OtoRhinoLaryngology News: 12/05/17

Τρίτη 5 Δεκεμβρίου 2017

Can pulpal floor debonding be detected from occlusal surface displacement in composite restorations?

Publication date: Available online 6 December 2017
Source:Dental Materials
Author(s): João Batista Novaes, Elissa Talma, Estevam Barbosa Las Casas, Wondwosen Aregawi, Lauren Wickham Kolstad, Sue Mantell, Yan Wang, Alex Fok
ObjectivesPolymerization shrinkage of resin composite restorations can cause debonding at the tooth–restoration interface. Theory based on the mechanics of materials predicts that debonding at the pulpal floor would half the shrinkage displacement at the occlusal surface. The aim of this study is to test this theory and to examine the possibility of detecting subsurface resin composite restoration debonding by measuring the superficial shrinkage displacements.MethodsA commercial dental resin composite with linear shrinkage strain of 0.8% was used to restore 2 groups of 5 model Class-II cavities (8-mm long, 4-mm wide and 4-mm deep) in aluminum blocks (8-mm thick, 10-mm wide and 14-mm tall). Group I had the restorations bonded to all cavity surfaces, while Group II had the restorations not bonded to the cavity floor to simulate debonding. One of the proximal surfaces of each specimen was sprayed with fine carbon powder to allow surface displacement measurement by Digital Image Correlation. Images of the speckled surface were taken before and after cure for displacement calculation. The experiment was simulated using finite element analysis (FEA) for comparison.ResultsGroup I showed a maximum occlusal displacement of 34.7±6.7μm and a center of contraction (COC) near the pulpal floor. Group II had a COC coinciding with the geometric center and showed a maximum occlusal displacement of 17.4±3.8μm. The difference between the two groups was statistically significant (p-value=0.0007). Similar results were obtained by FEA. The theoretical shrinkage displacement was 44.6 and 22.3μm for Group I and II, respectively. The lower experimental displacements were probably caused by slumping of the resin composite before cure and deformation of the adhesive layer.SignificanceThe results confirmed that the occlusal shrinkage displacement of a resin composite restoration was reduced significantly by pulpal floor debonding. Recent in vitro studies seem to indicate that this reduction in shrinkage displacement could be detected by using the most accurate intraoral scanners currently available. Thus, subject to clinical validation, the occlusal displacement of a resin composite restoration may be used to assess its interfacial integrity.

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Characterization, mechanistic analysis and improving the properties of denture adhesives

Publication date: Available online 6 December 2017
Source:Dental Materials
Author(s): Afsoon Fallahi, Nona Khadivi, Nima Roohpour, Andrew M. Middleton, Mehdi Kazemzadeh-Narbat, Nasim Annabi, Ali Khademhosseini, Ali Tamayol
ObjectiveDenture adhesives are widely used to avoid the detachment and sliding of dentures. However, the adhesion properties can be affected by variation in mouth conditions such as the level of salivation. The objective of this study was to understand the effect of environmental conditions on the adhesion properties of a commercially available denture adhesive named as Poligrip^® Free manufactured by GlaxoSmithKline Ltd., UK and to identify the reasons for the observed variation in its adhesion strength.MethodsThe failure mechanisms of denture adhesive have been assessed through using different physical, mechanical and thermal characterization experiments. All methods were used in different pH, temperatures, and salivation conditions and at the end, a strategy was proposed to overcome the failure of the paste in hyposalivation as well.ResultsIn vitro models mimicking the denture gingival interface were designed to evaluate the adhesion properties of the investigated adhesive. Changes in the adhesion strength in response to three major factors related to the oral conditions including level of salivation, pH, and temperature were measured. The results of lap shear, tensile test, and internal interactions suggested a cohesion failure, where the lowest adhesion strength was due to hyposalivation. Fourier transform infrared spectroscopy (FTIR) and rheological analysis confirmed the importance of hydrogen bonds and hydration in the adhesion strength of the paste.SignificanceThe investigated scenarios are widely observed in patient using denture adhesives and the clinical reports have indicated the inconsistency in adhesion strength of the commercial products. After identifying the potential reasons for such behavior, methods such as the addition of tripropylene glycol methyl ether (TPME) to enhance internal hydrogen bonds between the polymers are proposed to improve adhesion in the hyposalivation scenario.

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Practical and theoretical considerations on the fracture toughness testing of dental restorative materials

Publication date: Available online 6 December 2017
Source:Dental Materials
Author(s): Renan Belli, Michael Wendler, José I. Zorzin, Ulrich Lohbauer
BackgroundAn important tool in materials research, development and characterization regarding mechanical performance is the testing of fracture toughness. A high level of accuracy in executing this sort of test is necessary, with strict requirements given in extensive testing standard documents. Proficiency in quality specimen fabrication and test requires practice and a solid theoretical background, oftentimes overlooked in the dental community. Aims: In this review we go through some fundamentals of the fracture mechanics concepts that are relevant to the understanding of fracture toughness testing, and draw attention to critical aspects of practical nature that must be fulfilled for validity and accuracy in results. We describe our experience with some testing methodologies for CAD/CAM materials and discuss advantages and shortcomings of different tests in terms of errors in testing the applicability of the concept of fracture toughness as a single-value material-specific property.

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Bonding strategies for MIH-affected enamel and dentin

Publication date: Available online 6 December 2017
Source:Dental Materials
Author(s): Norbert Krämer, Ngoc-Han Nana Bui Khac, Susanne Lücker, Vitus Stachniss, Roland Frankenberger
ObjectivesAim of the present study was to evaluate resin composite adhesion to dental hard tissues affected by molar incisor hypomineralisation (MIH).Methods94 freshly extracted human molars and incisors (53 suffering MIH) were used. 68 teeth (35 with MIH) were used for μ-TBS tests in enamel and dentin, 26 (18 with MIH) for qualitative evaluation. Specimens were bonded with Clearfil SE Bond, Scotchbond Universal, and OptiBond FL. For MIH affected enamel, additional OptiBond FL groups with NaOCl and NaOCl+Icon were investigated. Beside fractographic analysis, also qualitative evaluations were performed using SEM at different magnifications as well as histological sectioning.ResultsHighest μ-TBS values were recorded with dentin specimens (ANOVA, mod. LSD, p<0.05). Results were independent of adhesive and dentin substrate (p>0.05). Pre-test failures did not occur in dentin specimens. Sound enamel specimens exhibited significantly higher μ-TBS values than MIH enamel (p<0.05). The two-step self-etch adhesive (Clearfil SE Bond) and the two-step etch-and-rinse adhesive (Scotchbond Universal) showed the lowest values in affected enamel specimens (p<0.05) with most pre-test failures (p<0.05). OptiBond FL on affected enamel showed better results than Clearfil SE Bond (p<0.05). An additional pre-treatment of affected enamel with NaOCl or NaOCl and Icon did not enhance enamel bonding (p>0.05), however, it caused less pre-test failures (p<0.05). Micromorphological analyses revealed that conventional phosphoric acid etching produces a much less pronounced etching pattern in affected enamel and a porous structure as weak link for the resin-enamel bond was identified.SignificanceBonding to porous hypomineralized MIH enamel is the limiting factor in adhesion to MIH teeth. MIH-affected dentin may be bonded conventionally.

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Photopolymerization of cell-laden gelatin methacryloyl hydrogels using a dental curing light for regenerative dentistry

Publication date: Available online 6 December 2017
Source:Dental Materials
Author(s): Nelson Monteiro, Greeshma Thrivikraman, Avathamsa Athirasala, Anthony Tahayeri, Cristiane M. França, Jack L. Ferracane, Luiz E. Bertassoni
Photopolymerized hydrogels, such as gelatin methacryloyl (GelMA), have desirable biological and mechanical characteristics for a range of tissue engineering applications.ObjectiveThis study aimed to optimize a new method to photopolymerize GelMA using a dental curing light (DL).MethodsLithium acylphosphinate photo-initiator (LAP, 0.05, 0.067, 0.1% w/v) was evaluated for its ability to polymerize GelMA hydrogel precursors (10% w/v) encapsulated with odontoblast-like cells (OD21). Different irradiances (1650, 2300 and 3700mW/cm²) and photo-curing times (5–20s) were tested, and compared against the parameters typically used in UV light photopolymerization (45mW/cm², 0.1% w/v Irgacure 2959 as photoinitiator). Physical and mechanical properties of the photopolymerized GelMA hydrogels were determined. Cell viability was assessed using a live and dead assay kit.ResultsComparing DL and UV polymerization methods, the DL method photopolymerized GelMA precursor faster and presented larger pore size than the UV polymerization method. The live and dead assay showed more than 80% of cells were viable when hydrogels were photopolymerized with the different DL irradiances. However, the cell viability decreased when the exposure time was increased to 20s using the 1650mW/cm² intensity, and when the LAP concentration was increased from 0.05 to 0.1%. Both DL and UV photocrosslinked hydrogels supported a high percentage of cell viability and enabled fabrication of micropatterns using a photolithography microfabrication technique.SignificanceThe proposed method to photopolymerize GelMA cell-laden hydrogels using a dental curing light is effective and represents an important step towards the establishment of chair-side procedures in regenerative dentistry.

