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

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

Regenerative treatment for tympanic membrane perforation using gelatin sponge with basic fibroblast growth factor

Publication date: Available online 22 January 2017
Source:Auris Nasus Larynx
Author(s): Kaoru Omae, Shin-ichi Kanemaru, Eiji Nakatani, Hideaki Kaneda, Tsutomu Nishimura, Risa Tona, Yasushi Naito, Atsuhiko Kawamoto, Masanori Fukushima
ObjectiveThe objective of this study was to evaluate safety and efficacy of regenerative treatment using gelatin sponge with basic fibroblast growth factor (bFGF) in patients with tympanic membrane perforation (TMP).MethodsThe current study was a prospective, multicenter, open-label, single-arm, and exploratory clinical trial to evaluate the safety and efficacy of the TM regeneration procedure (TMRP). Myringotomy was used to mechanically disrupt the edge of the TMP, and a gelatin sponge immersed in bFGF was then placed over the perforation. Fibrin glue was dripped over the sponge as a sealant. TMP closure was examined 4 weeks later and, if insufficient, TMRP was repeated a maximum of three more times. TMP closure and hearing improvement 12 weeks after the final TMRP as well as safety were evaluated.ResultsOf the 11 patients with TMP who participated in this study, one who fulfilled the exclusion criteria and did not undergo TMRP and one with cholesteatoma were excluded from the efficacy analysis. TMP closure and hearing improvement 12 weeks after the final TMRP were achieved in eight out of nine patients (88.9%). Mean bone conduction threshold significantly improved 12 weeks after the TMRP compared with baseline (35.7±20.3 vs 29.4±21.0dB, P=0.015). Six out of ten patients receiving TMRP experienced temporary adverse events: appendicitis (serious, severe), otorrhea (mild), otitis media (mild), and sudden hearing loss (mild). However, none were related to the protocol treatment.ConclusionTMP closure and hearing improvement were frequently confirmed following the TMRPs which were safely performed. These favorable outcomes were accompanied with significant improvement of the bone conduction threshold. These promising outcomes would encourage a large-scaled, randomized and pivotal clinical trial in the future. This trial is registered at http://ift.tt/1lXJedE (identifier: UMIN000006585).



http://ift.tt/2jOUCBr

Unilateral vocal fold adductor paralysis after tracheal intubation

Publication date: Available online 22 January 2017
Source:Auris Nasus Larynx
Author(s): Takao Goto, Takaharu Nito, Rumi Ueha, Akihito Yamauchi, Taku Sato, Tatsuya Yamasoba
Vocal fold immobility is a relatively rare complication that can occur after tracheal intubation. Differential diagnoses include a rare clinical entity called unilateral vocal fold adductor paralysis in which only branches entering the thyroarytenoid and lateral cricoarytenoid muscles of the recurrent laryngeal nerve become paralyzed. Computed tomography and laryngeal electromyography are required to distinguish this condition from others such as cricoarytenoid dislocation/subluxation. Here, we describe two patients who developed vocal fold adductor paralysis after intubation. Patient 1 was a 56-year-old man who underwent living-donor liver transplantation and was extubated on day 7 after surgery. Patient 2 was a 52-year-old man who received life support measures including intubation due to ventricular fibrillation, and was extubated two days later. Both were hoarse soon after extubation. Endoscopic laryngeal examination revealed normal abduction and insufficient adduction of paralyzed vocal folds. Computed tomography ruled out cricoarytenoid dislocation/subluxation and laryngeal electromyography confirmed unilateral vocal fold adductor paralysis. Laryngologists should consider this rare pathogenesis.



http://ift.tt/2jOThdO

Comparison of endoscopic transcanal myringoplasty and endoscopic type I tympanoplasty in repairing medium-sized tympanic perforations

Publication date: Available online 22 January 2017
Source:Auris Nasus Larynx
Author(s): Chih-Chieh Tseng, Ming-Tang Lai, Chia-Che Wu, Sheng-Po Yuan, Yi-Fang Ding
ObjectiveThe tympanomeatal flap elevation technique has been used in tympanoplasty for decades; however, this procedure has disadvantages. In recent years, endoscopic transcanal myringoplasty (ETM) has been increasingly practiced and has yielded positive results.This study compares the efficacy of ETM and endoscopic type I tympanoplasty (ETT) in repairing medium-sized perforations of the tympanic membrane.MethodsThis retrospective medical record review included patients undergoing surgery for medium-sized perforations of the tympanic membrane from January 1, 2013 to August 1, 2015. We divided our patients into 2 groups: the ETM group and ETT group. The main outcome measure was comparison of the graft take rates and hearing results between ETM and ETT.ResultsA total of 113 patients were enrolled in this study; of these patients, 64 underwent ETM and 49 received ETT. The overall graft take rates and improvement of air–bone gaps were comparable between the groups. However, the patients in the ETM group had shorter operative times and fewer follow-up visits over 3 months than those in the ETT group did.ConclusionWe recommend that ETM (instead of ETT) be used for repairing medium-sized perforations of the tympanic membrane.



