study is the first to describe the use of metaphors to explain molecular testing to cancer patients in the clinical setting.

Methods.

Oncologist-patient conversations about molecular testing were recorded, transcribed verbatim, and coded. If a metaphor was used, patients were asked to explain it and assess its helpfulness.

Results.

Sixty-six patients participated. Nine oncologists used metaphors to describe molecular testing; 25 of 66 (38%) participants heard a metaphor, 13 of 25 (52%) were questioned, 11 of 13 (85%) demonstrated understanding and reported the metaphor as being useful. Seventeen metaphors (bus driver, boss, switch, battery, circuit, broken light switch, gas pedal, key turning off an engine, key opening a lock, food for growth, satellite and antenna, interstate, alternate circuit, traffic jam, blueprint, room names, Florida citrus) were used to explain eight molecular testing terms (driver mutations, targeted therapy, hormones, receptors, resistance, exon specificity, genes, and cancer signatures).

Conclusion.

Because metaphors have proven to be a useful communication tool in other settings, these 17 metaphors may be useful for oncologists to adapt to their own setting to explain molecular testing terms. The Oncologist 2017;22:1–5

Implications for Practice: This article provides a snapshot of 17 metaphors that proved useful in describing 8 complicated molecular testing terms at 3 sites. As complex tumor sequencing becomes standard of care in clinics and widely used in clinical research, the use of metaphors may prove a useful communication tool, as it has in other settings. Although this study had a small sample, almost all of the patients who were exposed to metaphors in explaining molecular testing reported it as being helpful to their understanding. These 17 metaphors are examples of potentially useful communication tools that oncologists can adapt to their own practice.

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The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review

Background.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research.

Methods.

Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016.

Results.

Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full-length publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)-NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET.

Conclusion.

Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. The Oncologist 2017;22:1–14

Implications for Practice: This review presents the current clinical evidence for the antiproliferative activity of lanreotide Autogel in patients with midgut or pancreatic neuroendocrine tumors (NETs) and shows its effectiveness, safety, and tolerability in these patient populations. By systematically presenting all the clinical evidence, the review adds to existing publications by discussing results in a broad range of settings. The review also indicates future directions for investigation of the use of lanreotide Autogel in NETs originating in other locations, in combination therapy, or as maintenance therapy in progressive disease.

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Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer

Background.

Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer.

Methods.

Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m² orally twice daily, days 1–14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM + CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR + CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics.

Results.

Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1–36.1) weeks on RAM + CAP, 7.3 (6.3–13.0) weeks on ICR + CAP, and 19.0 (12.1–24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM + CAP versus CAP; 1.480, p = .0851, ICR + CAP versus CAP). Median OS was 67.4 weeks on RAM + CAP, 62.1 weeks on ICR + CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM + CAP versus CAP; 1.468, p = .1550, ICR + CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM + CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR + CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea.

Conclusion.

Combining RAM or ICR with CAP did not improve PFS in the targeted study population. The Oncologist 2017;22:1–10

Implications for Practice

Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.

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Survival of patients with colorectal peritoneal metastases is affected by treatment disparities among hospitals of diagnosis: A nationwide population-based study