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STRO-1 confers myofibroblast transdifferentiation in fibroblasts derived from oral submucous fibrosis

Abstract

Background

STRO-1 is a mesenchymal cell marker present on all clonogenic stromal precursors. Current evidence has indicated that the pathogenesis of fibrotic changes may be mediated by stemness properties. The aim of this study was to investigate the role of STRO-1 in areca quid chewing-associated oral submucous fibrosis (OSF).

Methods

Thirty OSF specimens and ten normal buccal mucosa were examined by immunohistochemistry. The activity of STRO-1 from fibroblasts cultured from normal buccal mucosa (BMFs) and OSF (OSFFs) were measureed and the effects of arecoline, a major areca nut alkaloid, on STRO-1 in BMFs. Compared the activities between sorted STRO-1⁺ cells and STRO-1^- cells from OSFF were measured by collagen gel contraction, migration, invasion abilities, and the expression of α-smooth muscle actin (α-SMA) and pro-α1 (I) chain of type I collagen.

Results

Our results first showed that the expression of STRO-1 was more evident in areca quid chewing-associated OSF than normal buccal mucosa tissues (p<0.05). Arecoline dose-dependently activated the level of STRO-1 in BMFs (p<0.05). The relative expression of STRO-1 was significantly higher in OSFFs compared with BMFs (p<0.05). In addition, the sorted STRO-1⁺ cells from OSFFs exhibited higher collagen gel contraction, migration, and invasion abilities as well as elevated expression of α-SMA and pro-α1 (I) chain of type I collagen than the negative subset (p<0.05).

Conclusion

These findings suggested that the stemness marker STRO-1 may be a crucial factor in the pathogenesis of areca quid chewing-associated OSF.

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Executive functioning, academic skills, and quality of life in pediatric patients with brain tumors post-proton radiation therapy

Abstract

Radiation therapy (RT) is integral in the treatment of pediatric brain tumors; however, photon RT (XRT) often results in intellectual decline, executive functioning (EF) deficits, academic underachievement/failure, and lower health-related quality of life (HRQoL). Proton RT (PRT) provides more targeted therapy, minimizing damage to the developing brain, yet few studies have examined its neuropsychological effects. This study investigated the role of EF in academic skills and HRQoL in a sample of children treated with PRT. A mediation model was proposed in which academic skills mediated relations between aspects of EF and school-based HRQoL (sHRQoL). Sixty-five children (x̅_age = 12.4; 43.9% male) treated with PRT completed follow-up neuropsychological testing as part of routine care. Measures included assessment of intellectual functioning, EF, attention, and academic skills (reading, math, spelling). Parents reported on children's EF and attention problems. sHRQoL was assessed via child self-report. Children who underwent PRT demonstrated relatively intact intelligence, academics, attention, EF, and sHRQoL, but were at risk for reduced processing speed. Poorer working memory and processing speed were related to lower sHRQoL. Better EF and faster processing speed were associated with better academic skills, which were linked to higher sHRQoL. Better working memory was associated with better math performance, which was linked to higher sHRQoL; this relationship did not hold for reading or spelling. Results highlight the importance of EF skills in academic performance and sHRQoL, and the need for routine screening of EF deficits and proactive supports. Supports may include cognitive rehabilitation and in-class accommodations. Overall, results compare favorably to XRT outcomes reported in the literature.

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MassARRAY-based simultaneous detection of hotspot somatic mutations and recurrent fusion genes in papillary thyroid carcinoma: the PTC-MA assay

Abstract

Purpose

We exploited the MassARRAY (MA) genotyping platform to develop the "PTC-MA assay", which allows the simultaneous detection of 13 hotspot mutations, in the BRAF, KRAS, NRAS, HRAS, TERT, AKT1, PIK3CA, and EIF1AX genes, and six recurrent genetic rearrangements, involving the RET and TRK genes in papillary thyroid cancer (PTC).

Methods

The assay was developed using DNA and cDNA from 12 frozen and 11 formalin-fixed paraffin embedded samples from 23 PTC cases, together with positive and negative controls.

Results

The PTC-MA assay displays high sensitivity towards point mutations and gene rearrangements, detecting their presence at frequencies as low as 5%. Moreover, this technique allows quantification of the mutated alleles identified at each tested locus.

Conclusions

The PTC-MA assay is a novel MA test, which is able to detect fusion genes generated by genomic rearrangements concomitantly with the analysis of hotspot point mutations, thus allowing the evaluation of key diagnostic, prognostic, and therapeutic markers of PTC in a single experiment without any informatics analysis. As the assay is sensitive, robust, easily achievable, and affordable, it is suitable for the diagnostic practice. Finally, the PTC-MA assay can be easily implemented and updated by adding novel genetic markers, according to clinical requirements.

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Diets rich in saturated fat and fructose induce anxiety and depression-like behaviours in the rat: is there a role for lipid peroxidation?

Summary

Epidemiological studies reveal associations between obesity/metabolic syndrome and mood disorders. We assessed behavioural changes in rats fed diets enriched in fat and fructose in different proportions and correlated the observed alterations with biochemical changes induced by the diets. Three groups of rats were used as follows: control (C) animals fed regular rat chow, rats fed high-fat diet (HF) and rats fed high-fat and high-fructose diet (HFHF). HF and HFHF animals were also given a 10% fructose solution as drinking water. Behavioural and biochemical parameters were determined. Anxiety was measured by the open-field and the social interaction test. Depression-like behaviour was evaluated by the forced swimming test. The object recognition test was utilized to assess effects on memory. Diet-exposed animals displayed signs of anxiety in the open-field (HF rats had reduced central time; HFHF rats had reduced number of central entries) and in the social interaction test (decreased time of interaction in HF group). In the forced swimming test, the immobility time was prolonged in the HFHF group. While different measures of anxiety scores correlated with visceral adiposity and dyslipidemia, results from both social interaction and forced swimming tests were significantly associated with lipid peroxidation, which in turn also correlated with the metabolic parameters. The experimental diets did not affect the object recognition memory. Both experimental diets induced metabolic derangements in rats and provoked similar anxiety- and depression-like behaviours. Lipid peroxidation seems to play a role in translating diet-induced metabolic alterations into behavioural disorders.

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The Turkish validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery

Cognitive impairment may be seen in as many as 43–70% of patients with multiple sclerosis (MS) and may be observed in all MS subtypes. The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS...

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3-D motion capture for long-term tracking of spontaneous locomotor behaviors and circadian sleep/wake rhythms in mouse

Publication date: 1 February 2018
Source:Journal of Neuroscience Methods, Volume 295
Author(s): Melissa Sourioux, Emma Bestaven, Etienne Guillaud, Sandrine Bertrand, Magali Cabanas, Lea Milan, Willy Mayo, Maurice Garret, Jean-René Cazalets
BackgroundLocomotor activity provides an index of an animal's behavioral state. Here, we report a reliable and cost-effective method that allows long-term (days to months) simultaneous tracking of locomotion in mouse cohorts (here consisting of 24 animals).New methodThe technique is based on a motion capture system used mainly for human movement study. A reflective marker was placed on the head of each mouse using a surgical procedure and labeled animals were returned to their individual home cages. Camera-recorded data of marker displacement resulting from locomotor movements were then analyzed with custom built software. To avoid any data loss, data files were saved every hour and automatically concatenated. Long-term recordings (up to 3 months) with high spatial (<1mm) and temporal (up to 100Hz) resolution of animal movements were obtained.ResultsThe system was validated by analyzing the spontaneous activity of mice from post-natal day 30–90. Daily motor activity increased up to 70days in correspondence with maturational changes in locomotor performance. The recorded actigrams also permitted analysis of circadian and ultradian rhythms in cohort sleep/wake behavior.Comparison with existing method(s)In contrast to traditional session-based experimental approaches, our technique allows locomotor activity to be recorded with minimal experimenter manipulation, thereby minimizing animal stress.ConclusionsOur method enables the continuous long-term (up to several months) monitoring of tens of animals, generating manageable amounts of data at minimal costs without requiring individual dedicated devices. The actigraphic data collected allows circadian and ultradian analysis of sleep/wake behaviors to be performed.

