Functional roles of short-term synaptic plasticity with an emphasis on inhibition

Publication date: April 2017
Source:Current Opinion in Neurobiology, Volume 43
Author(s): Haroon Anwar, Xinping Li, Dirk Bucher, Farzan Nadim
Almost all synapses show activity-dependent dynamic changes in efficacy. Numerous studies have explored the mechanisms underlying different forms of short-term synaptic plasticity (STP), but the functional role of STP for circuit output and animal behavior is less understood. This is particularly true for inhibitory synapses that can play widely varied roles in circuit activity. We review recent findings on the role of synaptic STP in sensory, pattern generating, thalamocortical, and hippocampal networks, with a focus on synaptic inhibition. These studies show a variety of functions including sensory adaptation and gating, dynamic gain control and rhythm generation. Because experimental manipulations of STP are difficult and nonspecific, a clear demonstration of STP function often requires a combination of experimental and computational techniques.



http://ift.tt/2jnRFod

Benign vascular lesions of the lips: diagnostic approach

ABSTRACT

Background

Although not rare, vascular lesions occurring in the lips sometimes poses a difficult in properly diagnosing and handling them. In the present study vascular lesions occurring in the lips were retrieved from an Oral Pathology Service.

Methods

Among 5,600 biopsies, 131 cases were found. The following diagnoses were attributed: caliber-persistent artery, infantile hemangioma, vascular malformation, venous lake, thrombus, papillary endothelial hyperplasia, and pyogenic granuloma. Clinical data were obtained from patients' records.

Results

The lesions` frequency were: pyogenic granuloma (48%), followed by venous lake (17.5%), thrombus (14.5%), papillary endothelial hyperplasia (9.1%), infantile hemangioma (6,1%), caliber persistent artery (3%) and vascular malformation (1.5%). GLUT-1 was positive only in infantile hemangioma. The other markers (CD34 and SMA) were positive in all lesions, except for podoplanin, which was negative.

Conclusion

It is important to be aware of the occurrence of different vascular lip lesions and their histomorphologies in order to properly handle them. Despite most lesions do not represent any risk to the patient, some of them can reach large dimensions and thus cause aesthetical trouble. Immunohistochemistry may help when the vascular character of the lesion is not promptly determined and to differentiate among some lesions.

http://ift.tt/2j3MWqX

Squamous cell carcinoma with enteric adenocarcinomatous differentiation

Abstract

We report a highly unusual case of a primary cutaneous squamous cell carcinoma with intermixed enteric-type adenocarcinomatous dedifferentiation and a small component of undifferentiated mesenchymal differentiation. We believe this is the first time this form of phenotypic plasticity has been described in cutaneous squamous cell carcinoma.

http://ift.tt/2jPgzjW

Treatment of adult diffuse pityriasis lichenoides chronica with narrowband ultraviolet B: experience and literature review

Summary

Pityriasis lichenoides chronica (PLC) is an infrequent dermatosis of unknown aetiology, wholse evolution and response to treatment differs between children and adults. When PLC is recalcitrant or unresponsive to topical treatment, phototherapy is one of the main treatments used. We carried out a prospective study of adult diffuse PLC treated with narrowband ultraviolet B (NB-UVB). We treated eight patients whose disease showed no response to topical therapy, and obtained a complete response rate of 88% in a mean of 23 sessions (cumulative dose 16.99 J/cm²). However, the relapse rate was 43% in the first 6 months. Our results are similar to those of other published studies but there is much variability between them in the doses applied and the number of sessions needed. Further studies are necessary to devise a protocol for NB-UVB treatment of PLC.

http://ift.tt/2iTo4Xw

Enlarging plaques and nodules on the face and legs

Click here for the corresponding questions to this CME article.

http://ift.tt/2khdENJ

Myaesthenia gravis exacerbation caused by axillary injection of botulinum toxin A for treatment of hyperhidrosis

Click here for the corresponding questions to this CME article.

http://ift.tt/2iTzgmY

A clinical evaluation of the efficacy of photodynamic therapy in the treatment of erosive oral lichen planus: A case series

Publication date: Available online 22 January 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Magdalena Sulewska, Ewa Duraj, Stefan Sobaniec, Alfreda Graczyk, Robert Milewski, Marta Wróblewska, Jan Pietruski, Małgorzata Pietruska
BackgroundErosive oral lichen planus (EOLP) poses a substantial risk of malignant transformation into squamous cell cancer. The absence of established treatment gives way to alternative therapeutic strategies, including photodynamic therapy. The aim of the study was to evaluate the efficacy of PDT in the treatment of EOLP.MethodsTwelve female patients aged 63-80 with 22 OLP lesions (16 on the buccal mucosa, 6 on gingiva and tongue), underwent authors' own PDT scheme with the use of 5% solution of 5-aminolevulinic acid (ALA) as photosensitizer. An ALA-saturated occlusive dressing was applied directly onto a lesion and surrounding mucosa 2hours prior to illumination with a custom-made diode lamp (light of 630nm, dose of 300mW). After a series of 10 weekly illumination sessions the patients were monitored for 12 months.ResultsThe mean size of lesions before treatment was 1.46cm²±1.44. The lesions on the buccal mucosa were smaller (1.06cm²±0.98) than those on the gingiva and tongue (2.63cm²±1.93). Post-treatment improvement encompassed 16 lesions, 5 of which were in remission. The mean reduction in size after 10-session therapy was 8,05%. The healing continued and further reduction in size (by 69.13%) took place during the 12-month observation: 39.62% of lesions within the buccal mucosa and full remission of all lesions on the gingiva and tongue.ConclusionsThe results suggest that PDT offers non-invasive treatment of lesions in oral mucosa and may become an alternative and complementary method to those currently in use. Further studies involving larger groups of patients should be undertaken before it becomes routine practice.



http://ift.tt/2jRT4a3

Synthesis, Spectral Characterization, Crystal structure, Cytotoxicity and Apoptosis − inducing Activity of two derivatives of 2-hydroxy-1,4-naphthaquinone

Publication date: Available online 22 January 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Kavitha Rani P.R., Annette Fernandez, Shiny P. Laila, Arunkumar B., Sreelakshmi C.S., Vishnu V.S.
A phenaxazone compound [5H–Benzo[a]phenoxazin–5–one (BP)]along with an aminoquinone[2–[(o–hydroxyphenyl)amino]–1,4–naphthaquinone (HAN)] derivatives were synthesized from lawsone using ultrasound irradiation technique. The structure of the compounds were characterized by elemental analysis and various spectral studies. Optoelectronic properties were studied using Schrodinger material science suit (2015). The compounds exhibit fluorescence emission in longer wave length it may find applications in photodynamic therapy. Single crystal X-ray diffraction studies reveals that the compound BP crystallizes in monoclinic space group. The antioxidant activity of HAN and BP were determined using DPPH radical scavenging assay and the results indicate that both the compounds have good antioxidant capacity, HAN having more scavenging activity than BP. Lead molecules were identified using insilico molecular socking studies as a green chemistry approach. iGEMDOCK, GOLD and Schrödinger softwares were used for these studies. The docking studies reveal that the structural modification of the parent compound gave more active compounds making them promising lead molecules. The lead molecules were subjected to in vitro studies. The cytotoxicity of BP and HAN was studied using human breast cancer (SKBR3) cell lines. The IC50 value of HAN was found to be 19.8μM while BP was found to have cell viability, less than 10% even at 25μM concentration. The chemotherapeutic agents kill the cancer cells mainly through apoptosis.HAN and BP wwere subjected to apoptosis studies. BP was found to more active than HAN. Thus it can be suggested that the mechanism of cell death may be through apoptosis.



http://ift.tt/2jHAdMH

Surgery combined with photodynamic therapy for the treatment of Hidradenitis Suppurativa: a report of 7 cases

Publication date: Available online 22 January 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Wenbo Bu, Xiulian Xu, Yan Wang, Liming Huang, Rong Zeng, Xu Chen, Fang Fang
Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease in the area of the apocrine sweat glands. The treatment of HS is relatively difficult. Therefore, surgery combined with PDT was applied to treat 7 cases of patients in this study, and treatment efficacy was observed. Simple surgical incisions and drainage were performed for patients with Hurley grade I. Surgical incisions and drainage as well as the removal of necrotic tissues were performed for patients with grades II and III. Immediately after surgery, PDT was performed. Their average Dermatology Life Quality Index (DLQI) was 24.14±4.26 before the surgery and 4.86±2.79 5 months after treatment, respectively. Scale (VSS) scores for evaluating scar formation were low to moderate after surgery and PDT. The experience of treating these 7 patients suggests that surgery combined with PDT might have a more pronounced effect, with the possible advantages of faster healing and less scarring.



http://ift.tt/2jRGR5a

Conductive nanogel-interfaced neural microelectrode arrays with electrically controlled in-situ delivery of manganese ions enabling high-resolution MEMRI for synchronous neural tracing with deep brain stimulation

Publication date: April 2017
Source:Biomaterials, Volume 122
Author(s): Wei-Chen Huang, Yu-Chih Lo, Chao-Yi Chu, Hsin-Yi Lai, You-Yin Chen, San-Yuan Chen
Chronic brain stimulation has become a promising physical therapy with increased efficacy and efficiency in the treatment of neurodegenerative diseases. The application of deep brain electrical stimulation (DBS) combined with manganese-enhanced magnetic resonance imaging (MEMRI) provides an unbiased representation of the functional anatomy, which shows the communication between areas of the brain responding to the therapy. However, it is challenging for the current system to provide a real-time high-resolution image because the incorporated MnCl2 solution through microinjection usually results in image blurring or toxicity due to the uncontrollable diffusion of Mn²⁺. In this study, we developed a new type of conductive nanogel-based neural interface composed of amphiphilic chitosan-modified poly(3,4 -ethylenedioxythiophene) (PMSDT) that can exhibit biomimic structural/mechanical properties and ionic/electrical conductivity comparable to that of Au. More importantly, the PMSDT enables metal-ligand bonding with Mn²⁺ ions, so that the system can release Mn²⁺ ions rather than MnCl2 solution directly and precisely controlled by electrical stimulation (ES) to achieve real-time high-resolution MEMRI. With the integration of PMSDT nanogel-based coating in polyimide-based microelectrode arrays, the post-implantation DBS enables frequency-dependent MR imaging in vivo, as well as small focal imaging in response to channel site-specific stimulation on the implant. The MR imaging of the implanted brain treated with 5-min electrical stimulation showed a thalamocortical neuronal pathway after 36 h, confirming the effective activation of a downstream neuronal circuit following DBS. By eliminating the susceptibility to artifact and toxicity, this system, in combination with a MR-compatible implant and a bio-compliant neural interface, provides a harmless and synchronic functional anatomy for DBS. The study demonstrates a model of MEMRI-functionalized DBS based on functional neural interface engineering and controllable delivery technology, which can be utilized in more detailed exploration of the functional anatomy in the treatment of neurodegenerative diseases.



http://ift.tt/2jNknCF

Fibroin particle-supported cationic lipid layers for highly efficient intracellular protein delivery