http://ift.tt/2j3tCu0

A new electroneurography as a prognostic tool for marginal mandibular nerve paralysis after parotid gland surgery: A preliminary evaluation

Publication date: Available online 22 January 2017
Source:Auris Nasus Larynx
Author(s): Shin-Ichi Haginomori, Shin-Ichi Wada, Takahiro Ichihara, Tetsuya Terada, Ryo Kawata
ObjectiveMarginal mandibular nerve paralysis is the most frequent complication of benign parotid tumor surgery and results in cosmetic deformity. The purpose of this study was to develop a new electroneurography method for marginal mandibular nerve paralysis using electroneurography (ENoG) and judge its usefulness for clinical practice.MethodsTwenty-seven patients who underwent surgery for benign parotid tumor were enrolled. We proposed and use the mandibular angle method, in which the recording electrode was placed on the skin above the depressor anguli oris muscle while the reference electrode was placed on the skin of the parietal region, and percutaneous electrical stimulation was applied to enclose the mandibular angle that could measure the function of the marginal mandibular nerve solely. Preoperative and postoperative ENoG values were compared in paralytic and non-paralytic patients.ResultsThe mean postoperative ENoG value (35.0%) was lower than the preoperative value (90.5%) in paralytic patients, whereas no difference was observed between preoperative (79.3%) and postoperative (69.5%) ENoG values in non-paralytic patients.ConclusionA new ENoG method (mandibular angle method) was thought to reflect marginal mandibular nerve injury and might be useful for determining the likelihood of paralysis.



http://ift.tt/2jP1ezM

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

Atopic dermatitis and early childhood caries: Results of the GUSTO study

Atopic dermatitis (AD) is a chronic, relapsing form of inflammatory skin disease, affecting approximately 10% of children in the United States.1 AD has been associated with sleep disturbances, along with various comorbid allergic conditions, resulting in poor quality of life. In the last decade, studies have demonstrated an epidermal skin barrier defect, caused by various genetic mutations, to be an additional predisposing factor.2 Early childhood caries (ECC), a chronic diet-mediated infectious oral disease, has been reported to be the most common chronic childhood disease in the United States.

http://ift.tt/2kgrYWO

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.



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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

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

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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.



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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

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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.



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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.



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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.



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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.



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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.



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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.



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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.



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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.



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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.



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The Mechanically Activated p38/MMP-2 Signaling Pathway Promotes Bone Marrow Mesenchymal Stem Cell Migration in Rats

Publication date: Available online 22 January 2017
Source:Archives of Oral Biology
Author(s): Zihui Yang, Baolei Wu, Sen Jia, Yinghua Zhao, Rui Hou, Xiaochang Liu, Xinge Wang, Litong Chen, Xinjie Yang, Delin Lei, Lei Wang
ObjectiveThe aim of the present study was to investigate the effect of static strain on bone marrow mesenchymal stem cell (BMMSC) migration and whether the p38/matrix metalloproteinase-2 (MMP-2) axis plays a role in induction of BMMSC migration under mechanical strain.DesignBoth in vivo and in vitro investigations were performed. Twelve adult male Sprague-Dawley rats were randomly divided into 2 groups (n=6 per group). Rats in the experimental group underwent right mandibular distraction osteogenesis, whereas rats in the control group were subjected to osteotomy in the mandible without distraction. Immunohistochemistry and immunofluorescence were performed to evaluate phospho-p38 (p-p38) and Nestin expression. BMMSCs were isolated from rat mandibles. BMMSCs in the experimental group were subjected to static mechanical strain for 2h, whereas those in the control group underwent no strain. The biological roles of static strain and the p38/MMP-2 axis in BMMSC migration were evaluated by Transwell assays and western blotting by inhibiting p38 phosphorylation.ResultsThere were significantly more Nestin⁺ cells in the bone calluses of the experimental group than in those of the control group. In addition, Nestin⁺/p-p38⁺ cell numbers were significantly higher in the experimental group than in the control group, indicating that static strain activated p38 signaling in BMMSCs in vivo. In accordance with in vivo results, static strain in vitro stimulated phosphorylation of p38 in BMMSCs. Furthermore, expression of MMP-2 was elevated in BMMSCs under static strain compared with the control, and strain-induced MMP-2 expression was abolished by inhibition of p38 phosphorylation in BMMSCs. Moreover, Transwell assay results showed that static strain promoted BMMSC migration, which was abolished by inhibition of p38 phosphorylation.ConclusionsThe present study demonstrated that static strain can promote the migration ability of BMMSCs via p38/MMP-2 signaling. To the best of our knowledge, this study is the first report demonstrating that the p38/MMP-2 axis governs BMMSC migration under static mechanical strain.