Graphical abstract

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Interleukin-17 regulates matrix metalloproteinase activity in human pulmonary tuberculosis

Abstract

Tuberculosis (TB) is characterised by extensive pulmonary matrix breakdown. Interleukin-17 (IL-17) is key in host defence in TB but its role in TB-driven tissue damage is unknown. We investigated the hypothesis that respiratory stromal cell matrix metalloproteinase (MMP) production in TB is regulated by T helper-17 (T_H-17) cytokines. Biopsies of patients with pulmonary TB were analysed by immunohistochemistry (IHC) and patient bronchoalveolar lavage fluid (BALF) MMP and cytokine concentrations measured by Luminex assays. Primary human airway epithelial cells were stimulated with conditioned medium from human monocytes infected with Mycobacterium tuberculosis (Mtb) and T_H-17 cytokines. MMP secretion, activity and gene expression were determined by ELISA, Luminex assay, zymography, RT-qPCR and dual luciferase reporter assays. Signalling pathways were examined using phospho-western analysis and siRNA. IL-17 is expressed in TB patient granulomas and MMP-3 is expressed in adjacent pulmonary epithelial cells. IL-17 had a divergent, concentration-dependent effect on MMP secretion, increasing epithelial secretion of MMP-3 (p<0.001) over 72 h whilst decreasing that of MMP-9 (p<0.0001); mRNA levels were similarly affected. Both IL-17 and Interleukin-22 (IL-22) increased fibroblast Mtb-dependent MMP-3 secretion but IL-22 did not modulate epithelial MMP-3 expression. Both IL-17 and IL-22, but not Interleukin-23 (IL-23), were significantly upregulated in BALF from TB patients. IL-17-driven MMP-3 was dependent on p38 MAP kinase and the PI 3-K p110α subunit. In summary, IL-17 drives airway stromal cell-derived MMP-3, a mediator of tissue destruction in TB, alone and with monocyte-dependent networks in TB. This is regulated by p38 MAP kinase and PI3-K pathways.

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Massive cortical reorganization is reversible following bilateral transplants of the hands: evidence from the first successful bilateral pediatric hand transplant patient

Abstract

In this repeated measures case study, we show that sensory deafferentation after limb amputation leads to changes in cortical somatotopic maps which are reversible after restoration of sensory input. Using magnetoencephalography (MEG), we observed in a child with bilateral hand transplants large-scale shifts in somatosensory lip cortical representation from anatomic hand area to anatomic face region. After recovery of tactile sensation in the digits, responses to finger stimulation were localized to orthotopic sensory cortex, but with atypical electrophysiologic features (amplitude and frequencies).

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Accuracy of computer-assisted orthognathic surgery

Publication date: Available online 5 December 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Giacomo De Riu, Paola Ilaria Virdis, Silvio Mario Meloni, Aurea Lumbau, Luigi Angelo Vaira
IntroductionThe purpose of this study was to retrospectively evaluate the difference between the planned and the actual movements of the jaws, using three-dimensional (3D) software for PC-assisted orthognathic surgery, to establish the accuracy of the procedure.Material and MethodsA retrospective study was performed with 49 patients who had undergone PC-guided bimaxillary surgery. The accuracy of the protocol was determined by comparing planned movements of the jaws with the actual surgical movements, analysing frontal and lateral cephalometries.ResultsThe overall results were deemed accurate, and differences among 12 the of 15 parameters were considered nonsignificant. Significant differences were reported for SNA (p = 0.008), SNB (p = 0.006), and anterior facial height (p = 0.033). The latter was significantly different in patients who had undergone genioplasty when compared with patients who had not.ConclusionVirtual surgical planning presented a good degree of accuracy for most of the parameters assessed, with an average error of 1.98 mm for linear measures and 1.19° for angular measures. In general, a tendency towards under-projection in jaws was detected, probably due to imperfect condylar seating. A slight overcorrection of SNA and SNB during virtual planning (approximately 2°) could be beneficial. Further progress is required in the development of 3D simulation of the soft tissue, which currently does not allow an accurate management of the facial height and the chin position.Virtual planning cannot replace the need for constant intraoperative monitoring of the jaws' movements and real-time comparisons between planned and actual outcomes. It is therefore appropriate to leave some margin for correction of inaccuracies in the virtual planning. In this sense, it may be appropriate to use only the intermediate splint, and then use the planned occlusion and clinical measurements to guide repositioning of the second jaw and chin, respectively.

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Minimizing Bacteria Around Macrotextured Breast Implants

Find out how to reduce the number of bacteria around macrotextured breast implants to prevent the incidence of implant-associated anaplastic large-cell lymphoma.
Plastic and Reconstructive Surgery

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Orbital cellulitis secondary to dacryocystitis: Is it common?

Publication date: Available online 6 December 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): Salman bin Amiruddin, Balwant Singh Gendeh

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An epidemiological study of 270 cases of carcinomas of the head and neck region in a Nigerian tertiary health care facility

Publication date: Available online 6 December 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): B. Fomete, R. Agbara, E.T. Adebayo, O.D. Osunde, D.S. Adeola
IntroductionOral cancer is the sixth most frequently occurring malignant tumor and is the major cause of morbidity and mortality with high metastatic and invasive tendency. The incidence of oral cancer differs widely in various parts of the world with a range of 2–10 per 100,000 populations per year, approximately 300,000 new cases. Incidence and mortality as a result of oral cancer are higher in developing countries when compared to developed countries. This is the reason for the occurrence of the peak age in later decades of life.Patients and methodsAll consecutive cases of histologically diagnosed cases of orofacial carcinomas seen at the Maxillofacial Unit, Ahmadu Bello University Teaching Hospital, Shika, Zaria, Nigeria over a 10 year period were retrospectively analyzed.ResultsOver the study period, a total of 1116 cases of maxillofacial conditions were seen in the unit out of which 270 represented orofacial cancers, giving a prevalence of 24.19%. Of the 270 cases, male accounted for 159(58.9%) while females were 111(41.1%) giving a male to female ratio of 1.43:1. The age ranged from 5 to 90 years, mean (SD), 48.4(16.12) years and patients in the 4th to 6th decades (47.7%) were mostly affected. There was no gender difference in terms of distribution of the tumors according to age.ConclusionSquamous cell carcinoma of the orofacial region has continued to pose great challenges to care givers and practitioners involved in their management.

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Study of interactions between odorant molecules and the hOR1G1 olfactory receptor by molecular modeling

Publication date: Available online 6 December 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): Assia Belhassan, Hanane Zaki, Samir Chtita, Mohamed Benlyas, Tahar Lakhlifi, Mohammed Bouachrine
In order to initiate the process of determining how the molecular level receptor-odorant interactions are related to odor perception, we used the SWISS-MODEL modeling server to predict the three dimensional (3D) structure of the human olfactory receptor (hOR1G1). The model was refined using minimization and side-chain optimization using SCWRL. We then used the Autodockvina and Autodock tools to predict the binding site and binding energy for the library of 13 odorants characterized by different retention/release property values to hOR1G1 receptor, to investigate the relationship between this property and the ligand-hOR1G1 interactions. We find that when the retention property increases, hydrogen bond interactions between ligands and olfactory receptor (hOR1G1) become favorable.