Publication date: April 2017
Source:Biomaterials, Volume 122
Author(s): Woo-Jin Kim, Bong-Soo Kim, Young-Dan Cho, Won-Joon Yoon, Jeong-Hwa Baek, Kyung-Mi Woo, Hyun-Mo Ryoo
Directly delivering therapeutic proteins into cells has promise as an intervention without side effects for protein deficiencies caused by genetic defects. However, as negatively charged macromolecules, proteins require carriers for achieving cellular uptake and maintaining their activity in the cytoplasm. The biodegradable natural polymer silk fibroin has demonstrated outstanding advantages as a protein drug scaffold in vitro and in vivo, but its usage has been limited in the extracellular space because of its negatively charged character. Here, we present an intracellular protein delivery system based on fibroin particles coated with cationic lipid layers, denoted as Fibroplex, the surface charge of which can be modulated. Fibroplex showed higher delivery efficiency than conventional delivery methods as well as long-term cargo release in the cytoplasm without toxicity. Furthermore, in vivo experiments showed that Fibroplex efficiently delivered tyrosinase and horseradish peroxidase, which led to hyper-pigmentation and tumor regression, respectively, suggesting its potential for therapeutic protein applications in hereditary diseases or cancer.



http://ift.tt/2jD1lMF

The possible protective role of pumpkin seed oil in an animal model of acid aspiration pneumonia: Light and electron microscopic study

Publication date: Available online 22 January 2017
Source:Acta Histochemica
Author(s): Nesreen Moustafa Omar, Nahla Reda Sarhan
Aspiration pneumonitis is a common problem occurring in many clinical disorders. Pumpkin seed oil (PO) is a rich source of antioxidants. This work aimed to assess the effect of PO on the lung histopathological changes induced by acid aspiration. Forty male albino rats assigned to four groups were used. Rats of control group were instilled intratracheally with normal saline 2mL/kg. HCL group instilled with 2mL/kg of HCL 0.1N, pH 1.25. PO group received pumpkin seed oil (PO) orally (∼1375mg/kgbw/day) for 7days. HCL+PO group instilled with 2mL/kg of HCL 0.1N, pH 1.25 and received PO at the same dose of PO group. Lung tissue samples were processed for light, electron microscopic and immunohistochemical study using anti inducible NO synthase (iNOS). The lung of HCL group demonstrated thickened interalveolar septa, inflammatory cell infiltration and significant increase in the area percent of collagenous fibers and immune expression of iNOS. Ultra structurally, disrupted alveolocapillay membrane, degenerated type II pneumocytes and plentiful alveolar macrophages were evident. PO administration partially attenuated these histological and ultra structural alterations and reduced iNOS immune-expression in lung tissue. In conclusion, PO has a protective effect against HCL aspiration lung injury most probably through its antioxidant activity.



http://ift.tt/2kgPoeK

Nanoscale toughening of carbon fiber reinforced/epoxy polymer composites (CFRPs) using a triblock copolymer

Publication date: 24 February 2017
Source:Polymer, Volume 111
Author(s): Nicholas T. Kamar, Lawrence T. Drzal, Andre Lee, Per Askeland
This work explored the incorporation of a triblock copolymer in carbon fiber reinforced epoxy polymer composites (CFRPs) to improve their mode-I fracture toughness, GIc (J/m²). The triblock copolymer poly (styrene)-block-poly (butadiene)-block-poly (methylmethacrylate) (SBM) was used to modify the CFRP matrix at 5, 10 and 15 phr concentrations, respectively. CFRPs were manufactured using an in-house sizing tower system, prepregger, vacuum bag and autoclave method. Mode-I fracture toughness testing revealed a 290% increase in GIc by incorporation of the reactive sizing on the fibers and 10 phr SBM in the matrix. Scanning electron microscopy of the SBM modified CFRP fracture surfaces showed that well distributed, sub 100 nm spherical micelles of SBM underwent cavitation and induced void growth and shear yielding toughening mechanisms to absorb fracture energy. It is noteworthy that longitudinal and transverse composite three point flexural testing showed that the SBM modified matrix did not decrease CFRP strength and stiffness up to 10 phr additive. Further, dynamic mechanical analysis revealed that SBM at 10 phr decreased the glass transition temperature (Tg) of CFRPs by only 2.9 °C; the Tg was then recovered at 15 phr SBM. Finally, the SBM modified CFRP GIc was compared to the neat matrix GIc at 0, 5, 10 and 15 phr SBM to develop a 'transfer factor' for SBM modified composites. It was found that only 10% of the increased matrix toughness was transferred from the SBM modified epoxy to the CFRPs. The presence of the rigid carbon fibers constrains plastic deformation of the modified epoxy and limits the toughness transfer in the composite.

Graphical abstract

http://ift.tt/2jnkKQE

Birefringence and strain-induced crystallization of stretched cellulose acetate propionate films

Publication date: 24 February 2017
Source:Polymer, Volume 111
Author(s): Shogo Nobukawa, Akichika Nakao, Kultida Songsurang, Panitha Pulkerd, Hikaru Shimada, Misaki Kondo, Masayuki Yamaguchi
We have investigated the wavelength dependence of the birefringence (Δn) for cellulose acetate propionate (CAP) films stretched at various draw ratios (DRs) and strain rates (SRs) by comparing with the result of cellulose triacetate (CTA). CAP exhibits extraordinary wavelength dispersion of Δn although CTA shows ordinary dispersion, indicating that Δn of CAP is determined by the acetyl and propionyl groups. For CAP, the extraordinary dispersion becomes stronger at higher DR and SR. Thermal analysis suggests that hot stretching induces crystallization of CAP and the crystal size increases with increasing DR and SR. Furthermore, the two-dimensional X-ray diffraction patterns of CAP and CTA (a semicrystalline polymer) exhibit orientation of the induced crystal. These results mean that the acetyl orientation in CAP becomes stronger than the propionyl orientation. This conclusion is reasonable because the acetyl group is more tightly confined to the pyranose ring than the propionyl group.

Graphical abstract

http://ift.tt/2jnewQT

Comparative proteomics of paired vocal fold and oral mucosa fibroblasts

Publication date: 23 February 2017
Source:Journal of Proteomics, Volume 155
Author(s): Michael Karbiener, Barbara Darnhofer, Marie-Therese Frisch, Beate Rinner, Ruth Birner-Gruenberger, Markus Gugatschka
Injuries of the vocal folds frequently heal with scar formation, which can have lifelong detrimental impact on voice quality. Current treatments to prevent or resolve scars of the vocal fold mucosa are highly unsatisfactory. In contrast, the adjacent oral mucosa is mostly resistant to scarring. These differences in healing tendency might relate to distinct properties of the fibroblasts populating oral and vocal fold mucosae. We thus established the in vitro cultivation of paired, near-primary vocal fold fibroblasts (VFF) and oral mucosa fibroblasts (OMF) to perform a basic cellular characterization and comparative cellular proteomics. VFF were significantly larger than OMF, proliferated more slowly, and exhibited a sustained TGF-β1-induced elevation of pro-fibrotic interleukin 6. Cluster analysis of the proteomic data revealed distinct protein repertoires specific for VFF and OMF. Further, VFF displayed a broader protein spectrum, particularly a more sophisticated array of factors constituting and modifying the extracellular matrix. Conversely, subsets of OMF-enriched proteins were linked to cellular proliferation, nuclear events, and protection against oxidative stress. Altogether, this study supports the notion that fibroblasts sensitively adapt to the functional peculiarities of their respective anatomical location and presents several molecular targets for further investigation in the context of vocal fold wound healing.Biological significanceMammalian vocal folds are a unique but delicate tissue. A considerable fraction of people is affected by voice problems, yet many of the underlying vocal fold pathologies are sparsely understood at the molecular level. One such pathology is vocal fold scarring - the tendency of vocal fold injuries to heal with scar formation -, which represents a clinical problem with highly suboptimal treatment modalities. This study employed proteomics to obtain comprehensive insight into the protein repertoire of vocal fold fibroblasts, which are the cells that predominantly synthesize the extracellular matrix in both physiological and pathophysiological conditions. Protein profiles were compared to paired fibroblasts from the oral mucosa, a neighboring tissue that is remarkably resistant to scarring. Bioinformatic analyses of the data revealed a number of pathways as well as single proteins (e.g. ECM-remodeling factors, transcription factors, enzymes) that were significantly different between the two fibroblast types. Thereby, this study has revealed novel interesting molecular targets which can be analyzed in the future for their impact on vocal fold wound healing.

Graphical abstract

http://ift.tt/2jG6Z0H

Oestrus synchronisation and superovulation alter the cervicovaginal mucus proteome of the ewe

Publication date: 23 February 2017
Source:Journal of Proteomics, Volume 155
Author(s): Jessie W. Maddison, Jessica P. Rickard, Naomi C. Bernecic, Guillaume Tsikis, Clement Soleilhavoup, Valerie Labas, Lucie Combes-Soia, Gregoire Harichaux, Xavier Druart, Tamara Leahy, Simon P. de Graaf
Although essential for artificial insemination (AI) and MOET (multiple ovulation and embryo transfer), oestrus synchronisation and superovulation are associated with increased female reproductive tract mucus production and altered sperm transport. The effects of such breeding practices on the ovine cervicovaginal (CV) mucus proteome have not been detailed. The aim of this study was to qualitatively and quantitatively investigate the Merino CV mucus proteome in naturally cycling (NAT) ewes at oestrus and mid-luteal phase, and quantitatively compare CV oestrus mucus proteomes of NAT, progesterone synchronised (P4) and superovulated (SOV) ewes. Quantitative analysis revealed 60 proteins were more abundant during oestrus and 127 were more abundant during the luteal phase, with 27 oestrus specific and 40 luteal specific proteins identified. The oestrus proteins most disparate in abundance compared to mid-luteal phase were ceruloplasmin (CP), chitinase-3-like protein 1 (CHI3L1), clusterin (CLU), alkaline phosphatase (ALPL) and mucin-16 (MUC16). Exogenous hormones greatly altered the proteome with 51 and 32 proteins more abundant and 98 and 53 proteins less abundant, in P4 and SOV mucus, respectively when compared to NAT mucus. Investigation of the impact of these proteomic changes on sperm motility and longevity within mucus may help improve sperm transport and fertility following cervical AI.SignificanceThis manuscript is the first to detail the proteome of ovine cervicovaginal mucus using qualitative and quantitative proteomic methods over the oestrous cycle in naturally cycling ewes, and also after application of common oestrus synchronisation and superovulation practices. The investigation of the mucus proteome throughout both the follicular and luteal periods of the oestrous cycle, and also after oestrous synchronisation and superovulation provides information about the endocrine control and the effects that exogenous hormones have on protein expression in the female reproductive tract. This information contributes to the field by providing important information on the changes that occur to the cervicovaginal mucus proteome after use of exogenous hormones in controlled breeding programs, which are commonly used on farm and also in a research setting.