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Aims & Scope/Editorial board

Publication date: March 2017
Source:Archives of Oral Biology, Volume 75





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Adhesion of Porphyromonas gingivalis and Tannerella forsythia to dentin and titanium with sandblasted and acid etched surface coated with serum and serum proteins – An in vitro study

Publication date: March 2017
Source:Archives of Oral Biology, Volume 75
Author(s): Sigrun Eick, Christian Kindblom, Danuta Mizgalska, Anna Magdoń, Karolina Jurczyk, Anton Sculean, Andreas Stavropoulos
ObjectiveTo evaluate the adhesion of selected bacterial strains incl. expression of important virulence factors at dentin and titanium SLA surfaces coated with layers of serum proteins.MethodsDentin- and moderately rough SLA titanium-discs were coated overnight with human serum, or IgG, or human serum albumin (HSA). Thereafter, Porphyromonas gingivalis, Tannerella forsythia, or a six-species mixture were added for 4h and 24h. The number of adhered bacteria (colony forming units; CFU) was determined. Arg-gingipain activity of P. gingivalis and mRNA expressions of P. gingivalis and T. forsythia proteases and T. forsythia protease inhibitor were measured.ResultsCoating specimens never resulted in differences exceeding 1.1 log10 CFU, comparing to controls, irrespective the substrate. Counts of T. forsythia were statistically significantly higher at titanium than dentin, the difference was up to 3.7 log10 CFU after 24h (p=0.002). No statistically significant variation regarding adhesion of the mixed culture was detected between surfaces or among coatings. Arg-gingipain activity of P. gingivalis was associated with log10 CFU but not with the surface or the coating. Titanium negatively influenced mRNA expression of T. forsythia protease inhibitor at 24h (p=0.026 uncoated, p=0.009 with serum).ConclusionsThe present findings indicate that: a) single bacterial species (T. forsythia) can adhere more readily to titanium SLA than to dentin, b) low expression of T. forsythia protease inhibitor may influence the virulence of the species on titanium SLA surfaces in comparison with teeth, and c) surface properties (e.g. material and/or protein layers) do not appear to significantly influence multi-species adhesion.



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Expression of hypoxia-induced semaphorin 7A correlates with the severity of inflammation and osteoclastogenesis in experimentally induced periapical lesions

Publication date: March 2017
Source:Archives of Oral Biology, Volume 75
Author(s): Miao He, Zhuan Bian
ObjectiveWhile hypoxia and inflammation are intimately linked, the effects of inflammatory hypoxia on the pathogenesis of periapical lesions remain largely unknown. The aim of this study was to examine hypoxia during the progression of experimentally induced rat periapical lesions, and to derive correlations between hypoxia-induced Semaphorin 7A (Sema7a) expression, severity of inflammation, and osteoclastogenesis in the lesions.DesignPeriapical lesions were developed after mandibular first molar pulp exposure in forty Sprague-Dawley rats. The animals were randomly divided into four groups and sacrificed at 0, 7, 14, and 28days after pulpal exposure. The bilateral mandibles containing the first molar were obtained and routinely prepared for histological, immunohistochemical, enzyme histochemical analyses and quantitative polymerase chain reaction detecting Sema7a mRNA expression. Data were analysed by one-way analysis of variance and the Pearson's correlation and linear tendency test.ResultsPeriapical tissues become hypoxic during the development of experimentally induced periapical lesions, with steadily increasing numbers of HIF-1α-positive cells that positively correlate with the expression of Sema7a mRNA in the lesions. Furthermore, significant positive correlates were derived for the expression of Sema7a and the degree of inflammatory infiltration and osteoclast number, respectively.ConclusionsHypoxia-induced Sema7a participates in the pathogenesis of periapical lesions, providing a novel therapeutic target for the treatment of this inflammatory disease in the future.