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Editorial Board

Publication date: July 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences, Volume 18, Issue 2

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The association between cardiovascular disease and type 2 diabetes in adults with atopic dermatitis: a systematic review and meta-analysis

Abstract

Recent studies examining the association between atopic dermatitis (AD) and cardiovascular disease (CVD) and type 2 diabetes have shown inconsistent results. We compared the risk of CVD and diabetes between adult patients with and without AD by searching the Pubmed, Embase, and Web of Science databases. Data extraction was done by two independent reviewers. We found a total of 2,855 citations, of which 53 were considered relevant based on title and abstract. Sixteen publications were included in the qualitative analysis, of which 13 were also included in a quantitative meta-analysis of crude data. No association was observed between AD and unspecified, but suspected type 2, diabetes (pooled odds ratio [OR] 1.11; 95% confidence interval [CI] 0.87-1.42), hypertension (pooled OR 1.16; 95% CI 0.98-1.37), stroke (pooled OR 1.15; 95% CI 0.95-1.39) or myocardial infarction (pooled OR 1.14; 95% CI 0.83-1.56), but a positive association was observed with angina pectoris (OR 1.73; 95% CI 1.27-2.37). Meta-analysis on adjusted data gave similar results. While adults with AD in some populations have increased prevalence of cardiovascular risk factors, such as obesity and smoking, it is unlikely that AD represents an independent and clinically relevant risk factor for cardiometabolic disease.

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Accuracy of computer-assisted orthognathic surgery

Towards understanding the dose and timing effect of hydrocortisone treatment on the scleral ossicle system within the chicken eye

Abstract

Previous work, almost four decades ago, showed that hydrocortisone (HC) treatment reduces the number of skeletogenic condensations that give rise to the scleral ossicles in the chicken eye. The scleral ossicles are a ring of overlapping intramembranous bones, the sclerotic ring, and are present in most reptiles, including birds. The scleral condensations that give rise to the scleral ossicles are induced by a series of overlying thickenings (or papillae) of the conjunctival epithelium. Here, we further explore the effects of altering the dosage and timing of HC treatment on the morphology and number of skeletogenic condensations and conjunctival papillae. We show that high doses can completely obliterate the entire sclerotic ring. Significantly, the reduction in papillae number we observed was less extreme than that of the scleral condensations, indicating that additional factors contribute to the observed skeletogenic condensation loss. Via immunohistochemical analyses, we show that HC treatment alters the spatial expression pattern of several extracellular matrix components (tenascin-C, decorin and procollagen I) and also alters the vasculature network within the sclera. This research provides important insights into understanding the role of the scleral tissue components in ossicle development within the vertebrate eye.

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Calpain-2 inhibitor treatment preferentially reduces tumor progression for human colon cancer cells expressing highest levels of this enzyme

Abstract

Calpain-2 levels are higher in colorectal tumors resistant to chemotherapy and previous work showed calpain-2 inhibitor therapy reduced inflammation-driven colorectal cancer, but direct effects of the inhibitor on colon cancer cells themselves were not demonstrated. In the present study, five human colon cancer cell lines were directly treated with a calpain-2 inhibitor and results showed increased cell death in 4 of 5 cell lines and decreased anchorage-independent growth for all cell five lines. When tested for levels of calpain-2, three cell lines exhibited increasing levels of this enzyme: HCT15 (low), HCC2998 (medium), and HCT116 (significantly higher). This was consistent with gel shift assays showing that calpain-2 inhibitor reduced of NF-κB nuclear translocation most effectively in HCT116 cells. Ability of calpain-2 inhibitor to impede tumor progression in vivo was evaluated using intrarectal transplant of luciferase-expressing cells for these three cell lines. Results showed that calpain-2 inhibitor therapy reduced tumor growth and increased survival only in mice injected with HCT116 cells. These data suggest calpain-2 inhibitor treatment may be most effective on colorectal tumors expressing highest levels of calpain-2.

Calpain-2 inhibitor therapy reduces inflammation in the colon, but its direct effects on colon cancer cells are unknown. This study shows in vitro and in vivo that calpain-2 inhibitor has the strongest therapeutic effects on colon cancer cells expressing the highest levels of calpain-2.

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[ 18 F]-BMS-747158-02PET imaging for evaluating hepatic mitochondrial complex 1dysfunction in a mouse model of non-alcoholic fatty liver disease

Abstract

Background

Mitochondrial dysfunction is one of the main causes of non-alcohol fatty liver disease (NAFLD). [¹⁸F]-BMS-747158-02 (¹⁸F-BMS) which was originally developed as a myocardial perfusion imaging agent was reported to bind mitochondrial complex-1 (MC-1). The aim of this study was to investigate the potential use of ¹⁸F-BMS for evaluating hepatic MC-1 activity in mice fed a methionine- and choline-deficient (MCD) diet.

Male C57BL/6J mice were fed a MCD diet for up to 2 weeks. PET scans with ¹⁸F-BMS were performed after 1 and 2 weeks of the MCD diet. ¹⁸F-BMS was intravenously injected into mice, and the uptake (standardized uptake value (SUV)) in the liver was determined. The binding specificity for MC-1 was assessed by pre-administration of rotenone, a specific MC-1 inhibitor. Hepatic MC-1 activity was measured using liver homogenates generated after each positron emission tomography (PET) scan. Blood biochemistry and histopathology were also assessed.

Results

In control mice, hepatic ¹⁸F-BMS uptake was significantly inhibited by the pre-injection of rotenone. The uptake of ¹⁸F-BMS was significantly decreased after 2 weeks of the MCD diet. The SUV at 30–60 min was well correlated with hepatic MC-1 activity (r = 0.73, p < 0.05). Increases in plasma ALT and AST levels were also noted at 1 and 2 weeks. Mild hepatic steatosis with or without minimal inflammation was histopathologically observed at 1 and 2 weeks in mice liver on the MCD diet. However, inflammation was observed only at 2 weeks in mice on the MCD diet.

Conclusions

The present study demonstrated that ¹⁸F-BMS is a potential PET probe for quantitative imaging of hepatic MC-1 activity and its mitochondrial dysfunction induced by steatosis and inflammation, such as in NAFLD.

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Sugar-based collagen membrane cross-linking increases barrier capacity of membranes

Abstract

Objectives

This study examines the permeability and barrier capacity of a sugar cross-linked resorbable collagen membrane ex vivo and in vivo.

Materials and methods

In an ex vivo study, injectable platelet-rich fibrin (i-PRF), a peripheral blood-derived human leukocyte-and-platelet-rich plasma was used to analyze membrane permeability. in vivo subcutaneous implantation in Wistar rats (n = 4 per time point and group) was used to investigate the barrier capacity of the membrane. The induced in vivo cellular reaction was evaluated at 3, 15, and 30 days and compared to sham OP (control) without biomaterial using histological, immunohistochemical, and histomorphometric methods.

Results

Ex vivo, the membrane was impenetrable to leukocytes, platelets, and fibrin from peripheral human blood concentrate (PRF). In vivo, the membrane maintained its structure and remained impervious to cells, connective tissue, and vessels over 30 days. CD-68-positive cell (macrophage) numbers significantly decreased from 3 to 15 days, while from day 15 onwards, the number of multinucleated giant cells (MNGCs) increased significantly. Correspondingly, a rise in implantation bed vascularization from 15 to 30 days was observed. However, no signs of degradation or material breakdown were observed at any time point.

Conclusion

Ex vivo and in vivo results showed material impermeability to cellular infiltration of human and murine cells, which highlights the membrane capacity to serve as a barrier over 30 days. However, whether the induced MNGCs will lead to material degradation or encapsulation over the long term requires further investigation.

Clinical relevance

The data presented are of great clinical interest, as they contribute to the ongoing discussion concerning to what extent an implanted material should be integrated versus serving only as a barrier membrane.

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Radiomics based analysis to predict local control and survival in hepatocellular carcinoma patients treated with volumetric modulated arc therapy

Abstract

Background

To appraise the ability of a radiomics based analysis to predict local response and overall survival for patients with hepatocellular carcinoma.

Methods

A set of 138 consecutive patients (112 males and 26 females, median age 66 years) presented with Barcelona Clinic Liver Cancer (BCLC) stage A to C were retrospectively studied. For a subset of these patients (106) complete information about treatment outcome, namely local control, was available. Radiomic features were computed for the clinical target volume. A total of 35 features were extracted and analyzed. Univariate analysis was used to identify clinical and radiomics significant features. Multivariate models by Cox-regression hazards model were built for local control and survival outcome. Models were evaluated by area under the curve (AUC) of receiver operating characteristic (ROC) curve. For the LC analysis, two models selecting two groups of uncorrelated features were analyzes while one single model was built for the OS analysis.