Graphical abstract

http://ift.tt/2jFYvXq

Association of posterior EEG alpha with prioritization of religion or spirituality: A replication and extension at 20-year follow-up

Publication date: Available online 22 January 2017
Source:Biological Psychology
Author(s): Craig E. Tenke, Jürgen Kayser, Connie Svob, Lisa Miller, Jorge E. Alvarenga, Karen Abraham, Virginia Warner, Priya Wickramaratne, Myrna M. Weissman, Gerard E. Bruder
A prior report (Tenke et al., 2013 Biol. Psychol. 94:426–432) found that participants who rated religion or spirituality (R/S) highly important had greater posterior alpha after 10 years compared to those who did not. Participants who subsequently lowered their rating also had prominent alpha, while those who increased their rating did not. Here we report EEG findings 20 years after initial assessment. Clinical evaluations and R/S ratings were obtained from 73 (52 new) participants in a longitudinal study of family risk for depression. Frequency PCA of current source density transformed EEG concisely quantified posterior alpha. Those who initially rated R/S as highly important had greater alpha compared to those who did not, even if their R/S rating later increased. Furthermore, changes in religious denomination were associated with decreased alpha. Results suggest the possibility of a critical stage in the ontogenesis of R/S that is linked to posterior resting alpha.



http://ift.tt/2khlA5E

Differential effects of eating and drinking on wellbeing − An ecological ambulatory assessment study

Publication date: Available online 22 January 2017
Source:Biological Psychology
Author(s): Jana Strahler, Urs M. Nater
IntroductionVarious behaviors, such as physical activity and sleep, have been shown to have stress-reducing and beneficial effects on wellbeing. In contrast, the rewarding effects of eating and drinking have rarely been investigated, particularly using ecologically valid approaches, and little is known about mediating mechanisms on the biological level.MethodsSeventy-seven healthy young adults completed items on eating and drinking as well as momentary wellbeing (measured by mood, energy, tension, stress and fatigue levels) on an iPod touch 5x/day for 4 consecutive days. With each entry, a saliva sample was collected for the later assessment of cortisol, alpha-amylase and salivary flow rate as markers of neuroendocrine and autonomic activity, respectively.ResultsHierarchical linear models showed better momentary wellbeing on various scales after the consumption of juice, coffee and alcohol. Having a snack predicted lower fatigue levels. In contrast, consuming high-fat food resulted in impaired wellbeing. With regard to affect-induced eating as well as biomarkers, only a few associations emerged as significant. However, autonomic activity partially mediated the alcohol-stress association.ConclusionThese findings corroborate previous reports that dietary behaviors could have rewarding effects, but also challenge the assumption of a general mood-enhancing and stress-relieving effect of certain foods. Findings on biomarkers provide first insights into underlying biological mechanisms. Research on further assumed mechanisms (reward-associated brain networks) and moderators (hedonic overeating) is highly warranted. Moreover, implications for addiction research are discussed.



http://ift.tt/2jdIF7z

Ro52 autoantibodies arise from self-reactive progenitors in a mother of a child with neonatal lupus

Publication date: Available online 22 January 2017
Source:Journal of Autoimmunity
Author(s): Joanne H. Reed, Miroslaw K. Gorny, Liuzhe Li, Timothy Cardozo, Jill P. Buyon, Robert M. Clancy
The detection of cardiac conduction defects in an 18–24 week old foetus in the absence of structural abnormalities predicts with near certainty the presence of autoantibodies against 60kD and 52kD SSA/Ro in the mother regardless of her health status. Previous studies have emphasized these autoantibodies as key mediators of tissue injury. The aim of this study was to focus on the anti-Ro52 response to determine whether these autoantibodies originate from progenitors that are inherently self-reactive or from B-cells that acquire self-reactivity during an immune response.We traced the evolution of two anti-Ro52 autoantibodies isolated from circulating IgG1-switched B-cells from an asymptomatic mother of a child with third degree congenital heart block. The autoantibodies were expressed as their immune form and as pre-immune ancestors by reverting somatic mutations to germline sequence. The reactivity of pre-immune and immune antibodies for Ro52, Ro60, La and DNA was measured. Both anti-Ro52 autoantibodies exhibited a low frequency of somatic mutations (3–4%) and utilised the same heavy and light chain genes but represented distinct clones based on differing complementarity determining region sequences. Pre- and post-immune antibodies showed specific binding to Ro52 with no measurable reactivity for other autoantigens. Ro52 binding was higher for immune antibodies compared to pre-immune counterparts demonstrating that autoreactivity was enhanced by affinity maturation. These data indicate that Ro52 reactivity is an intrinsic property of the germline antibody repertoire in a mother with a pathogenic antibody defined by cardiac injury in her offspring, and implies defects in both central and peripheral tolerance mechanisms.



http://ift.tt/2khp5sX

MicroRNA-155 contributes to enhanced resistance to apoptosis in monocytes from patients with rheumatoid arthritis

Publication date: Available online 22 January 2017
Source:Journal of Autoimmunity
Author(s): Megha Rajasekhar, Anton M. Olsson, Kathryn J.A. Steel, Mirella Georgouli, Ushan Ranasinghe, Christine Brender Read, Klaus S. Frederiksen, Leonie S. Taams
Monocytes and macrophages are key mediators of inflammation in rheumatoid arthritis (RA). Their persistence at the inflammatory site is likely to contribute to immunopathology. We sought to characterise one mechanism by which persistence may be achieved: resistance to apoptosis and the role of mir-155 in this process. CD14+ monocytes from peripheral blood (PBM) and synovial fluid (SFM) of RA patients were found to be resistant to spontaneous apoptosis relative to PBM from healthy control (HC) individuals. RA SFM were also resistant to anti-Fas-mediated apoptosis and displayed a gene expression profile distinct from HC and RA PBM populations. Gene expression profiling analysis revealed that the differentially expressed genes in RA SFM vs. PBM were enriched for apoptosis-related genes and showed increased expression of the mir-155 precursor BIC. Following identification of potential mir-155 target transcripts by bioinformatic methods, we show increased levels of mature mir-155 expression in RA PBM and SFM vs. HC PBM and a corresponding decrease in SFM of two predicted mir-155-target mRNAs, apoptosis mediators CASP10 and APAF1. Using miR mimics, we demonstrate that mir-155 over-expression in healthy CD14+ cells conferred resistance to spontaneous apoptosis, but not Fas-induced death in these cells, and resulted in increased production of cytokines and chemokines. Collectively our data indicate that CD14+ cells from patients with RA show enhanced resistance to apoptosis, and suggest that an increase in mir-155 may partially contribute to this phenotype.



http://ift.tt/2jmqIBy

Epitope-dependent mechanisms of CD27 neutralization revealed by X-ray crystallography

Publication date: March 2017
Source:Molecular Immunology, Volume 83
Author(s): Galina Obmolova, Alexey Teplyakov, Thomas J. Malia, Nicole Wunderler, Deborah Kwok, Linda Barone, Raymond Sweet, Tatiana Ort, Michael Scully, Gary L. Gilliland
CD27 is a T and B cell co-stimulatory protein of the TNF receptor superfamily dependent on the availability of the TNF-like ligand CD70. Two anti-CD27 neutralizing monoclonal antibodies were obtained from mouse hybridoma and subsequently humanized and optimized for binding the target. The two antibodies are similar in terms of their CD27-binding affinity and ability to block NF-κB signaling, however their clearance rates in monkeys are very different. The pharmacokinetics profiles could be epitope dependent. To identify the epitopes, we determined the crystal structure of the ternary complex between CD27 and the Fab fragments of these non-competing antibodies. The structure reveals the binding modes of the antibodies suggesting that their mechanisms of action are distinctly different and provides a possible explanation of the in vivo data.

Graphical abstract

http://ift.tt/2k53qkn

Editorial Board/ Publication Information

Publication date: February 2017
Source:Molecular Immunology, Volume 82





http://ift.tt/2k5dF87

Fabrication of topical metered dose film forming sprays for pain management

Publication date: 30 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 100
Author(s): Sneha Ranade, Amrita Bajaj, Vaishali Londhe, Najib Babul, Danny Kao
Topical film-forming metered dose spray formulations were designed for management of pain. Ropivacaine, a local anesthetic is explored for its topical efficacy in alleviating pain. Metered dose spray containers, organic solvents, film forming polymers and permeation enhancers were utilized to fabricate the Metered Dose topical spray. Factors like viscosity, spray pattern, spray angle, volume of actuation, droplet size distribution of the metered dose spray formulation and drying time, flexibility and wash-ability of the film formed after spraying were assessed. Permeation of the drug into the porcine skin was observed based on ex-vivo diffusion studies and confocal microscopy. The results indicated a high level of drug concentration in the skin layers. Anti-nociceptive efficacy of the formulations was assessed on Wistar rats by hot plate and tail flick tests, based on the response to pain perception. The results were comparable to the conventional lidocaine gel. Topical film forming sprays have the ability to provide an accurate, long lasting and patient compliant delivery of drugs on the skin as compared to conventional gels.

Graphical abstract

http://ift.tt/2j1NLAu

Critical Review of the Addition of Tumor Treating Fields (TTFields) to the Existing Standard of Care for Newly Diagnosed Glioblastoma Patients

Publication date: Available online 22 January 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): M. Mehta, P. Wen, R. Nishikawa, D. Reardon, K. Peters
Since 2005, the standard of care for patients with newly diagnosed glioblastoma (GBM) has consisted of maximal resection followed by radiotherapy plus daily temozolomide (TMZ), followed by maintenance TMZ. In patients selected for clinical trials, median overall survival (OS) and progression-free survival (PFS) with this regimen is 15 to 17 months and 6 to 7 months, respectively. There have been various, largely unsuccessful attempts to improve on this standard of care. With the FDA approval of the tumor-treating fields (TTFields) device, Optune, for recurrent GBM (2011), and the more recent EF-14 interim trial results and approval for newly diagnosed GBM patients, several questions have arisen. A roundtable of experts was convened at the 2015 ASCO meeting to engage in an open conversation and debate of the EF-14 results presented at that meeting and their implications for neuro-oncology practice and clinical research. In October 2015, subsequent to the roundtable discussion, TTFields received FDA approval for newly diagnosed GBM.



http://ift.tt/2kfPNhm

Management of Aromatase Inhibitor Induced Musculoskeletal Symptoms in Postmenopausal Early Breast Cancer: A Systematic Review and Meta-analysis

Publication date: Available online 22 January 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Kate Roberts, Kirsty Rickett, Ristan Greer, Natasha Woodward




http://ift.tt/2iRJcgS

Primary mediastinal large B-cell lymphoma

Publication date: Available online 21 January 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Andrés Ferreri, Maurizio Martelli
Primary mediastinal large B-cell lymphoma (PMLBCL) is a distinct clinical and biological disease from other types of DLBCL. It is more frequent in young female and constitutes 6%-10% of all DLBCL. PMLBCL is characterized by a diffuse proliferation of medium to large B-cells associated with sclerosis. Molecular analysis shows it to be a distinct entity from other DLBCL. Rituximab CHOP/MACOP-B-like regimens followed by with mediastinal radiotherapy (RT) were associated with a 5-years PFS of 75%-85%. More intensive regimens, as DA-EPOCH-R without mediastinal RT, have shown very promising results, but this therapeutic advance needs to be confirmed in further prospective trials. The role of consolidative mediastinal RT should be still better assess in prospective comparative studies. PET-CT scan is a powerful tool to define the real quality of response and it is hoped that future prospective trials may allow its role in the de-escalation of mediastinal RT



http://ift.tt/2kfRMm4

Synergy with interferon-lambda 3 and sorafenib suppresses hepatocellular carcinoma proliferation

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Yuke Yan, Liang Wang, Jingjing He, Pengcheng Liu, Xi Lv, Yawu Zhang, Xiaodong Xu, Lingyi Zhang, Youcheng Zhang
Hepatocellular carcinoma (HCC) is a common and fatal malignancy of the liver. Sorafenib is a small molecule multikinase inhibitor that acts against different cancer cell lines and is used for the treatment of HCC. However, some advanced HCC patients fail to respond to sorafenib, and those who do lack a meaningful clinical benefit. Interferon-lambda 3 (IFN-λ3) is a type III interferon with antiviral, antiproliferative, and immunomodulatory functions. Here, we evaluated the use of IFN-λ3 as an adjuvant treatment with sorafenib in HCC. In the present study, CCK-8 and colony formation assay results showed that treatment with a combination of IFN-λ3 and sorafenib suppresses the viability of HepG2 and SMMC7721 liver cancer cell lines more than treatment with either alone. In addition, flow cytometry results confirmed that treatment with a combination of IFN-λ3 and sorafenib promotes the loss of mitochondrial membrane potential and induces the production of ROS more than treatment with either alone. Furthermore, using a subcutaneous SMMC7721 tumor model, treatment with a combination of IFN-λ3 and sorafenib significantly reduced the tumor growth/volume and induced apoptosis compared to treatment with sorafenib alone. These results show that combined treatment with IFN-λ3 and sorafenib facilitates a synergistic effect on suppressing HCC cancer growth and promoting cell apoptosis in vitro and in vivo. Thus, IFN-λ3 in combination with sorafenib might prove to be a useful adjunctive strategy for the clinical treatment of HCC.