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Microbiological and clinical assessment of the abutment and non-abutment teeth of partial removable denture wearers

Publication date: March 2017
Source:Archives of Oral Biology, Volume 75
Author(s): Luciana Costa, Cássio do Nascimento, Valéria Oliveira Pagnano de Souza, Vinícius Pedrazzi
ObjectiveThe aim of this study was assessing the changes in both clinical and microbiological parameters of healthy individuals after rehabilitation with removable partial denture (RPD).Design11 women received unilateral or bilateral free-end saddle RPD in the mandibular arch. Clinical and microbiological parameters of abutment, non-abutment, and antagonist teeth were assessed at baseline (RPD installation) and after 7, 30, 90, and 180days of function. The Checkerboard DNA–DNA hybridization technique was used to identify and quantify up to 43 different microbial species from subgingival biofilm samples. Probing depth, gingival recession, and bleeding on probing were also investigated over time.ResultsThe total and individual microbial genome counts were shown significantly increased after 180days with no significant differences between abutment, non-abutment, or antagonist teeth. Streptococcus spp., Aggregatibacter actinomycetemcomitans, and other species associated to periodontitis (Peptostreptococcus anaerobius, Prevotella nigrescens, and Tannerella forsythia), as well as opportunistic Candida spp., were recovered in moderate counts. Abutment teeth presented higher values of gingival recession when compared with non-abutment or antagonist teeth, irrespectively time of sampling (p<0.05). No significant differences were found between groups regarding bleeding on probing or probing depth over time.ConclusionsOverall, the microbial counts significantly increased after 6 months of denture loading for both abutment and non-abutment teeth with no significant differences regarding the microbial profile over time. Bleeding on probing and probing depth showed no significant difference between groups over time whereas gingival recession increased in the abutment teeth.



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Tumor necrosis factor-Alpha stimulates cytokine expression and transient sensitization of trigeminal nociceptive neurons

Publication date: March 2017
Source:Archives of Oral Biology, Volume 75
Author(s): Zachary L. Durham, Jordan L. Hawkins, Paul L. Durham
ObjectiveElevated levels of tumor necrosis factor- alpha (TNF-α) in the capsule of the temporomandibular joint (TMJ) are implicated in the underlying pathology of temporomandibular disorders (TMD). TMD are a group of conditions that result in pain in the TMJ and/or muscles of mastication, and are associated with significant social and economic burdens. The goal of this study was to investigate the effect of elevated TNF-α levels in the TMJ capsule on nocifensive behavioral response to mechanical stimulation of trigeminal neurons and regulation of cytokines within the trigeminal ganglion.DesignMale Sprague-Dawley rats were injected bilaterally in the TMJ capsule with TNF-α and changes in nocifensive head withdrawal responses to mechanical stimulation of cutaneous tissue directly over the capsule was determined using von Frey filaments. Cytokine levels in trigeminal ganglia were determined by protein array analysis at several time points post injection and correlated to nocifensive behavior.ResultsTNF-α caused a significant increase in the average number of nocifensive responses when compared to naive and vehicle treated animals 2h post injection, but levels returned to control levels at 24h. Based on array analysis, the levels of eight cytokines were significantly elevated above vehicle control levels at 2h following TNF-α injection, but all eight had returned to the vehicle control levels after 24h.ConclusionsOur findings provide evidence that elevated levels of TNF-α in the joint capsule, which is reported to occur in TMD, promotes nociception in trigeminal ganglia neurons via a mechanism that temporally correlates with differential regulation of several cytokines.



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Altered autophagy and sympathetic innervation in salivary glands from high-fat diet mice

Publication date: March 2017
Source:Archives of Oral Biology, Volume 75
Author(s): Polliane Morais de Carvalho, Maria Beatriz Duarte Gavião, Guy Howard Carpenter
Objectiveto investigate the effects of a high fat diet (HFD) on salivary glands in vivo, in a mouse model. In particular, whether it will induce the appearance of fat cells in salivary glands, alterations related to autophagy, mTOR pathway and sympathetic innervation.Design27 adult female ICR mice were separated in six groups. Three groups fed with (HFD) containing 55% fat, for one, two and three month and another three groups fed with normal diet (2.7% of fat), for the same time periods. The submandibular glands and liver were dissected and part homogenized for protein analyses and part fixed in formalin for histological analyses.ResultsAfter three months the HFD fed mice total body weight fold change increased compared to controls. The Oil Red O staining showed no fat cells deposit in salivary gland however a large increase was observed in liver after three months of HFD. Adiponectin levels were significantly decreased in the HFD group after three months. The group fed with HFD for three months showed increased conversion of the LC3 autophagy marker in salivary gland. mTOR showed no activation regarding the time point studied. Tyrosine hydroxylase significantly decreased after two and three month of HFD.ConclusionHFD caused several changes after three months however the earliest change was noticed after two months regarding sympathetic innervation. This suggests neural alteration may drive other diet induced changes in salivary glands. These early changes may be the starting point for longer term alterations of salivary glands with alterations in diet.