Results

The univariate analysis lead to the identification of 15 significant radiomics features but the analysis of cross correlation showed several cross related covariates. The un-correlated variables were used to build two separate models; both resulted into a single significant radiomic covariate: model-1: energy p < 0.05, AUC of ROC 0.6659, C.I.: 0.5585–0.7732; model-2: GLNU p < 0.05, AUC 0.6396, C.I.:0.5266–0.7526.

The univariate analysis for covariates significant with respect to local control resulted in 9 clinical and 13 radiomics features with multiple and complex cross-correlations. After elastic net regularization, the most significant covariates were compacity and BCLC stage, with only compacity significant to Cox model fitting (Cox model likelihood ratio test p < 0.0001, compacity p < 0.00001; AUC of the model is 0.8014 (C.I. = 0.7232–0.8797)).

Conclusion

A robust radiomic signature, made by one single feature was finally identified. A validation phases, based on independent set of patients is scheduled to be performed to confirm the results.

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Concordance of FDG PET/CT metabolic tumour volume versus DW-MRI functional tumour volume with T2-weighted anatomical tumour volume in cervical cancer

Abstract

Background

¹⁸F–fluoro-deoxyglucose positron emission tomography with computed tomography (FDG PET/CT) has been employed to define radiotherapy targets using a threshold based on the standardised uptake value (SUV), and has been described for use in cervical cancer. The aim of this study was to evaluate the concordance between the metabolic tumour volume (MTV) measured on FDG PET/CT and the anatomical tumour volume (ATV) measured on T2-weighted magnetic resonance imaging (T2W-MRI); and compared with the functional tumour volume (FTV) measured on diffusion-weighted MRI (DW-MRI) in cervical cancer, taking the T2W-ATV as gold standard.

Methods

Consecutive newly diagnosed cervical cancer patients who underwent FDG PET/CT and DW-MRI were retrospectively reviewed from June 2013 to July 2017.

Volumes of interest was inserted to the focal hypermetabolic activity corresponding to the cervical tumour on FDG PET/CT with automated tumour contouring and manual adjustment, based on SUV 20%–80% thresholds of the maximum SUV (SUVmax) to define the MTV_20–80, with intervals of 5%.

Tumour areas were manually delineated on T2W-MRI and multiplied by slice thickness to calculate the ATV.

FTV were derived by manually delineating tumour area on ADC map, multiplied by the slice thickness to determine the FTV_(manual). Diffusion restricted areas was extracted from b0 and ADC map using K-means clustering to determine the FTV_{(semi-automated)}.

The ATVs, FTVs and the MTVs at different thresholds were compared using the mean and correlated using Pearson's product-moment correlation.

Results

Twenty-nine patients were evaluated (median age 52 years). Paired difference of mean between ATV and MTV was the closest and not statistically significant at MTV₃₀ (−2.9cm³, −5.2%, p = 0.301). This was less than the differences between ATV and FTV_{(semi-automated)} (25.0cm³, 45.1%, p < 0.001) and FTV_(manual) (11.2cm³, 20.1%, p = 0.001). The correlation of MTV₃₀ with ATV was excellent (r = 0.968, p < 0.001) and better than that of the FTVs.

Conclusions

Our study demonstrated that MTV₃₀ was the only parameter investigated with no statistically significant difference with ATV, had the least absolute difference from ATV, and showed excellent positive correlation with ATV, suggesting its superiority as a functional imaging modality when compared with DW-MRI and supporting its use as a surrogate for ATV for radiotherapy tumour contouring.

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Overexpression of Cullin7 is associated with hepatocellular carcinoma progression and pathogenesis

Abstract

Background

Overexpression of Cullin7 is associated with some types of malignancies. However, the part of Cullin7 in hepatocellular carcinoma remains unclear. The aim of this study was to investigate the role of Cullin7 in pathogenesis and the progression of hepatocellular carcinoma.

Methods

In the present study, the expression of Cullin7 in hepatocellular carcinoma cell lines and five surgical hepatocellular carcinoma specimens was detected with quantitative reverse transcription PCR and western blotting. In addition, the protein expression of Cullin7 was examined in 162 cases of archived hepatocellular carcinoma using immunohistochemistry.

Results

We found elevated expression of both mRNA and protein levels of Cullin7 in hepatocellular carcinoma cell lines, and Cullin7 protein was significantly upregulated in hepatocellular carcinoma compared with paired normal hepatic tissues. The immunohistochemistry analysis revealed that overexpression of Cullin7 occurred in 69.1% of hepatocellular carcinoma samples, which was a significantly higher rate than that in adjacent normal hepatic tissue (P < 0.01). Statistical analysis found that overexpression of Cullin7 was significantly associated with lymph node metastasis, tumor thrombus of the portal vein and advanced clinical stage (P < 0.05). Furthermore, by overexpressing Cullin7 in hepatocellular carcinoma HepG2 cells, we revealed that Cullin7 could significantly enhance cell proliferation, growth, migration and invasion. Conversely, knocking down Cullin7 expression with short hairpin RNAi in hepatocellular carcinoma HepG2 cells inhibited cell proliferation, growth, migration and invasion.

Conclusion

Our studies provide evidence that overexpression of Cullin7 plays an important role in the pathogenesis and progression of hepatocellular carcinoma and may be a valuable marker for hepatocellular carcinoma management.

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Study protocol for a cluster-randomized trial to compare human papillomavirus based cervical cancer screening in community-health campaigns versus health facilities in western Kenya

Abstract

Background

Despite guidelines for cervical cancer prevention in low-resource countries, a very small proportion of women in these settings undergo screening, and even fewer women are successfully treated. Using pilot data from western Kenya and World Health Organization recommendations, we developed a protocol to implement evidence-based cervical cancer screening and linkage to treatment strategies to the rural communities. We describe the protocol for a cluster-randomized trial to compare two implementation strategies for human-papillomavirus (HPV)-based cervical cancer screening program using metrics described in the RE-AIM (reach, efficacy, adaption, implementation and maintenance) framework.

Methods

The study is a three-year, two-phase cluster-randomized trial in 18 communities in western Kenya. During Phase 1, six control communities were offered screening in health facilities; and six intervention communities were offered screening in community health campaigns. Screening was done with human-papillomavirus testing through self-collected specimens. Phase 1 ended and we are working in partnership with communities to further contextualize the implementation strategy for screening, and develop an enhanced linkage to treatment plan. This plan will be tested in an additional six communities in Phase 2 (enhanced intervention). We will compare the reach, efficacy, cost-effectiveness and adaptability of the implementation strategies.

Discussion

Effective low-cost cervical cancer prevention technologies are becoming more widely available in low- and middle-income countries. Despite increasing government support for cervical cancer prevention, there remains a sizeable gap in service availability. We will use implementation science to identify the most effective strategies to fill this gap through development of context-specific evidence-based solutions. This protocol design and results can help guide implementation of cervical cancer screening in similar settings, where women are most underserved and at highest risk for disease.

Trial registration

This trial is registered at ClinicalTrials.gov, NCT02124252.

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Decreased expression of the β 2 integrin on tumor cells is associated with a reduction in liver metastasis of colorectal cancer in mice

Abstract

Background

Lymphocyte Function-Associated Antigen-1 (LFA-1; CD18/CD11a) is one of the main adhesion molecules used by immune cells to infiltrate the liver under inflammatory conditions. Recently, the expression of this integrin has also been reported on several solid tumors, including colorectal cancer. However, its functional role in the metastatic progression to the liver remains unknown. Using in vitro assays and an experimental orthotopic in vivo model of liver metastasis, we aimed to elucidate the role of tumor LFA-1 in the metastatic progression by means of the partial depletion of the β₂ subunit of LFA-1, required for integrin activation, firm adhesion and signaling.

Methods

To do so, we evaluated the effects of β₂ reduction on the murine colon carcinoma C26 cell line on their pro-metastatic features in vitro and their metastatic potential in vivo in a mouse model of colon carcinoma metastasis to the liver.

Results

The reduction in β₂ integrin expression correlated with a slower proliferation, and a reduced adhesion and migration of C26 cells in an in vitro setting. Additionally, tumor cells with a reduced in β₂ integrin expression were unable to activate the liver sinusoidal endothelial cells (LSECs). This resulted in a recovery of the cytotoxic potential of liver lymphocytes which is compromised by LSECs activated by C26 cells. This was related to the abrogation of RNA expression of inflammatory and angiogenic cytokines by C26 cells after their activation with sICAM-1, the main ligand of β₂α_L. Furthermore, in vivo tumor cell retention and metastasis were profoundly reduced, along with a decrease in the recruitment and infiltration of myeloid derived suppressor cells (MDSCs) and lymphocytes to the liver.