http://ift.tt/2jPPnll

Periostin contributes to arsenic trioxide resistance in hepatocellular carcinoma cells under hypoxia

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Yujin Liu, Feng Gao, Weixiang Song
Hypoxia has been suggested to induce chemoresistance in tumor cells. In this study, we aimed to test the hypothesis that hypoxia-inducible factor-1alpha (HIF-1α)/periostin axis might promote arsenic trioxide resistance in hepatocellular carcinoma (HCC) cells under hypoxia. HCC cells were exposed to hypoxia and measured for periostin expression. Loss-of-function studies were done to assess the role of periostin in arsenic trioxide resistance. In vivo xenograft mouse studies were performed to determine the effect of periostin silencing on HCC susceptibility to arsenic trioxide. It was found that periostin expression was significantly increased in SMMC7721 and Hep3B HCC cells after hypoxic treatment. Depletion of HIF-1α blocked the upregulation of periostin induced by hypoxia. HCC cells under hypoxia displayed more resistant to arsenic trioxide than those under normoxia. Interestingly, downregulation of periostin re-sensitized hypoxic SMMC7721 and Hep3B cells to arsenic trioxide, which was accompanied by increased apoptosis. Luciferase reporter assay revealed that periostin overexpression enhanced HIF-1α-dependent transcriptional activity and induced the expression of vascular endothelial growth factor, Mcl-1, and Bcl-xL in SMMC7721 cells. Administration of arsenic trioxide resulted in a significant inhibition of SMMC7721 tumor growth. Notably, downregulation of periostin significantly enhanced the anticancer effect of arsenic trioxide against SMMC7721 tumors and reduced the percentage of Ki-67-positive proliferating cells. Taken together, periostin contributes to arsenic trioxide resistance in HCC under hypoxic microenvironment, which is likely associated with promotion of HIF-1α-dependent activation of survival genes. Targeting periostin may represent a promising strategy to improve arsenic trioxide-based anticancer therapy against HCC.



http://ift.tt/2k4SWBA

Y-27632, a Rho-associated protein kinase inhibitor, inhibits systemic lupus erythematosus

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Yuanyuan Wang, Yang Lu, Jixia Chai, Meiqun Sun, Xiaodong Hu, Wenxin He, Min Ge, Changhao Xie
The purpose of the present study was to evaluate whether Rho-kinase inhibition (Y-27632) modulated the expressions of nuclear factor kappaB (NF-κB) in systemic lupus erythematosus. 20 wild type mice and 20 MRL/lpr mice were applied for the research. The animals were randomly assigned to wild type, wild type+Y-27632 group, MRL/lpr group and MRL/lpr+Y-27632 group. 5mg/kg Y-27632 was intravenously injected to inhibit the ROCK expressions.Y-27632 significantly decreased the serum levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α) and increased IL-10 level in serum of MRL/lpr mice. Flow cytometry (FCM) studies also showed that Y-27632 remarkably increased Regulatory cells(Treg) cell percentage in spleen cells. Western blot analysis demonstrated Y-27632 downregulated the expressions of ROCK1, ROCK2, upregulated the expression of forkhead/winged helix transcription factor(Foxp3), and inhibited the phosphorylations of NF-κBp65 and IκBα. The findings showed that the inhibition of ROCK was beneficial for the prevention of systemic lupus erythematosus, which possibly by suppressing NF-κB activation.



http://ift.tt/2jPQP7b

Effect of troxerutin on 2-aminoanthracene and DNA interaction and its anti-mutagenic property

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): A. Subastri, K. Harikrishna, M. Sureshkumar, Ghedeir M. Alshammari, B. Aristatile, C. Thirunavukkarasu
One of the pivotal mechanisms projected for bioflavonoids in cancer chemoprevention is through their intervention against mutagen-DNA interaction. Recent literatures emphasize the role of troxerutin (TXER) as an emerging anticancer agent. However, there are no reports on its intervention in any carcinogen-DNA interaction. The present study investigates the possibility of TXER, in prevention of 2-aminoanthracene (2-AA) contact with DNA. Steady state and time resolved fluorescence spectroscopy results, highlight the direct contact of 2-AA with DNA, while presence of TXER prevented this interaction. Gel-electrophoresis study clearly revealed that, TXER inhibits 2-AA+UVA radiation induced DNA damage. Fluorescence microscopic studies elucidated that, TXER treatment obstructs the 2-AA interaction with cellular DNA, while molecular docking showed the energetically favourable structure of TXER/2-AA/TXER complex. Further anti-mutagenicity experiment revealed that, TXER prevents the mutation induced colony formation in mutant strain of S. typhymurium. Our in vitro and ex vivo experimental findings provide imperative evidence about the protective role of TXER against environmental carcinogens through the inhibition of carcinogen-DNA interaction, implicating its potential for therapeutic applications in cancer.

Graphical abstract

http://ift.tt/2k4I32F

Silencing of IRF3 alleviates chronic neuropathic pain following chronic constriction injury

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Rui Li, Li-guo Wang, Qi Wang, Zhi-hua Li, Ya-li Ma, Qing-Duo Guo
Interferon regulatory factor 3 (IRF3) is a member of IRF family which plays an important role in neuronal survival and neuroprotection. However, the role of IRF3 in neuropathic pain remains unclear. Thus, in this study, we investigated the effect of IRF3 on neuropathic pain in a rat chronic constriction injury (CCI) model. Our results showed that IRF3 was up-regulated in the dorsal root ganglion (DRG) in CCI rats. Intrathecal short-hairpin RNA (shRNA)-IRF3 attenuated mechanical allodynia and thermal hyperalgesia in CCI rats, as well as inhibited the production of TNF-α and IL-1β in the DRG of CCI rats. Furthermore, we revealed that sh-IRF3 greatly suppressed the expression of p-NF-κB p65 and IκBα degradation in the DRG of CCI rats. In conclusion, our data suggest that knockdown of IRF3 may alleviate neuropathic pain by inhibiting the activation of NF-κB signaling pathway. Therefore, IRF3 may provide an important target for the treatment of neuropathic pain.



http://ift.tt/2k4LPZB

Co-delivery of docetaxel and curcumin prodrug via dual-targeted nanoparticles with synergistic antitumor activity against prostate cancer

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Jieke Yan, Yuzhen Wang, Yuxiu Jia, Shuangde Liu, Chuan Tian, Wengu Pan, Xiaoli Liu, Hongwei Wang
PurposeCombination therapy is increasingly used as a primary cancer treatment regimen. In this report, we designed EGFR peptide decorated nanoparticles (NPs) to co-deliver docetaxel (DTX) and pH sensitive curcumin (CUR) prodrug for the treatment of prostate cancer.ResultsEGFR peptide (GE11) targeted, pH sensitive, DTX and CUR prodrug NPs (GE11-DTX-CUR NPs) had an average diameter of 167nm and a zeta potential of −37.5mV. The particle size of the NPs was adequately maintained in serum and a sustained drug release pattern was observed. Improved inhibition of cancer cell and tumor tissue growth was shown in the GE11-DTX-CUR NPs group compared to the other groups.ConclusionIt can be summarized that DTX and CUR prodrug could be delivered into tumor cells simultaneously by the GE 11 targeting and the EPR effect of NPs. The resulting GE11-DTX-CUR NPs is a promising system for the synergistic antitumor treatment of prostate cancer.



http://ift.tt/2jPGiZD

Sorafenib: A potential therapeutic drug for hepatic fibrosis and its outcomes

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Rui Ma, Jiang Chen, Yuelong Liang, Shuang Lin, Linghua Zhu, Xiao Liang, Xiujun Cai
Hepatic fibrosis is a common response to liver injury that occurs in almost all liver diseases and is characterized by an excessive deposition of extracellular matrix, which can cause hepatic dysfunction and develop into cirrhosis. There is no curative treatment except liver transplantation and few treatments have been thoroughly validated in the clinic or commercialized as a therapy. Recently, sorafenib, an FDA approved molecular targeted drug for the treatment of advanced hepatocellular and renal cell carcinomas, has been reported to exert anti-fibrotic effects in liver fibrosis. Animal models showed that sorafenib ameliorated intrahepatic vascular resistance, reduced portal hypertension, and reduced intrahepatic fibrosis, inflammation and angiogenesis. In this review, we highlight the potential molecular, cellular, microenvironmental mechanisms underlying the antifibrotic effects of sorafenib in fibrotic liver disease, and briefly discuss the potential of sorafenib for hepatic fibrogenesis and major complications in clinical treatments. There is a long way to go before sorafenib can be applied in preclinical practice and clinical therapy of liver fibrosis. Further studies are required to clarify its anti-fibrotic role, effective dose, and side effects.



http://ift.tt/2k4LPJ5

HCRP1 downregulation promotes hepatocellular carcinoma cell migration and invasion through the induction of EGFR activation and epithelial-mesenchymal transition

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Jiawen Xu, Xi Zhang, Hongliang Wang, Shujian Ge, Taihong Gao, Lin Song, Xinxing Wang, Hui Li, Yejun Qin, Zhenhai Zhang
Hepatocellular carcinoma related protein 1 (HCRP1), which is essential for internalization and degradation of ubiquitinated membrane receptors, is downregulated in several tumors and strongly affects the outcomes of cancer patients. It is reported the expression of HCRP1 is inversely related to epidermal growth factor receptor (EGFR) in breast cancer and lead to resistance to cetuximab in ovarian cancer. However, its exact mechanism in the progression of Hepatocellular carcinoma (HCC) remains unknown. Herein, HCRP1 expression and its clinical significance were examined in 101 HCC patients using immunohistochemistry. Cell proliferation, migration and invasion assays were conducted in HCC cell lines. EGFR activation and degradation were then observed after EGF inducing in HCRP1 knockdown HepG2 cells. In addition, we also detected whether epithelial-to-mesenchymal transition (EMT) was involved in the malignancy promoted by HCRP1. The results showed that 59 of the 101 HCC cases exhibited downregulation of HCRP1 expression (P<0.01) as compared to 30 benign liver lesions and 20 normal liver tissues, all of which showed a high level of HCRP1. HCRP1 expression was significantly related to age (P=0.017), pathological grade (P=0.003), tumor encapsulation (P=0.037), recurrence (P=0.039) and death (P=0.015), but unrelated to cirrhosis (P=0.216), tumor size (P=0.273), and distant metastasis (P=0.554). Lower HCRP1 expression was correlated with shorter RFS and OS (P<0.001), and decreased HCRP1 level is an independent prognostic marker in HCC patients (P<0.05). Overexpression of HCRP1 decreased and knockdown increased HCC cell proliferation, migration and invasion. HCRP1 depletion increased EGFR activation and inhibited EGFR degradation. EMT phenotype was promoted after HCRP1 downregulation via increase of Snail and Twist1 and activation of Akt phosphorylation in HepG2 cells. Conversely, upregulation of HCRP1 in SMMC-7721 cells led to the opposite effect. In conclusion, our study indicated that downregulation of HCRP1 is a valuable prognostic factor involved in EGFR regulation and acquisition of the mesenchymal phenotype of HCC cells.



http://ift.tt/2jPSr0R

Loss of ErbB2-PI3K/Akt signaling prevents zinc pyrithione-induced cardioprotection during ischemia/reperfusion