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Koen P. Rovers, Geert A. Simkens, Pauline A. Vissers, Valery E. Lemmens, Victor J. Verwaal, Andre J. Bremers, Marinus J. Wiezer, Jacobus W. Burger, Patrick H. Hemmer, Henk Boot, Wilhelmina M. van Grevenstein, Wilhelmus J. Meijerink, Arend G. Aalbers, Cornelis J. Punt, Pieter J. Tanis, Ignace H. de Hingh
BackgroundIn the Netherlands, surgery for peritoneal metastases of colorectal cancer (PMCRC) is centralised, whereas PMCRC is diagnosed in all hospitals. This study assessed whether hospital of diagnosis affects treatment selection and overall survival (OS).MethodsBetween 2005 and 2015, all patients with synchronous PMCRC without systemic metastases were selected from the Netherlands Cancer Registry. Treatment was classified as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), systemic therapy or other/no treatment. Hospitals of diagnosis were classified as: (1) non-teaching or academic/teaching hospital and (2) HIPEC centre or referring hospital. Referring hospitals were further classified based on the frequency of CRS/HIPEC as high-, medium- or low-frequency hospital. Multivariable regression analyses were used to assess the independent influence of hospital categories on the likelihood of CRS/HIPEC and OS.ResultsA total of 2661 patients, diagnosed in 89 hospitals, were included. At individual hospital level, CRS/HIPEC and systemic therapy ranged from 0% to 50% and 6% to 67%, respectively. Hospital of diagnosis influenced the likelihood of CRS/HIPEC: 33% versus 13% for HIPEC centres versus referring hospitals (odds ratio (OR) 3.66 [2.40−5.58]) and 11% versus 17% for non-teaching hospitals versus academic/teaching hospitals (OR 0.60 [0.47–0.77]). Hospital of diagnosis affected median OS: 14.1 versus 9.6 months for HIPEC centres versus referring hospitals (hazard ratio (HR) 0.82 [0.67–0.99]) and 8.7 versus 11.5 months for non-teaching hospitals versus academic/teaching hospitals (HR 1.15 [1.06–1.26]). Compared with diagnosis in medium-frequency referring hospitals, median OS was increased in high-frequency referring hospitals (12.6 months, HR 0.82 [0.73−0.91]) and reduced in low-frequency referring hospitals (8.1 months, HR 1.12 [1.01–1.24]).ConclusionTreatment disparities among hospitals of diagnosis and their impact on survival indicate suboptimal treatment selection for PMCRC.



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Phase-II trials in osteosarcoma recurrences: A systematic review of past experience

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Natacha Omer, Marie-Cécile Le Deley, Sophie Piperno-Neumann, Perrine Marec-Berard, Antoine Italiano, Nadège Corradini, Carine Bellera, Laurence Brugières, Nathalie Gaspar
BackgroundThe most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined.ObjectiveTo study consistency in phase-II clinical trials evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results.MethodsSystematic review of clinical trials registered on clinicaltrials.gov, clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II).ResultsAmong the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%.ConclusionNo robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point.



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Anthropometrics at birth and risk of a primary central nervous system tumour: A systematic review and meta-analysis

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Marios K. Georgakis, Eleni I. Kalogirou, Athanasios Liaskas, Maria A. Karalexi, Paraskevi Papathoma, Kyriaki Ladopoulou, Maria Kantzanou, Georgios Tsivgoulis, Eleni Th. Petridou
BackgroundThe aetiology of primary central nervous system (CNS) tumours remains largely unknown, but their childhood peak points to perinatal parameters as tentative risk factors. In this meta-analysis, we opted to quantitatively synthesise published evidence on the association between birth anthropometrics and risk of primary CNS tumour.MethodsEligible studies were identified via systematic literature review; random-effects meta-analyses were conducted for the effect of birth weight and size-for-gestational-age on childhood and adult primary CNS tumours; subgroup, sensitivity, meta-regression and dose–response by birth weight category analyses were also performed.ResultsForty-one articles, encompassing 53,167 CNS tumour cases, were eligible. Birth weight >4000 g was associated with increased risk of childhood CNS tumour (OR: 1.14, [1.08–1.20]; 22,330 cases). The risk was higher for astrocytoma (OR: 1.22, [1.13–1.31]; 7456 cases) and embryonal tumour (OR: 1.16, [1.04–1.29]; 3574 cases) and non-significant for ependymoma (OR: 1.12, [0.94–1.34]; 1374 cases). Increased odds for a CNS tumour were also noted among large-for-gestational-age children (OR: 1.12, [1.03–1.22]; 10,339 cases), whereas insufficient data for synthesis were identified for other birth anthropometrics. The findings remained robust across subgroup and sensitivity analyses controlling for several sources of bias, whereas no significant heterogeneity or publication bias were documented. The limited available evidence on adults (4 studies) did not reveal significant associations between increasing birth weight (500-g increment) and overall risk CNS tumour (OR: 0.99, [0.98–1.00]; 1091 cases) or glioma (OR: 1.03, [0.98–1.07]; 2052 cases).ConclusionsThis meta-analysis confirms a sizeable association of high birth weight, with childhood CNS tumour risk, particularly astrocytoma and embryonal tumour, which seems to be independent of gestational age. Further research is needed to explore underlying mechanisms, especially modifiable determinants of infant macrosomia, such as gestational diabetes.