Conclusion

Taken together, our findings uncovered the modulatory role for the tumor β₂ subunit of the LFA-1 integrin in the metastatic progression of colorectal cancer to the liver by impairing activation of liver endothelium and thus, the local immune response in the liver. Besides, this integrin also showed to be critical in vivo for tumor cell retention, cytokine release, leukocyte recruitment and metastasis development. These data support a therapeutical potential of the integrin LFA-1 as a target for the treatment of colorectal liver metastasis.

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Editorial Board

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News and announcement

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Reliability of temporal bone high-resolution CT in patients with facial paralysis in temporal bone fracture

Publication date: Available online 5 December 2017
Source:American Journal of Otolaryngology
Author(s): Yaofeng Chen, Kai Zhang, Yanfeng Xu, Yanxu Che, Linna Guan, Yefeng Li
ObjectiveThis study aimed to investigate the reliability of temporal bone high-resolution CT (HRCT) in patients with traumatic facial paralysis.MethodsHRCT with cross-sectional scanning and multi-planar reformation (MPR) was performed on 26 cases with traumatic facial paralysis, and the preoperative imaging manifestations were compared with surgical findings.ResultsPreoperative HRCT revealed fallopian canal damage at the posterior genu in 1 case, geniculate ganglion in 22 cases, labyrinthine segment in 4 cases, tympanic segment in 13 cases and mastoid segment in 0 case, while surgical findings confirmed fallopian canal damage at the posterior genu in 7 cases, geniculate ganglion in 23 cases, labyrinthine segment in 4 cases, tympanic segment in 17 cases and mastoid segment in 7 cases. The accuracy of temporal bone HRCT in revealing damage at those segments of fallopian canal was 14.3%, 95.7%, 100%, 76.5, and 0%, respectively.ConclusionTemporal bone HRCT can generally estimate the extent of damage and provide important information for traumatic facial paralysis before surgery. However, it is unreliable in revealing the damage of fallopian canal at the posterior genu and mastoid segment.

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Intestinal permeability and Ménière's disease

Publication date: Available online 5 December 2017
Source:American Journal of Otolaryngology
Author(s): F. Di Berardino, E. Ciusani, C. Caccia, V. Leoni, U. De Grazia, E. Filipponi, D. Zanetti, L. Elli
PurposeMénière disease (MD) is a multifactorial chronic disabling condition characterized by episodic vertigo, ear fullness, and hearing loss. MD patients often complain of aspecific gastrointestinal symptoms associated with autonomic dysregulation, frequently outweighed by the otological manifestations. Dietary modifications have been reported to improve the typical MD symptoms in some cases. Our purpose was to test the urinary levels of lactulose and mannitol (double sugar test) and the fecal calprotectin, both markers of altered intestinal permeability, in subjects with definite MD in an active and inactive stage.Materials and methodsTwenty-six with definite unilateral MD were studied: 14 patients were symptomatic for at least 3months with moderate to severe vertigo spells and a functional level ≥4; 12 patients had been asymptomatic (no vertigo spells) for at least 3months and had a functional level=1 at the time of testing. Twenty healthy volunteers were recruited as "control group".ResultsLactulose and mannitol absorption was significantly increased in the symptomatic M patients compared to the asymptomatic group (p<0.02 and p<0.004, respectively) and to the controls. FC were also higher than normal only in the symptomatic group. (p<0.01).ConclusionsAn altered intestinal permeability, according to the two assays, was found only in symptomatic MD patients. The rationale for a possible relationship between MD and intestinal permeability is forwarded. The double-sugar test and FC quantification might be implemented in the MD diagnostic workup.

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Symptomatic unilateral vocal fold paralysis following cardiothoracic surgery

Publication date: Available online 6 December 2017
Source:American Journal of Otolaryngology
Author(s): Cassandra Puccinelli, Mara C. Modzeski, Diana Orbelo, Dale C. Ekbom
PurposeUnilateral vocal fold paralysis (UVFP) is a complication associated with cardiothoracic procedures that presents clinically as dysphonia and/or dysphagia with or without aspiration. The literature lacks both data on recovery of mobility and consensus on best management. Herein, our goals are to 1) Identify cardiothoracic procedures associated with symptomatic UVFP at our institution; 2) Review timing and nature of laryngology diagnosis and management; 3) Report spontaneous recovery rate of vocal fold mobility.Materials and methodsRetrospective case series at single tertiary referral center between 2002 and 2015. 141 patients were included who underwent laryngology interventions (micronized acellular dermis injection laryngoplasty and/or type 1 thyroplasty) to treat symptomatic UVFP diagnosed subsequent to cardiothoracic surgery.ResultsPulmonary procedures were most often associated with UVFP (n=50/141; 35.5%). 87.2% had left-sided paralysis (n=123/141). Median time to diagnosis was 42days (x¯=114±348). Over time, UVFP was diagnosed progressively earlier after cardiothoracic surgery. 63.4% of patients (n=95/141) underwent injection laryngoplasty as their initial intervention with median time from diagnosis to injection of 11days (x¯=29.6±54). 41.1% (n=58/141) ultimately underwent type 1 thyroplasty at a median of 232.5days (x¯=367±510.2) after cardiothoracic surgery. 10.2% (n=9/88) of those with adequate follow-up recovered full vocal fold mobility.ConclusionsMany cardiothoracic procedures are associated with symptomatic UVFP, predominantly left-sided. Our data showed poor recovery of vocal fold mobility relative to other studies. Early diagnosis and potential surgical medialization is important in the care of these patients.

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FOXA1 inhibits hepatocellular carcinoma progression by suppressing PIK3R1 expression in male patients

Abstract

Background

Forkhead box A1 (FOXA1) expression is associated with various types of tumors; however, the function and underlying mechanism of FOXA1 in the development of hepatocellular carcinoma (HCC) remains obscure.

Methods

Here, we investigated the role of FOXA1 in the development of HCC by applying gene function gain and loss analysis to HepG2 and Hep3B cell lines, and comparing outcomes with those of clinical HCC samples.

Results

Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), which encodes protein PI3Kp85 (p85), was identified as a FOXA1 target gene. Analyses of the mechanism and function revealed that FOXA1 suppresses hepatocellular carcinoma cell viability and motility by inhibiting PI3K/Akt signaling through direct inhibition of PIK3R1 transcription. Moreover, in clinical samples from male HCC patients, FOXA1 expression was much lower, whereas PI3Kp85 levels were much higher in tumor than in non-tumor tissues. Elevated PI3Kp85 is an unfavorable factor in HCC.

Conclusions

As a tumor suppressor, FOXA1 targets PIK3R1 directly to inhibit PI3K/Akt signaling pathway, thus exerting a negative regulatory effect on proliferation, migration, and invasion of HCC in male patients.

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Identification and validation of a 44-gene expression signature for the classification of renal cell carcinomas

Abstract

Background

Renal cancers account for more than 3% of all adult malignancies and cause more than 23,400 deaths per year in China alone. The four most common types of kidney tumours include clear cell, papillary, chromophobe and benign oncocytoma. These histological subtypes vary in their clinical course and prognosis, and different clinical strategies have been developed for their management. Some kidney tumours can be very difficult to distinguish based on the pathological assessment of morphology and immunohistochemistry.

Methods

Six renal cell carcinoma microarray data sets, including 106 clear cell, 66 papillary, 42 chromophobe, 46 oncocytoma and 35 adjacent normal tissue samples, were subjected to integrative analysis. These data were combined and used as a training set for candidate gene expression signature identification. In addition, two independent cohorts of 1020 RNA-Seq samples from The Cancer Genome Atlas database and 129 qRT-PCR samples from Fudan University Shanghai Cancer Center (FUSCC) were analysed to validate the selected gene expression signature.

Results

A 44-gene expression signature derived from microarray analysis was strongly associated with the histological differentiation of renal tumours and could be used for tumour subtype classification. The signature performance was further validated in 1020 RNA-Seq samples and 129 qRT-PCR samples with overall accuracies of 93.4 and 93.0%, respectively.

Conclusions

A 44-gene expression signature that could accurately discriminate renal tumour subtypes was identified in this study. Our results may prompt further development of this gene expression signature into a molecular assay amenable to routine clinical practice.