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Sandhya Thokala, Santhipriya Inapurapu, Vijaya Lakshmi Bodiga, Praveen Kumar Vemuri, Sreedhar Bodiga
ObjectivesThe purpose of this study was to determine if zinc homeostasis is affected during ischemia/reperfusion, if so, whether zinc pyrithione limits myocardial cell death and improves hemodynamics when administered as an adjunct to reperfusion and if ErbB receptor tyrosine kinases that are important for the long-term structural integrity of the heart are indispensable for reperfusion salvage.MethodsIsolated perfused rat hearts were subjected to 35min of global ischemia and reperfused for 120min to determine the relative intracellular zinc levels by TSQ staining. The hearts were reperfused in the presence of incremental concentrations of zinc pyrithione for the first 10min during reperfusion. Silencing or blockade of ErbB2 using a monoclonal antibody, ErbB2 kinase inhibition and PI3kinase inhibition was used to study their critical role in zinc pyrithione-induced cardioprotection.ResultsWe found that there was a profound decrease in intracellular zinc after ischemia/reperfusion resulting in increased apoptosis, caspase-3 activation, and infarct size. A dose-dependent reduction of infarct size with zinc pyrithione in the range of 5–20μmol/l (optimal protection was seen at 10μmol/l with infarct size of 16±2% vs. I/R vehicle, 33±2%, p<0.01). Increased TUNEL staining and caspase-3 activity observed after ischemia/reperfusion were attenuated by zinc pyrithione administration during the reperfusion. Moreover, this protection was sensitive to silencing and blockade of ErbB2, inhibition of ErbB2 kinase activity or PI3-kinase activity. Western blot analysis revealed that zinc pyrithione resulted in decreased caspase-3 activation, rapid stabilization of ErbB2/ErbB1 heterodimers, and increased activation of PI3K/Akt signaling cascade.ConclusionsZinc pyrithione attenuates lethal perfusion-induced injury in a manner that is reliant on ErbB2/PI3K/Akt activity.



http://ift.tt/2k4Fwp0

Cordycepin inhibits airway remodeling in a rat model of chronic asthma

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Xia Fei, Xue Zhang, Guo-qing Zhang, Wu-ping Bao, Ying-ying Zhang, Min Zhang, Xin Zhou
The potential suppression role of cordycepin (Cor) on airway remodeling in a rat model of chronic asthma was investigated in this paper. We evaluated the anti-remodeling of Cor (50mg/kg) combined with or without budesonide (BUD) and investigated the possible underlying molecular mechanisms. We found that Cor attenuated immunoglobulin (Ig) E, alleviated the airway wall thickness, and decreased eosinophils and neutrophils in the bronchoalveolar lavage fluid (BALF). Notably, Cor reduced the up-regulation of IL-5, IL-13 and TNF-α in the BALF. Cor also regulated the increase of A2AARmRNA and the decrease of TGF-β1 expression. Furthermore, Cor markedly blocked p38MAPK signaling pathway activation in the OVA-driven asthmatic mice. The combination treatment of Cor and BUD showed profound efficacy in regulating the levels of inflammatory cells and the expression of IL-13, TGF-β1 and A2AARmRNA. Collectively, this study demonstrated that Cor combined with glucocorticoids treatment shows synergistically profound efficacy in inhibiting airway remodeling, and some benefits of Cor may result from the increased A2AARmRNA expression, the reduced TGF-β1 levels and the inhibition of Th2-cytokines through the suppression of the p38MAPK signaling pathways.



http://ift.tt/2jPGh81

Betulinic acid promotes TRAIL function on liver cancer progression inhibition through p53/Caspase-3 signaling activation

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Ying Xu, Jing Li, Qian-Jun Li, Yan-Ling Feng, Feng Pan
Betulinic acid (BA), isolated from the tree bark, is a pentacyclic triterpenoid, showing inhibitory role in cancer cells. However, the effects of BA treatment on liver cancer have little to be known. Thus, the study is conducted to explore the in vitro and in vivo role of BA in liver cancer. And the interactions between BA and tumor necrosis factor-related apoptosis-inducing ligand of APO2, also known as TRAIL, were investigated in liver cancer cells. A synergistic effect of BA and APO2 combination on apoptosis induction in liver cancer cells was observed. The cancer cells were insensitive to APO2 single therapy. However, liver cancer cells receiving BA were sensitive to APO2-triggered apoptotic response by enhancing Caspases cleavage, due to elevation of decoy receptor 1 and 2 (DcR1 and DcR2) dependent on p53. Bcl-2 family members of Bcl-2 and Mcl-1, belonging to anti-apoptosis, were decreased, whereas Bad and Bak, as pro-apoptotic members, were increased for BA and APO2 combined treatment. Additionally, the mouse xenograft model suggested that BA and APO2 in combination markedly inhibited liver cancer growth in comparison to BA or APO2 monotherapy without toxicity. The present study revealed a dramatically therapeutic strategy for promoting APO2-induced anti-cancer effects on liver cancer cells via BA combination.



http://ift.tt/2k4Q7An

SIRT1 inhibits releases of HMGB1 and HSP70 from human umbilical vein endothelial cells caused by IL-6 and the serum from a preeclampsia patient and protects the cells from death

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Yongxiang Yin, Yaling Feng, Hua Zhao, Ziyu Zhao, Hua Yua, Jianjuan Xu, Haisha Che
Preeclampsia (PE), a pregnancy-specific disorder, is associated with inappropriate maternal inflammatory response, oxidative stress, and vascular endothelial cell dysfunction and damage. Releases of high mobility group box-1 (HMGB1) and heat-shock protein 70 (HSP70) into serum are considered to participate in the pathogenesis of PE. The deacetylase, sirtuin 1 (SIRT1), has protective effects against inflammation, apoptosis, and oxidative stress in various pathological conditions. We established a PE mouse model by injection of phosphatidylserine/dioleoyl-phosphatidycholine compounds, followed by measurement of the SIRT1 protein level in the placenta via Western blotting and the serum HMGB1 and HSP70 concentrations via enzyme-linked immunosorbent assay (ELISA). SIRT1 was down-regulated in the placenta of PE mice, in accompany with increased serum HMGB1 and HSP70 concentrations. We incubated human umbilical vein endothelial cells (HUVECs) with IL-6 and the serum from a PE patient individually to mimic status of vein endothelial cells in PE. Western blot and Immunofluorescent assays showed that HMGB1 and HSP70 protein levels were decreased in the cells, but they were increased in the cell medium based on ELISA. These suggested that HMGB1 and HSP70 were forced to be released from the cells. SIRT1 knockdown promoted the releases of HMGB1 and HSP70, whereas its over-expression inhibited the releases. Moreover, SIRT1 protected the cells from death. Collectively, SIRT1 inhibits the releases of HMGB1 and HSP70 from HUVECs caused by IL-6 and the serum from PE patient and protects the cells from death, thus SIRT1 is probably a potentially protective factor in placenta against PE.



http://ift.tt/2jPIFMo

Effects of JS-K, a novel anti-cancer nitric oxide prodrug, on gene expression in human hepatoma Hep3B cells

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Ray Dong, Xueqian Wang, Huan Wang, Zhengyun Liu, Jie Liu, Joseph E. Saavedra
JS-K is a novel anticancer nitric oxide (NO) prodrug effective against a variety of cancer cells, including the inhibition of AM-1 hepatoma cell growth in rats. To further evaluate anticancer effects of JS-K, human hepatoma Hep3B cells were treated with JS-K and the compound control JS-43-126 at various concentrations (0–100μM) for 24h, and cytotoxicity was determined by the MTS assay. The compound control JS-43-126 was not cytotoxic to Hep3B cells at concentrations up to 100μM, while the LC50 for JS-K was about 10μM. To examine the molecular mechanisms of antitumor effects of JS-K, Hep3B cells were treated with 1–10μM of JS-K for 24h, and then subjected to gene expression analysis via real time RT-PCR and protein immunostain via confocal images. JS-K is a GST-α targeting NO prodrug, and decreased immunostaining for GST-α was associated with JS-K treatment. JS-K activated apoptosis pathways in Hep3B cells, including induction of caspase-3, caspase-9, Bax, TNF-α, and IL-1β, and immunostaining for caspase-3 was intensified. The expressions of thrombospondin-1 (TSP-1) and the tissue inhibitors of metalloproteinase-1 (TIMP-1) were increased by JS-K at both transcript and protein levels. JS-K treatment also increased the expression of differentiation-related genes CD14 and CD11b, and depressed the expression of c-myc in Hep3B cells. Thus, multiple molecular events appear to be associated with anticancer effects of JS-K in human hepatoma Hep3B cells, including activation of genes related to apoptosis and induction of genes involved in antiangiogenesis and tumor cell migration.



http://ift.tt/2k4JYEd

Icariin promotes proliferation and osteogenic differentiation of rat adipose-derived stem cells by activating the RhoA-TAZ signaling pathway

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Yaping Ye, Xingzhi Jing, Na Li, Yingxing Wu, Bingbing Li, Tao Xu
Icariin, the main active flavonoid glucoside isolated from Herba epimedii, has been demonstrated to be a potential alternative therapy to prevent postmenopausal osteoporosis. Icariin has also been shown to regulate the proliferation and osteogenic differentiation of rat bone marrow stromal cells (rBMSCs). However, the detailed molecular mechanism of icariin has remained largely unknown. Besides, no investigation has focused on the relevance of icariin in the regulation of rat adipose-derived stem cells (rASCs) proliferation and osteogenic differentiation. In the present study, we detected that icariin promotes proliferation and osteogenic differentiation of rASCs in a concentration range from 10⁻⁸M to 10⁻⁶M, with 10⁻⁷M to be the optimal concentration. We found that 10⁻⁷M icariin significantly increased active RhoA protein expression and ROCK substrate molecule p-MYPT1 expression in rASCs. C3 (the RhoA inhibitor) treatment abrogated the increased proliferation and osteogenic differentiation of rASCs induced by icariin. Interestingly, we also found that C3 abrogated the activation of TAZ induced by icariin. Depletion of TAZ by siRNA transfection significantly blocked icariin promoted proliferation and osteogenic differentiation of rASCs. However, icariin induced active RhoA protein expression was not affected by TAZ specific siRNA transfection, suggesting that RhoA lies upstream of TAZ. Taken together, our data indicate that icariin promotes proliferation and osteogenic differentiation of rASCs by activating the RhoA-TAZ signaling pathway.



http://ift.tt/2jPJqot

Hydroxysafflor yellow A promotes neovascularization and cardiac function recovery through HO-1/VEGF-A/SDF-1α cascade

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Guo Wei, Ying Yin, Jialin Duan, Chao Guo, Yanrong Zhu, Yanhua Wang, Miaomiao Xi, Aidong Wen
AimThe present study was to investigate the proangiogenic and cardioprotective effects of hydroxysafflor yellow A (HSYA) against myocardial infarction (MI) injury and the underlying mechanisms.MethodsMI model was induced by ligation of the left coronary artery in normal and heme oxygenase-1 (HO-1) knockout mice and the ones receiving vascular endothelial growth factor-A (VEGF-A) or stromal cell-derived factor-1α (SDF-1α) antagonists. They were treated with three doses or single dose of HSYA for 28days. The cardiac function, endothelial progenitor cells (EPCs) mobilization, angiogenesis, the expression of HO-1, VEGF-A, SDF-1α and apoptosis or fibrosis related proteins in the peri-infarct area were evaluated at respective times. We further examined the effect of HSYA on EPCs CXC chemokiner receptor 4 (CXCR4) expression and the role of SDF-1α on EPCs function in vitro.ResultsHSYA could dose dependently reduce left ventricular function impairment, myocardial apoptosis and fibrosis, and promote EPCs mobilization and myocardial neovascularization. Further, HO-1 knockout abolished HSYA-induced up-regulation of HO-1, VEGF-A and SDF-1α. VEGF antagonist significantly reduced HSYA-increased VEGF-A and SDF-1α levels and SDF-1 antagonist abolished HSYA-simulated up-regulation of SDF-1α. Meanwhile, HO-1 knockout, administration of VEGF and SDF-1 antibodies abrogated HSYA-promoted expression of the marker proteins of newborn microvessels and cardiac functional recovery. In vitro, HSYA dose dependently promoted (CXCR4) expression on EPCs. SDF-1α significantly accelerated EPCs function which was reversed by CXCR4 antagonist.ConclusionHSYA could promote EPCs function through the HO-1/VEGF-A/SDF-1α signaling cascade, which contributed largely to myocardial neovascularization and further improved cardiac function in MI mice.