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Regulation of matrix metalloproteinase secretion by green tea catechins in a three-dimensional co-culture model of macrophages and gingival fibroblasts

Publication date: March 2017
Source:Archives of Oral Biology, Volume 75
Author(s): Marie-Pierre Morin, Daniel Grenier
ObjectivesElevated levels of matrix metalloproteinases (MMPs) have been associated with the active phases of tissue and bone destruction in periodontitis, an inflammatory disease characterized by a significant breakdown of tooth support. In the present study, we used a three-dimensional (3D) co-culture model of macrophages and gingival fibroblasts to investigate the ability of a green tea extract and its major constituent epigallocatechin-3-gallate (EGCG) to regulate the secretion of MMP-3, -8, and -9.MethodsThe 3D co-culture model was composed of gingival fibroblasts embedded in a type I collagen matrix overlaid with macrophages. Two arbitrary ratios were tested. The ratio composed of 1 macrophage to 10 fibroblasts was used to mimic a slightly inflamed periodontal site while the ratio composed of 10 macrophages to 1 fibroblast was used to mimic a severely inflamed periodontal site. The 3D co-culture model was pre-treated for 2h with either the green tea extract or EGCG. It was then stimulated with Aggregatibacter actinomycetemcomitans lipopolysaccharide (LPS). The model was also first stimulated with LPS for 2h and then incubated with the green tea extract or EGCG. The concentrations of secreted MMP-3, -8, and -9 were quantified by enzyme-linked immunoassays.ResultsWhen the 3D co-culture model was stimulated with A. actinomycetemcomitans LPS, the 10:1 ratio of macrophages to gingival fibroblasts was associated with a highest secretion of MMP-3 and -9 and, to a lesser extent, MMP-8, than the 1:10 ratio. Non-cytotoxic concentrations of the green tea extract or EGCG reduced the basal secretion levels of all three MMPs. A 2-h treatment with the green tea extract or EGCG prior to the stimulation with LPS resulted in a dose-dependent decrease in MMP secretion, with MMP-9 showing the most significant decrease. A decrease in MMP secretion was also observed when the green tea extract or EGCG was added following a 2-h stimulation with LPS.ConclusionsOur results suggested that green tea catechins, and more specifically EGCG, offer promising prospects for the development of a novel adjunctive treatment for periodontitis because of their ability to decrease the secretion of MMPs, which are important tissue-destructive enzymes produced by mucosal and immune cells.



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Effect of orthodontic force on expression levels of ten cytokines in gingival crevicular fluid

Publication date: Available online 21 January 2017
Source:Archives of Oral Biology
Author(s): Livia Nunes, Luciana Quintanilha, Giuseppe Perinetti, Jonas Capelli Junior
Various types of inflammatory mediators are involved in the cascade of biological events behind tissue remodeling allowing orthodontic tooth movement. This split-mouth longitudinal study aimed to evaluate the gingival crevicular fluid (GCF) levels of ten cytokines, IL-6, IL-8, IL-10, IL-13, IL-17, IFN-γ, GM-CSF, MCP-1, MIP-1β and TNF-α, during initial orthodontic treatment. The sample comprised 15 healthy patients (9 males and 6 females, 13.9±2.5 years). The lower (test) incisors were moved using fixed appliance carrying a 0.014-inch nickel titanium wire, whereas the upper (control) incisors were bonded without any force. The GCF was collected from the test and control teeth before fixed appliance mounting (baseline) and after 1, 7 and 21 days. In 6 sites per tooth, from canine to canine, periodontal conditions were defined as the percentage of sites with visible plaque and bleeding on probing. The total GCF cytokines levels were quantified using multianalysis Luminex technology. Throughout the experimental term, and for both test and control teeth, the mean percentage of sites with visible plaque and bleeding on probing were generally below 25% and 15%, respectively, although variability was also seen. In the test teeth, the GCF levels of all the cytokines remained constant throughout the experimental term. On the contrary, significant reductions were seen in the control teeth for each cytokine. Moreover, significantly greater levels of IL-6, GM-CSF, MCP-1 and TNFα were seen in the test teeth as compared to the control teeth at 7 days. The reasons for the differential behavior in the levels of all the investigated cytokines between the test and control teeth may be related to the presence of orthodontic forces and/or subclinical tissue inflammation. Further investigation is needed to elucidate potential roles for these biomarkers in the tissue remodeling incident to orthodontic tooth movement.



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Announcements

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





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Editorial Board

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





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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.



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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




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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.



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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.



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