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Sugar-based collagen membrane cross-linking increases barrier capacity of membranes

Abstract

Objectives

This study examines the permeability and barrier capacity of a sugar cross-linked resorbable collagen membrane ex vivo and in vivo.

Materials and methods

Results

Conclusion

Clinical relevance

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IL-24 is a common and specific autoantigen of IgE in chronic spontaneous urticaria

Publication date: Available online 5 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Oliver Schmetzer, Elisa Lakin, Fatih A. Topal, Patricia Preusse, Denise Freier, Martin K. Church, Marcus Maurer
BackgroundThe efficacy of omalizumab (anti-IgE) and elevated IgE levels in chronic spontaneous urticaria (CSU) suggest autoallergic mechanisms.ObjectiveTo identify autoallergic targets of IgE in CSU patients.MethodsSera of CSU patients together with idiopathic anaphylaxis patients and healthy controls (seven of each) were screened for IgE-autoantibodies using an array of >9,000 proteins. Sera of 1062 CSU patients and 482 healthy controls were used in an IgE-anti-Interleukin-24 (IL-24) specific ELISA to investigate the association of IgE-anti-IL-24 and CSU.ResultsBy array analyses, over 200 IgE-autoantigens were found in CSU patients that were not in controls. Of the 31 IgE-autoantigens detected in >70% of patients, eight were soluble or membrane bound and expressed in skin. Of these, only IgE-autoantibodies to IL-24 were found in all CSU patients. In vitro studies showed IL-24 to release histamine from human mast cells sensitized with purified IgE of CSU patients but not controls. By ELISA analyses, the mean ± SD levels of IgE-anti-IL-24 were 0.52 ± 0.24 IU/ml in CSU and 0.27 ± 0.08 IU/ml in controls with 80% of CSU patients but only 20% of controls having levels >0.33 IU/ml (P< 0.0001). IgE-anti-IL-24 showed acceptable predictive properties for CSU, with a likelihood ratio of 3.9. Clinically, IgE-anti-IL-24 levels showed an association with disease activity as assessed by the urticaria activity score and with reduced basophil counts.ConclusionOur findings show that CSU patients frequently exhibit IgE-autoantibodies against many autoantigens and that IL-24 is a common, specific, and functional autoantigen of IgE-antibodies in CSU.

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PGE2 suppresses human group 2 innate lymphoid cell function

Publication date: Available online 5 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Jovana Maric, Avinash Ravindran, Luca Mazzurana, Åsa K. Björklund, Aline Van Acker, Anna Rao, Danielle Friberg, Sven-Erik Dahlén, Akos Heinemann, Viktoria Konya, Jenny Mjösberg
BackgroundGroup 2 innate lymphoid cells (ILC2) are involved in the initial phase of type 2 inflammation and can amplify allergic immune responses by orchestrating other type 2 immune cells. PGE2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation.ObjectiveWe set out to investigate how PGE2 regulates human ILC2 function.MethodsThe effects of PGE2 on human ILC2 proliferation, intracellular cytokine and transcription factor expression were assessed by flow cytometry. Cytokine production was measured by ELISA and real-time quantitative PCR was performed to detect PGE2 receptor expression.ResultsPGE2 inhibited the expression of GATA3, as well as the production of type 2 cytokines, IL-5 and IL-13, from human tonsil and blood ILC2 in response to stimulation with a combination of IL-25, IL-33, TSLP and IL-2. Furthermore, PGE2 downregulated the expression of IL-2Rα (CD25). In line with that observation, PGE2 decreased ILC2 proliferation. These effects were mediated by the combined action of the EP2 and EP4 receptors, which were specifically expressed on ILC2.ConclusionOur findings reveal that PGE2 limits ILC2 activation and propose that selective EP2 and EP4 receptor agonists might serve as promising therapeutic approach in treating allergic diseases by suppressing ILC2 function.

Graphical abstract

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Generation of adult human T cell progenitors for immunotherapeutic applications

Publication date: Available online 5 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Laura Simons, Kuiying Ma, Corinne de Chappedelaine, Ranjita Devi Moiranghtem, Elodie Elkaim, Juliette Olivré, Sandrine Susini, Kevin Appourchaux, Christian Reimann, Hanem Sadek, Olivier Pellé, Nicolas Cagnard, Elisa Magrin, Chantal Lagresle-Peyrou, Tom Taghon, Antonio Rausell, Marina Cavazzana, Isabelle André-Schmutz

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Thymic stromal lymphopoietin does not activate human basophils

Publication date: Available online 5 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Nina Salabert-Le Guen, Caroline Hémont, Agathe Delbove, Caroline Poli, Cécile Braudeau, Aurélie Fantou, Karine Amouriaux, Gaelle Bériou, Jérôme C. Martin, Luc Colas, Vassili Soumelis, Régis Josien

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Modulating allergic response by engineering the major Parietaria allergens

Publication date: Available online 5 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Angela Bonura, Daniela Di Blasi, Bianca Barletta, Cinzia Butteroni, Silvia Corinti, Francesco Gervasi, Raphael MelisMario, Carina Uasuf, Cibella Fabio, Gabriella Di Felice, Paolo Colombo
An engineered recombinant hybrid composed of the two major Parietaria allergens (PjEDcys) with reduced allergenicity, retained immunogenicity but immunomodulatory activity for Allergen Immunotherapy of Parietaria allergic patients.

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Changes in regulatory B cell levels in bone marrow, blood and sputum of asthmatics following inhaled allergen challenge

Publication date: Available online 6 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): John-Paul Oliveria, Amani I. El-Gammal, Michelle Yee, Caitlin D. Obminski, Tara X. Scime, Rick M. Watson, Karen Howie, Paul M. O'Byrne, Roma Sehmi, Gail M. Gauvreau

Teaser

Capsule Summary: Following allergen exposure in the airways of subjects with allergic asthma, Bregs appear to efflux from the bone marrow and accumulate in the lungs with a possible role in dampening local inflammatory responses.

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Polyunsaturated fatty acids in plasma at 8 years and subsequent allergic disease

Publication date: Available online 5 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Jessica Magnusson, Sandra Ekström, Inger Kull, Niclas Håkansson, Sara Nilsson, Magnus Wickman, Erik Melén, Ulf Risérus, Anna Bergström
BackgroundPolyunsaturated fatty acids (PUFAs) are hypothesized to modulate the risk of allergic disease. However, evidence from previous studies is inconclusive, and limited longitudinal data exist using circulating biomarkers of PUFA intake and metabolism.ObjectiveWe aimed to investigate associations between n-3 and n-6 PUFAs at age 8 years and asthma, rhinitis, and aeroallergen sensitization at age 16 years.MethodsProportions of n-3 PUFAs (very long-chain n-3 [VLC n-3; sum of eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid] and α-linolenic acid) and n-6 PUFAs (linoleic acid and arachidonic acid [AA]) in blood samples at age 8 years were measured for 940 children from the prospective Swedish birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiology). Allergic disease phenotypes were defined by using questionnaires and IgE measures at the ages of 8 and 16 years. Logistic regression was used to examine potential associations.ResultsA higher proportion of total VLC n-3 PUFAs in plasma at age 8 years was associated with a reduced risk of prevalent asthma, rhinitis, and aeroallergen sensitization at age 16 years and with incidence of asthma between 8 and 16 years (adjusted odds ratio, 0.67; 95% CI, 0.47-0.94). AA was associated with a reduced risk of asthma, aeroallergen sensitization, and allergic rhinitis. The findings were most evident for allergic phenotypes of asthma and rhinitis. Additionally, AA was associated with an increased probability of asthma and rhinitis remission between 8 and 16 years of age.ConclusionHigher proportions of certain VLC n-3 and very long-chain n-6 PUFAs in plasma phospholipids at age 8 years were associated with a reduced risk of allergic disease at age 16 years.