http://ift.tt/2k4LHcW

miR-1307 promotes the proliferation of prostate cancer by targeting FOXO3A

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Xiaodi Qiu, Ying Dou
microRNAs have emerged as important regulators in various cancers, including prostate cancer. In this study, we investigated the role of miR-1307 in cell proliferation of prostate cancer. We found miR-1307 was overexpressed in prostate cancer cells and tissues, overexpression of miR-1307 significantly promoted cell proliferation and tumorigenesis in vitro investigated by MTT assay, colony formation assay and soft agar growth assay, meanwhile overexpression of miR-1307 inhibited cell cycle inhibitors p21 and p27 both in mRNA and protein levels. Knockdown of miR-1307 reduced these effects, confirming miR-1307 promotes prostate cancer cell proliferation. FOXO3A (Forkhead box protein O3a) was the target of miR-1307, miR-1307 directly bound to the 3′UTR of FOXO3A. Simultaneous knockdown of miR-1307 and FOXO3A promoted cell proliferation of prostate cancer. In summary, our results suggested miR-1307 contributed to prostate cancer proliferation by targeting FOXO3A.



http://ift.tt/2iRrKJk

Protein coding gene CRNKL1 as a potential prognostic biomarker in esophageal adenocarcinoma

Publication date: Available online 22 January 2017
Source:Artificial Intelligence in Medicine
Author(s): Zhen Li, Qianlan Yao, Songjian Zhao, Zhen Wang, Yixue Li
BackgroundEsophageal adenocarcinoma (EAC) is one of the most aggressive gastroesophageal cancers. PTGS2, EGFR, ERBB2 and TP53 are the traditional EAC prognostic biomarkers, but they are still limited in their ability to effectively predict the overall survival.ObjectivesTo identify an improved biomarker for predicting the prognosis of EAC by using the expression profile.Materials and methodsDifferential co-expression analysis and differential expression analysis were performed to identify the related genes of EAC. The 5-fold cross-validation was used to select a prognostic biomarker from the 532 EAC related genes.ResultsCRNKL1 was identified as a prognostic biomarker to predict the survival of EAC patients. It could significantly stratify EAC patients into high-risk and low-risk groups and was much better than the traditional biomarkers. Furthermore, ROC curve also verified that CRNKL1 with the highest area under the curve (AUC), reaching a sensitivity of 83.33% and a specificity of 78.57%.ConclusionsOur research proposed that CRNKL1 might be a novel prognostic biomarker with better predictive ability by comparing with the traditional biomarkers, which provided a preferable opportunity in the clinical applications of EAC.



http://ift.tt/2j1FMTW

Announcements

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2





http://ift.tt/2j1t47V

Editorial Board

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2





http://ift.tt/2jPsLl0

Impact of splenic node dissection on short-term outcome and survival following esophagectomy

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2
Author(s): J. Liu, X. Liu, J. Zhang, Q. Liu, W. Hu
BackgroundThe purpose of this study was to investigate the impact of splenic node dissection on short-term outcomes and survival after esophagectomy in patients with thoracic esophageal squamous cell carcinoma (ESCC).MethodsWe retrospectively analyzed the clinical data of 1282 consecutive patients with thoracic ESCC who underwent esophagectomy in the First Affiliated Hospital of Zhengzhou University from January 2005 to December 2013.ResultsOf all 1282 patients, there were 964 without splenic node dissection and 318 with splenic node dissection. The average operative time in the splenic node nondissection group was significantly shorter than dissection group, and blood loss in the nondissection group was significantly less than dissection group (all p < 0.05). The comparison of overall survival curves between the splenic node nondissection group and dissection group showed no significant difference (p > 0.05). In the dissection group, there were 15 patients (4.7%) with confirmed splenic node metastasis by postoperative pathologic examination. Patients with splenic node metastasis had a worse cumulative survival compared with those without splenic node metastasis (p < 0.05). Compared with nondissection group, prophylactic splenic node dissection failed to improve the survival rate significantly (p > 0.05).ConclusionThe frequency of splenic node metastasis is low in thoracic ESCC. Splenic node metastasis indicates a worse prognosis for patients with thoracic ESCC. Splenic node dissection might be futile for patients with thoracic ESCC.



http://ift.tt/2j1v3Jt

Reply to: Exercising patient-centredness in prehabilitation programs

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2
Author(s): A.F.J.M. Heldens, B.C. Bongers, J. de Vos-Geelen, N.L.U. van Meeteren, A.F. Lenssen




http://ift.tt/2jPrhHB

Associations of defect mismatch repair genes with prognosis and heredity in sporadic colorectal cancer

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2
Author(s): L. Ghanipour, K. Jirström, M. Sundström, B. Glimelius, H. Birgisson
BackgroundMicrosatellite instability arises due to defect mismatch repair (MMR) and occurs in 10–20% of sporadic colorectal cancer. The purpose was to investigate correlations between defect MMR, prognosis and heredity for colorectal cancer in first-degree relatives.Material and methodsTumour tissues from 318 patients consecutively operated for colorectal cancer were analysed for immunohistochemical expression of MLH1, MSH2 and MSH6 on tissue microarrays. Information on KRAS and BRAF mutation status was available for selected cases.ResultsForty-seven (15%) tumours displayed MSI. No correlation was seen between patients exhibiting MSI in the tumour and heredity (p = 0.789). Patients with proximal colon cancer and MSI had an improved cancer-specific survival (p = 0.006) and prolonged time to recurrence (p = 0.037). In a multivariate analysis including MSI status, gender, CEA, vascular and neural invasion, patients with MSS and proximal colon cancer had an impaired cancer-specific survival compared with patients with MSI (HR, 4.32; CI, 1.46–12.78). The same prognostic information was also seen in distal colon cancer; no recurrences seen in the eight patients with stages II and III distal colon cancer and MSI, but the difference was not statistically significant.ConclusionNo correlation between MSI and heredity for colorectal cancer in first-degree relatives was seen. Patients with MSI tumours had improved survival.



http://ift.tt/2j1oMgG

Correlation between lymph node count and survival and a reappraisal of lymph node ratio as a predictor of survival in gastric cancer: A multi-institutional cohort study

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2
Author(s): J.H. Lee, J.-W. Kang, B.-H. Nam, G.S. Cho, W.J. Hyung, M.C. Kim, H.-J. Lee, K.W. Ryu, S.W. Ryu, D.W. Shin, C.-Y. Kim
PurposeThe purpose of this study is to evaluate the correlation between lymph node count (LNC) and survival and to evaluate whether lymph node ratio (LNR) which is related to LNC is a better predictor of survival for gastric cancer than the N category of UICC/AJCC through a multi-institutional cohort study.MethodsThe study cohort included 3284 patients from eight institutions. Lower and upper quartiles of LNC were used for comparisons. The cut-off values (0, 0.06, 0.27, and 0.49) for the LNR categories were based on Classification and Regression Trees techniques. Akaike information criteria (AIC) for Cox regression models was used to evaluate goodness of fit between competing predictor variables (LNR vs. N category).ResultsThe 5-year disease-specific survival (DSS) rates of lower and upper quartiles of LNC were 82.2% and 84.8%. In the subgroup analysis of pN category, the upper quartile of LNC showed better survival than the lower quartile in pN2, pN3a, and pN3b subgroups. Regarding LNR, 5-year DSS of LNR 0, 0–0.06, 0.06–0.27, 0.27–0.49, and >0.49 was 95.3%, 88.7%, 70.6%, 42.7%, and 17.2% respectively. Multivariate analysis showed that pT, pN, LNR, residual tumor status, distant metastasis, and tumor differentiation significantly affected survival. The analysis also confirmed superiority of LNR compared with N category in the AIC analysis.ConclusionHigher LNC correlated with better survival in patients with pN2, pN3a, and pN3b gastric cancer. Our data indicate that LNR is a better predictor of survival than N category of UICC/AJCC.



http://ift.tt/2jPwYoQ

Intra-operative navigation of a 3-dimensional needle localization system for precision of irreversible electroporation needles in locally advanced pancreatic cancer

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2
Author(s): L. Bond, B. Schulz, T. VanMeter, R.C.G. Martin
IntroductionIrreversible electroporation (IRE) uses multiple needles and a series of electrical pulses to create pores in cell membranes and cause cell apoptosis. One of the demands of IRE is the precise needle spacing required. Two-dimensional intraoperative ultrasound (2-D iUS) is currently used to measure inter-needle distances but requires significant expertise. This study evaluates the potential of three-dimensional (3-D) image guidance for placing IRE needles and calculating needle spacing.Patients and methodsA prospective clinical evaluation of a 3-D needle localization system (Explorer™) was evaluated in consecutive patients from April 2012 through June 2013 for unresectable pancreatic adenocarcinoma. 3-D reconstructions of patients' anatomy were generated from preoperative CT images, which were aligned to the intraoperative space.ResultsThirty consecutive patients with locally advanced pancreatic cancer were treated with IRE. The needle localization system setup added an average of 6.5 min to each procedure. The 3-D needle localization system increased surgeon confidence and ultimately reduced needle placement time.ConclusionIRE treatment efficacy is highly dependent on accurate needle spacing. The needle localization system evaluated in this study aims to mitigate these issues by providing the surgeon with additional visualization and data in 3-D. The Explorer™ system provides valuable guidance information and inter-needle distance calculations.



http://ift.tt/2j1uiQk

Assessing the role of primary tumour resection in patients with synchronous unresectable liver metastases from pancreatic neuroendocrine tumour of the body and tail. A propensity score survival evaluation

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2
Author(s): E. Bertani, N. Fazio, D. Radice, C. Zardini, G. Spinoglio, A. Chiappa, D. Ribero, R. Biffi, S. Partelli, M. Falconi
BackgroundThe role of primary tumour surgery in pancreatic neuroendocrine tumours (PNETs) with unresectable liver metastases is controversial and international guidelines do not recommend surgery in such cases. Resectability of the primary tumour has never been considered in outcome comparisons between operated and non-operated patients.MethodsFrom two institutional prospective databases of patients affected by PNET and unresectable liver metastases, 63 patients who underwent a left-pancreatectomy at diagnosis were identified and compared with a group of 30 patients with a potentially resectable but not-resected primary tumour located in the body or tail. The endpoint was overall survival (OS).ResultsThe two groups significantly differed at baseline with regard to liver tumour burden Ki-67 labelling index, site of pancreas, results of the ¹⁸FDG PET-CT and age. In the operated patients, surgical morbidity comprised 7 cases of pancreatic fistula. Postoperative mortality was nil. Median OS for patients undergoing left-pancreatectomy was 111 months vs 52 for the non operated patients (p = 0.003). At multivariate analysis after propensity score adjustment, no surgery as well as liver tumour burden>25% and higher Ki-67 index were associated with an increased risk of death during follow-up. In patients with unresectable primary tumour, OS was similar in comparison to that in the resectable but non-resected patients, and significantly worse than that in the resected patients (p = 0.032).ConclusionIn PNETs located in the body or tail and diffuse liver metastases distal pancreatectomy may be justified in selected patients. Randomized studies may be safely proposed in future on this topic.