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Advanced breast cancer rates in the epoch of service screening: The 400,000 women cohort study from Italy

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Donella Puliti, Lauro Bucchi, Silvia Mancini, Eugenio Paci, Susanna Baracco, Cinzia Campari, Debora Canuti, Claudia Cirilli, Natalina Collina, Giovanni Maria Conti, Enza Di Felice, Fabio Falcini, Maria Michiara, Rossella Negri, Alessandra Ravaioli, Priscilla Sassoli de' Bianchi, Monica Serafini, Manuel Zorzi, Adele Caldarella, Luigi Cataliotti, Marco Zappa
BackgroundThe objective of this study was to evaluate if mammography screening attendance is associated with a reduction in late-stage breast cancer incidence.MethodsThe cohort included over 400,000 Italian women who were first invited to participate in regional screening programmes during the 1990s and were followed for breast cancer incidence for 13 years. We obtained individual data on their exposure to screening and correlated this with total and stage-specific breast cancer incidence. Socio-economic status and pre-screening incidence data were used to assess the presence of self-selection bias.ResultsOverall, screening attendance was associated with a 10% excess risk of in situ and invasive breast cancer (IRR = 1.10; 95% confidence interval (CI): 1.06–1.14), which dropped to 5% for invasive cancers only (IRR = 1.05; 95% CI: 1.01–1.09). There were significant reductions among attenders for specific cancer stages; we observed a 39% reduction for T2 or larger (IRR = 0.61; 95% CI: 0.57–0.66), 19% for node positives (IRR = 0.81; 95% CI: 0.76–0.86) and 28% for stage II and higher (IRR = 0.72; 95% CI: 0.68–0.76). Our data suggest that the presence of self-selection bias is limited and, overall, invited women experienced a 17% reduction of advanced cancers compared with pre-screening rates.ConclusionsComparing attenders' and non-attenders' stage-specific breast cancer incidence, we have estimated that screening attendance is associated with a reduction of nearly 30% for stages II+.



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Rationale for stimulator of interferon genes–targeted cancer immunotherapy

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Thaiz Rivera Vargas, Isis Benoit-Lizon, Lionel Apetoh
The efficacy of checkpoint inhibitor therapy illustrates that cancer immunotherapy, which aims to foster the host immune response against cancer to achieve durable anticancer responses, can be successfully implemented in a routine clinical practice. However, a substantial proportion of patients does not benefit from this treatment, underscoring the need to identify alternative strategies to defeat cancer. Despite the demonstration in the 1990's that the detection of danger signals, including the nucleic acids DNA and RNA, by dendritic cells (DCs) in a cancer setting is essential for eliciting host defence, the molecular sensors responsible for recognising these danger signals and eliciting anticancer immune responses remain incompletely characterised, possibly explaining the disappointing results obtained so far upon the clinical implementation of DC-based cancer vaccines. In 2008, STING (stimulator of interferon genes), was identified as a protein that is indispensable for the recognition of cytosolic DNA. The central role of STING in controlling anticancer immune responses was exemplified by observations that spontaneous and radiation-induced adaptive anticancer immunity was reduced in the absence of STING, illustrating the potential of STING-targeting for cancer immunotherapy. Here, we will discuss the relevance of manipulating the STING signalling pathway for cancer treatment and integrating STING-targeting based strategies into combinatorial therapies to obtain long-lasting anticancer immune responses.



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Can chance cause cancer? A causal consideration

Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Mats Julius Stensrud, Susanne Strohmaier, Morten Valberg, Odd Olai Aalen
The role of randomness, environment and genetics in cancer development is debated. We approach the discussion by using the potential outcomes framework for causal inference. By briefly considering the underlying assumptions, we suggest that the antagonising views arise due to estimation of substantially different causal effects. These effects may be hard to interpret, and the results cannot be immediately compared. Indeed, it is not clear whether it is possible to define a causal effect of chance at all.



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