http://ift.tt/2jPrgU3

Calendar

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2





http://ift.tt/2jPrfPZ

The modified Glasgow prognosis score predicts for overall and disease-free survival following cytoreductive surgery and HIPEC in patients with pseudomyxoma peritonei of appendiceal origin

Publication date: February 2017
Source:European Journal of Surgical Oncology (EJSO), Volume 43, Issue 2
Author(s): G.H.C. Tan, C.A. Novo, S. Dayal, K. Chandrakumaran, F. Mohamed, T. Cecil, B.J. Moran
BackgroundThe modified Glasgow prognostic score (incorporating C-reactive protein and albumin) predicts survival in patients with gastro-intestinal tract cancer but has not been evaluated in patients with peritoneal malignancy. The aim was to evaluate the modified Glasgow score preoperatively in patients undergoing complete cytoreductive surgery (CCRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for pseudomyxoma peritonei (PMP) of appendiceal origin.MethodsProspectively collected data from patients with PMP of appendiceal origin following CCRS and HIPEC between January 2007 and December 2011 were analysed. The mGPS was calculated from preoperative C-reactive protein and albumin. Predicted overall survival (OS) and disease-free survival (DFS) for each mGPS score were calculated using the Kaplan–Meier model. In a separate analysis, a comparison was made between mGPS and Tumour Markers (TM).Results260 patients were included in the study. The mGPS of 0, 1, and 2 were found in 111, 130, and 19 patients respectively. The median follow-up was 48 months. For mGPS-0, -1, and -2, the predicted OS was 82.2, 73.7, and 69.2 months and the DFS was 73.5, 62.9, and 54.4 months respectively. As mGPS increases, there is a reduction in long-term survival. There was no difference between mGPS and TM.ConclusionPreoperative mGPS may be a cost effective prognostic tool for predicting OS and DFS in patients following complete CRS-HIPEC, and performs well compared to TM for predicting patients at high risk of recurrence.



http://ift.tt/2j1qw9S

Functional interaction between BDNF and mGluR II in vitro: BDNF down-regulated mGluR II gene expression and an mGluR II agonist enhanced BDNF-induced BDNF gene expression in rat cerebral cortical neurons

Publication date: Available online 21 January 2017
Source:Peptides
Author(s): Shingo Suzuki, Hisatsugu Koshimizu, Naoki Adachi, Hidetada Matsuoka, Satoko Fushimi, Junichiro Ono, Ken-ichi Ohta, Takanori Miki
Accumulating evidence suggests functional interaction between brain-derived neurotrophic factor (BDNF) and metabotropic glutamate receptor (mGluR) signaling pathways in the central nervous system (CNS). To date, eight subtypes of mGluRs, mGluR1–8, have been identified, and a previous study suggested that BDNF leads to down-regulation of GluR2 mRNA in rat cerebral cortical cultures. However, precise transcriptomic effects of BDNF on other mGluRs and their cellular significance on the BDNF signaling pathway remain largely unknown. In this study, we assessed the transcriptomic effects of BDNF on mGluR1–8 in primary cultures of rat cerebral cortical neurons, and transcriptomic impacts of mGluR(s) whose expression is regulated by BDNF, on BDNF target genes. Real-time quantitative PCR (RT-qPCR) revealed that stimulation of the cultures with 100ng/mL BDNF led to marked reductions not only in the gene expression levels of mGluR2, but also in those of mGluR3, both of which belong to group II mGluRs (mGluR II). There were, on the other hand, no changes in the amounts of mGluR I (mGluR1 and 5) and III (mGluR4, 6, 7, and 8) mRNA. Further, 10ng/mL of BDNF, which mainly activates the high-affinity BDNF receptor, TrkB, but not the low-affinity receptor, p75^NTR, was able to induce down-regulation of mGluR II mRNA. The BDNF-induced suppression of mGluR II was not significantly attenuated in the presence of tetrodotoxin (TTX), a blocker for voltage-gated sodium channels. In addition, on stimulation with BDNF (100ng/mL), no significant down-regulation of mGluR II mRNA was seen in cultured astrocytes, which only express the truncated form of TrkB. Finally, we assessed the transcriptomic effect of mGluR II on the expressions of BDNF target genes, BDNF and activity-regulated cytoskeleton-associated protein (Arc). LY404039, an mGluR II agonist, enhanced the BDNF-induced up-regulation of BDNF, but not Arc. On the other hand, LY341495, an mGluR II antagonist, down-regulated BDNF mRNA levels. Collectively, these observations demonstrated the detailed functional interaction between BDNF and mGluR II: Activation of mGluR II positively regulates self-induced BDNF expression, and, in turn, BDNF negatively regulates the gene expression of mGluR II in a neuronal activity-independent manner, in cortical neurons, but not in astrocytes.



http://ift.tt/2jcUOti

Incidence, mortality and receptor status of breast cancer in African Caribbean women: Data from the cancer registry of Guadeloupe

Publication date: April 2017
Source:Cancer Epidemiology, Volume 47
Author(s): J. Deloumeaux, S. Gaumond, B. Bhakkan, Nsome Manip M'Ebobisse, W. Lafrance, Pierre Lancelot, D. Vacque, Y. Negesse, A. Diedhiou, P. Kadhel
BackgroundGeographical disparities in breast cancer incidence and outcomes are reported worldwide. Women of African descent show lower incidence, higher mortality rates and earlier age of onset. We analyzed data from the cancer registry of Guadeloupe for the period 2008–2013.MethodsWe describe breast cancer characteristics by molecular subtype, as well as estimated observed and net survival. We used Cox proportional hazard models to determine associations between cancer subtypes and death rate, adjusted for variables of interest.ResultsOverall, 1275 cases were recorded with a mean age at diagnosis of 57(±14) years. World standardized incidence and mortality were respectively 71.9/100,000 and 14.1/100,000 person-years. Age-specific incidence rates were comparable to European and US populations below the age of 45, and higher in Guadeloupean women aged between 45 and 55 years. Overall, 65.1% of patients were hormone receptor (HR)+ and 20.1% were HR-. Triple negative breast cancers (TNBC) accounted for 14% of all cases, and were more frequent in patients under 40 (21.6% vs. 13.4%, p=0.02). Five-year net survival was 84.9% [81.4-88.6]. It was higher for HR+/Her2+ and HR+/Her2- subtypes, and lower for HR-/Her2+ and TNBC patients.ConclusionWe found high age-specific incidence rates of breast cancer in women aged 45 to 55 years, which warrants further investigation in our population. However, this population of mainly African descent had good overall survival rates, and data according to subtypes are consistent with those reported internationally. These results may suggest that poorer survival in other African descent populations may not be an inherent feature of the disease but may be amenable to improvement.



http://ift.tt/2k49n0O

A sensitive bisphenol A voltammetric sensor relying on AuPd nanoparticles/graphene composites modified glassy carbon electrode

Publication date: 1 May 2017
Source:Talanta, Volume 166
Author(s): Bingyuan Su, Huilin Shao, Na Li, Xiaomei Chen, Zhixiong Cai, Xi Chen
In this work, a sensitive bisphenol A (BPA) electrochemical sensor was assembled using a surfactant-free AuPd nanoparticles-loaded graphene nanosheets (AuPdNPs/GNs) modified electrode. The AuPdNPs monodispersed on GNs were successfully prepared by the spontaneous redox reaction between bimetallic precursors and GNs. Because no surfactant or halide ions were involved in the proposed synthesis, the prepared composite was enabled to directly modify a glassy carbon electrode without any pre-treatments. Moreover, due to the synergetic effect of Au and Pd, AuPdNPs/GNs displayed high electrochemical activity with well-defined voltammetric peaks of BPA oxidation and lower overpotential compared with monometallic PdNPs and AuNPs supported GNs. According to the results of differential pulse voltammetry (DPV), under optimized conditions, a good linear response was observed for the concentration of BPA in the range of 0.05–10μM with a detection limit of 8nM. The developed electrochemical sensor was successfully applied to determine BPA in food package. This study indicated that AuPdNPs/GNs based electrochemical sensor can be a promising and reliable tool for rapid analysis of emergency pollution affairs of BPA.

Graphical abstract

http://ift.tt/2jcvFiH

Titanium (IV) ion-modified covalent organic frameworks for specific enrichment of phosphopeptides

Publication date: 1 May 2017
Source:Talanta, Volume 166
Author(s): Heping Wang, Fenglong Jiao, Fangyuan Gao, Yayao Lv, Qiong Wu, Yan Zhao, Yehua Shen, Yangjun Zhang, Xiaohong Qian
To date, plenty of new alternative materials for phosphopeptides enrichment prior to mass spectrometry (MS) analysis appear, especially immobilized metal ion affinity chromatography (IMAC) materials. The variable combinations with different metal ions, chelating ligands and solid supports offer full of optionality for IMAC. However, further improvement was predicted by the tedious and complex synthetic process. In this work, a novel covalent organic framework (COF)-based IMAC material (denoted TpPa-2-Ti⁴⁺) was prepared simply by direct immobilizing Ti (IV) into TpPa-2 COFs without any extra chelating ligands. The structure and composition of as-prepared composites were confirmed by PXRD, FT-IR and XPS, and a new flower-shaped Ti⁴⁺-IMAC with regular micro-nano hierarchical structure was observed in the SEM and TEM images. The obtained titanium (IV) ion-modified covalent organic frameworks demonstrated low limit of detection (4 fmol) and largely-satisfactory selectivity (β-casein: BSA=1:100) for phosphopeptide capturing from β-casein. Similarly, 18 and 17 phosphopeptides could be easily detected in the tryptic digest of α-casein or the digest mixture of α-casein and BSA (1:50). They were also successfully applied for enrichment of phosphopeptides from non-fat milk and HeLa cells with high sensitivity and satisfactory selectivity. All above results showed that the new titanium (IV) ion-modified covalent organic framework is expected to be a potential IMAC for phosphopeptide enrichment in large-scale phosphoproteomics studies.

Graphical abstract

http://ift.tt/2jctSdc

Bifunctional polydopamine thin film coated zinc oxide nanorods for label-free photoelectrochemical immunoassay

Publication date: 1 May 2017
Source:Talanta, Volume 166
Author(s): Yan Yang, Weihua Hu
Photoelectrochemical (PEC) detection is a promising method for label-free immunoassay by reporting the specific biological recognition events with electrical signals. However, it is challenging to rationally incorporate immunosensing components with a photocurrent conversion interface, which generally necessitates multistep fabrication and careful tailoring of various components such as photoactive material and biological probe. For high detection reliability and reproducibility, it is highly desirable to rationally construct an efficient PEC interface with architecture as simple as possible. In this work, a novel yet simple PEC immunosensor based on bio-inspired polydopamine (PDA) thin film-coated zinc oxide (ZnO) nanorods was reported. In this PEC immunosensor, the PDA thin film serves simultaneously as a unique sensitizer for charge separation as well as a functional layer for probe antibody attachment. The photocurrent on this electrode under illumination decreases upon the immunoreaction on the surface, possibly due to the blocking effect of formed immunocomplexes on the access of reducing reagent to the photoelectrode, thus offering a simple and reliable platform for PEC label-free immunoassay. By using an antibody-antigen pair as a model, successful label-free immunoassay was achieved with a detection limit of 10pgmL⁻¹ and a dynamic range from 100pgmL⁻¹ to 500ngmL⁻¹. This work demonstrates intriguing electro-optical property and bioconjugation activity of PDA film and may pave the way toward advanced PEC immunoassays.

Graphical abstract

http://ift.tt/2jcvJ1P

Silica – Boronate affinity material for quick enrichment of intracellular nucleosides

Publication date: 1 May 2017
Source:Talanta, Volume 166
Author(s): Shuxia Wang, Huihui Li, Xiujuan Guan, Ting Cheng, Haixia Zhang
Boronic acid modified materials have been widely used to adsorb nucleosides, but their adsorption capacities require further improvement. Most cis-diol containing biomolecules are in very low abundance along with interfering components in real samples, and need to be enriched specially. In this study, we synthesize a kind of silica absorbent modified with boronic acid derivative, using amorphous silica as raw material and obtaining high adsorption capacity for adenosine. In addition, the adsorption equilibrium can be completed within 10s and 1min for the desorption. Finally, the material was successfully applied to enrich nucleosides from cells and the spiked recoveries were found between 82.21% and 118.9%. The results showed that the prepared adsorbent has potential to effectively enrich cis-diol substances from cell samples.

Graphical abstract

http://ift.tt/2jcvG6f

Selective enrichment of glycopeptides/phosphopeptides using Fe3O4@Au-B(OH)2@mTiO2 core-shell microspheres

Publication date: 1 May 2017
Source:Talanta, Volume 166
Author(s): Dongpo Xu, Guoquan Yan, Mingxia Gao, Chunhui Deng, Xiangmin Zhang
In this work, the bifunctional Fe3O4@Au-B(OH)2@mTiO2 core-shell core-shell microspheres were designed and synthesized for the selective enrichment of glycopeptides/ phosphopeptides. Due to the bifunctional property of the titanium dioxide and the boronic acid group, the microspheres were successfully applied to the enrichment of phosphopeptides and glycopeptides, evaluated by capturing phosphopeptides from tryptic digestion of model phosphoprotein bovine β-casein diluted to 2.0pgμL⁻¹ (8.0×10^–17molμL⁻¹) and glycopeptides from tryptic digestion of model glycoprotein horseradish peroxidase (HRP) diluted to 80pgμL⁻¹ (2.0×10^–15molμL⁻¹). The enrichment selectivity of the bifunctional microspheres was evaluated by capturing phosphopeptides from a peptide mixture of β-casein and bovine serum albumin (BSA) with the molar ratio of 1:1000 (4.2×10^–12mol of β-casein and 4.2×10⁻⁹mol of BSA in 100μL) and glycopeptides from a peptide mixture of HRP and BSA up to the ratio of 1:100 (5.0×10^–12mol of HRP and 5.0×10⁻¹⁰mol of BSA in 100μL).

Graphical abstract

http://ift.tt/2jcFPzN

Bottlenose dolphins engaging in more social affiliative behaviour judge ambiguous cues more optimistically

Publication date: 30 March 2017
Source:Behavioural Brain Research, Volume 322, Part A
Author(s): Isabella L.K. Clegg, Heiko G. Rödel, Fabienne Delfour
Cognitive bias tests measure variation in emotional appraisal and are validated methods to assess animals' affective states. However, the link between social behaviours and cognitive bias has not yet been investigated. Bottlenose dolphins are a gregarious species for whom welfare research is increasing in importance, and thus are a good model to test such an association. We adapted a spatial location judgement bias test for eight captive bottlenose dolphins to investigate the link between cognitive bias and social behaviour, where we conducted behavioural observations outside of training sessions and did not experimentally induce an affective state. Subjects showed stable individual differences in cognitive biases across the three test days. Furthermore, dolphins showing more synchronous swimming, a fundamental affiliative behaviour, judged ambiguous cues significantly more optimistically. Our longer-term data showed cognitive bias and synchronous swimming frequency were significantly associated for up to two months preceding the test, but disappeared prior to that, suggesting that here cognitive bias differences were reflected by transitory affective states rather than longer-term traits. We hypothesise that the frequency of synchronous swimming may induce affective states and/or be induced by them; either way, it has strong potential as an indicator of affective state in this species and beyond.



http://ift.tt/2kfeKtu

Prognostic value of survivin and DNA topoisomerase IIα in diffuse and anaplastic astrocytomas

Publication date: Available online 21 January 2017
Source:Pathology - Research and Practice
Author(s): R.K. Varughese, A.J. Skjulsvik, S.H. Torp
Distinguishing WHO grade II astrocytomas from grade III is a difficult task. This study looks into the potential prognostic use of mitotic activity and the proliferation markers Ki67/MiB-1 (Ki67), survivin and DNA topoisomerase IIα (TIIα) in 59 WHO grade II diffuse astrocytomas (DA) and 33 WHO grade III anaplastic astrocytomas (AA), IDH1 R132H-mutated and not otherwise specified (NOS) by means of immunohistochemistry. All proliferation markers showed higher expression in AA compared with DA. Only Ki67 had significantly greater expression in astrocytomas, NOS vs. astrocytomas, IDH1-mutated. Uni-/multivariable COX-regression analyses showed that greater expression of both survivin and TIIα were associated with poorer survival when stratified for IDH1-mutation status and, additionally, achieved hazard rates surpassing clinically established prognostic factors such as age and WHO performance status. Ki67 achieved only statistical significance in univariable analyses, whereas mitoses did not reveal any relation to survival. IDH1-mutated astrocytomas had significantly better survival than astrocytomas, NOS. Among IDH1-mutated astrocytomas no significant difference in survival was shown between DA and AA. Our findings suggest a potential usefulness of proliferation markers in the prognostic setting of astrocytomas independent of IDH1-mutation status, and survivin and TIIα are potential candidates in that regard.



http://ift.tt/2kgrKTv

INVESTIGATON OF BRAF MUTATION ANALYSIS WITH DIFFERENT TECHNICAL PLATFORMS IN METASTATİC MELANOMA

Publication date: Available online 21 January 2017
Source:Pathology - Research and Practice
Author(s): Ebru Sener, Pinar Yildirim, Ayca Tan, Ozay Gokoz, Gaye Guler Tezel
In metastatic melanoma, the detection of somatic mutations in the BRAF gene is crucial regarding patient selection for targeted therapy. Several screening methodsve been developed to identify BRAF gene mutations. In this study, our objective was to evaluate the detection of the BRAF V600 mutations using two molecular methods, real-time polymerase chain (real-time PCR) assay and pyrosequencing, and immunohistochemistry (IHC), and to compare the results of these different technical platforms.This study included 98 patients diagnosed with metastatic melanoma at the Hacettepe University, Department of Pathology between 2002 and 2014. BRAF mutation analysis was tested with real-time PCR, pyrosequencing and IHC methods. The results of all three tests were compared with are reference test, and the sensitivity, specificity rates and kappa coefficient values were analysed for each test.We successfully analysed BRAF mutations using all three methods in 92 patients. According to our findings, the pyrosequencing method had the highest kappa value regarding the determination of BRAF V600 mutations. The kappa values were at almost perfect agreement levels in pyrosequencing and real-time PCR assay (kappa coefficient for pyrosequencing=0.895 (95% CI: 0.795–0.995); kappa coefficient for real-time PCR=0.871 (95% CI: 0.761–0.981). The kappa value was at a substantial agreement level in the IHC analysis (kappa coefficient=0.776 (95% CI: 0.629–0.923).According to our results, we found that real-time PCR and pyrosequencing methods were equally excellent in determination of BRAF V600 mutations. The IHC method, which is commonly used in routine pathology practice, can also be safely used as a screening test for determination of BRAF V600 mutations.



http://ift.tt/2jlw9AJ

Chicoric acid suppresses BAFF expression in B lymphocytes by inhibiting NF-κB activity

Publication date: March 2017
Source:International Immunopharmacology, Volume 44
Author(s): Lingxi Chen, Gang Huang, Min Gao, Xiaodong Shen, Wei Gong, Zhizhen Xu, Yijun Zeng, Fengtian He
B cell activating factor belonging to the TNF family (BAFF) plays a critical role in the pathogenesis of autoimmune diseases. The inhibition of BAFF expression is an emerging therapeutic approach for these disorders. Chicoric acid (CA), a bioactive phytochemical found in several widely used traditional medicinal plants, has significant anti-inflammatory activity and anti-arthritic effects. However, the role of CA in modulation of BAFF expression remains unknown. In this study, we demonstrated that CA reduced BAFF expression in human B lymphocyte cell lines and decreased the DNA-binding activity of nuclear factor-κB (NF-κB) in the BAFF promoter region. Furthermore, CA inhibited both the nuclear translocation of p65 (the subunit of NF-κB) and the phosphorylation of IκBα (inhibitor of NF-κB). These results suggest that CA suppresses BAFF expression by inhibiting NF-κB activity, and CA may serve as a novel therapeutic agent to down-regulate excessive BAFF expression in autoimmune diseases.



http://ift.tt/2jc3vEm

Effect of bone morphogenetic protein on Zn-HAp and Zn-HAp/collagen composite: A systematic in vivo study

Publication date: December 2017
Source:Research in Veterinary Science, Volume 115
Author(s): Howa Begam, Samit Kumar Nandi, Abhijit Chanda, Biswanath Kundu
Due to good biocompatibility and osteoconductivity, hydroxyapatite (HAp) and its composite with different polymers have been widely investigated for the application in the field of bone tissue engineering. The present study reports the, in vivo performance of zinc doped HAp and HAp/collagen composite (HAC) using bone morphogenetic protein-2. It was done for a span of two months on New Zealand rabbit model. After two months postoperatively, there was no marked inflammatory reaction in experimental groups and control groups. The histological images showed well-formed bony matrix with well differentiated haversian system. From the fluorochrome labeling study, it was observed that higher amount of new bone formed in case of bone morphogenetic protein-2 (BMP-2) loaded Zn-HAp (50%) and HAC (27%) specimens than control. The percentage of new bone formation was significantly higher in case of BMP loaded Zn-HAp group than BMP loaded HAC group. From the SEM images similar trend was observed. As the HAC specimen consists of amorphous phase, it had a negative impact on new bone formation.

Graphical abstract

http://ift.tt/2jbWYtg

Chemical degradation of selected Zn-based corrosion products induced by C60 cluster, Ar cluster and Ar+ ion sputtering in the focus of X-ray photoelectron spectroscopy (XPS)

Publication date: 1 May 2017
Source:Applied Surface Science, Volume 403
Author(s): R. Steinberger, J. Sicking, J. Weise, J. Duchoslav, T. Greunz, D.C. Meyer, D. Stifter
Monoatomic ion sputtering is a common concept for surface sensitive analysis methods to clean surfaces prior investigation or to obtain information from deeper regions. However, severe damage of the materials – linked to preferential sputtering, ion implantation, atomic mixing and in worst case chemical degradation – can affect the validity of the analysis. Hence, the impact of C60 cluster etching, furthermore, of Ar⁺ ion bombardment with and without azimuthal sample rotation and also the application of heavy projectiles (Xe⁺ ions) was investigated to find a concept, which is less destructive or with less critical influence on the chemical nature of the investigated materials. In this work the focus is set on hydrozincite and zinc oxide, two common corrosion products of Zn-based coatings. As a main point, all the obtained results from (i) Ar⁺ ion, (ii) Ar cluster, and (iii) C60 cluster etching on the degradation kinetics of hydrozincite were compared with respect to the reached sputter depth. In addition, the sputter rate of all three methods was experimentally determined for ZnO. In total, fully non-destructive conditions could not be found, but valuable knowledge on the type and rate of degradation, which is essential to choose the most suited sputter concept.

Graphical abstract

http://ift.tt/2jbPxm2