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Effect of Grass Sublingual Tablet Immunotherapy is Similar in Children and Adults: A Bayesian Approach To Design Pediatric Sublingual Immunotherapy Trials

Publication date: Available online 5 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Amarjot Kaur, David Skoner, Joseph Ibrahim, Qing Li, Richard F. Lockey, Michael Blaiss, Albrecht Bufe, Jens Strodl Andersen, Giorgio Walter Canonica, Hendrik Nolte
BackgroundLarge sample sizes are needed for sublingual immunotherapy (SLIT) trials due to inherent data variability secondary to inconsistent allergen exposure. Obtaining large sample sizes for pediatric SLIT trials is challenging, but a Bayesian approach using prior adult data can reduce the necessary sample size.ObjectiveTo describe how a Bayesian framework utilizing prior information from adult trials can be used to improve pediatric SLIT clinical development.MethodsData were compiled using a frequentist approach (conventional clinical trial approach independent of prior data) from trials conducted during the clinical development of timothy grass SLIT-tablet.ResultsThe treatment effect of timothy grass SLIT-tablet was considered similar between pediatric (N=795) and adult (N=2299) data pools, with relative total combined symptom plus medication score improvement (95% CI) vs placebo of 21% (11.0, 30.4) and 20% (14.6, 24.4), respectively. Phleum pratense-specific IgG4 and IgE blocking factor increased from baseline in both children and adults treated with timothy grass SLIT-tablet. Given the reasonable assumption in similarity of treatment response between adults and children, a Bayesian approach is described to demonstrate rigorous efficacy criterion for pediatric trials incorporating information from prior adult trials, and thereby reduce the sample size.ConclusionsData support the similarity of efficacy and immunologic changes between children and adults treated with SLIT for allergic rhinoconjunctivitis. Therefore, it is appropriate to utilize data from adult trials to design feasible trials in children, which may reduce unsafe off-label use by promoting more quickly proper labeling of approved products.

Teaser

Capsule Summary SLIT effects are similar between children and adults. Analytical approaches that allow borrowing information from adult data are appropriate and will make future pediatric SLIT trials more feasible and therefore, quicker to complete, possibly reducing unsafe off-label use of non-approved SLIT formulations.

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Cover 1

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6

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Brief Overview of This Month's JACI

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6

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Advances in environmental and occupational disorders in 2016

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6
Author(s): William J. Sheehan, Jonathan M. Gaffin, David B. Peden, Robert K. Bush, Wanda Phipatanakul
In this review we highlight recent studies that advance the knowledge and understanding of the effects of various environmental factors and associated immune responses in patients with allergic diseases. This review will focus on new literature regarding allergic and immune responses to a variety of environmental factors, including aeroallergens, stinging insects, fungi, pollutants, viral respiratory tract infections, climate change, and microbial exposures.

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Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6

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Editorial Board

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6

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Information for Readers

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6

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News & Notes

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6

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Continuing Medical Education Calendar

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6

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Biomarkers in connective tissue diseases

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6
Author(s): Neelakshi R. Jog, Judith A. James
Autoimmune connective tissue diseases are clinically variable, making biomarkers desirable for assessing future disease risk, supporting early and accurate diagnosis, monitoring disease activity and progression, selecting therapeutics, and assessing treatment response. Because of their correlations with specific clinical characteristics and often with disease progression, autoantibodies and other soluble mediators are considered potential biomarkers. Additional biomarkers might reflect downstream pathologic processes or appear because of ongoing inflammation and damage. Because of overlap between diseases, some biomarkers have limited specificity for a single autoimmune connective tissue disease. This review describes select current biomarkers that aid in the diagnosis and treatment of several major systemic autoimmune connective tissue disorders: systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and anti-neutrophil cytoplasmic antibody–associated vasculitides. Newly proposed biomarkers that target various stages in disease onset or progression are also discussed. Newer approaches to overcome the diversity observed in patients with these diseases and to facilitate personalized disease monitoring and treatment are also addressed.

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Biomarkers in connective tissue diseases

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6

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Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6
Author(s): Mohamed H. Shamji, Stephen R. Durham
Allergen immunotherapy is effective in patients with IgE-dependent allergic rhinitis and asthma. When immunotherapy is given continuously for 3 years, there is persistent clinical benefit for several years after its discontinuation. This disease-modifying effect is both antigen-specific and antigen-driven. Clinical improvement is accompanied by decreases in numbers of effector cells in target organs, including mast cells, basophils, eosinophils, and type 2 innate lymphoid cells. Immunotherapy results in the production of blocking IgG/IgG4 antibodies that can inhibit IgE-dependent activation mediated through both high-affinity IgE receptors (FcεRI) on mast cells and basophils and low-affinity IgE receptors (FcεRII) on B cells. Suppression of TH2 immunity can occur as a consequence of either deletion or anergy of antigen-specific T cells; induction of antigen-specific regulatory T cells; or immune deviation in favor of TH1 responses. It is not clear whether the altered long-term memory resides within the T-cell or the B-cell compartment. Recent data highlight the role of IL-10–producing regulatory B cells and "protective" antibodies that likely contribute to long-term tolerance. Understanding mechanisms underlying induction and persistence of tolerance should identify predictive biomarkers of clinical response and discover novel and more effective strategies for immunotherapy.

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Biomarkers for severe eosinophilic asthma

Publication date: December 2017
Source:Journal of Allergy and Clinical Immunology, Volume 140, Issue 6
Author(s): Steven W. Yancey, Oliver N. Keene, Frank C. Albers, Hector Ortega, Stewart Bates, Eugene R. Bleecker, Ian Pavord
The last decade has seen the approval of several new biologics for the treatment of severe asthma-targeting specific endotypes and phenotypes. This review will examine how evidence generated from the mepolizumab clinical development program showed that blood eosinophil counts, rather than sputum or tissue eosinophil counts, evolved as a pharmacodynamic and predictive biomarker for the efficacy of treatment with mepolizumab in patients with severe eosinophilic asthma. Based on the available evidence and combined with clinical judgement, a baseline blood eosinophil threshold of 150 cells/μL or greater or a historical blood eosinophil threshold of 300 cells/μL or greater will allow selection of patients with severe eosinophilic asthma who are most likely to achieve clinically significant reductions in the rate of exacerbations with mepolizumab treatment.

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Initial intravenous immunoglobulin doses should be based on adjusted body weight in obese patients with primary immunodeficiency disorders

Immunoglobulin therapy plays a critical role in the treatment of immunodeficiency disorders as well as autoimmune and inflammatory conditions. In immunodeficient patients, there has been controversy whether in...

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The interictal mesial temporal lobe epilepsy network

Summary

Objective

Identification of patient-specific epileptogenic networks is critical to designing successful treatment strategies. Multiple noninvasive methods have been used to characterize epileptogenic networks. However, these methods lack the spatiotemporal resolution to allow precise localization of epileptiform activity. We used intracranial recordings, at much higher spatiotemporal resolution, across a cohort of patients with mesial temporal lobe epilepsy (MTLE) to delineate features common to their epileptogenic networks. We used interictal rather than seizure data because interictal spikes occur more frequently, providing us greater power for analyzing variances in the network.

Methods

Intracranial recordings from 10 medically refractory MTLE patients were analyzed. In each patient, hour-long recordings were selected for having frequent interictal discharges and no ictal events. For all possible pairs of electrodes, conditional probability of the occurrence of interictal spikes within a 150-millisecond bin was computed. These probabilities were used to construct a weighted graph between all electrodes, and the node degree was estimated. To assess the relationship of the highly connected regions in this network to the clinically identified seizure network, logistic regression was used to model the regions that were surgically resected using weighted node degree and number of spikes in each channel as factors. Lastly, the conditional spike probability was normalized and averaged across patients to visualize the MTLE network at group level.

Results

We generated the first graph of connectivity across a cohort of MTLE patients using interictal activity. The most consistent connections were hippocampus to amygdala, anterior fusiform cortex to hippocampus, and parahippocampal gyrus projections to amygdala. Additionally, the weighted node degree and number of spikes modeled the brain regions identified as seizure networks by clinicians.

Significance

Apart from identifying interictal measures that can model patient-specific epileptogenic networks, we also produce a group map of network connectivity from a cohort of MTLE patients.

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On Exploring Vocal Ornamentation in Byzantine Chant

A special vocal ornament in Byzantine chant (BC), the single cycle ornamentation structure (SCOS), is defined and compared with the vibrato with respect to its time (rate, extent) and spectral (slope [SS], relative speaker's formant [SPF] level, formant frequencies [Fi] and bandwidths [Bi], and noise-to-harmonics ratio [NHR]) characteristics.

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A polymorphism within the vitamin D transporter gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab (bev). Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bev were included in this study. 278 patients receiving FOLFIRI and cetuximab (cet) (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed. Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D binding protein, and treated with FOLFIRI/bev had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable P=0.001) and multivariable analyses P=0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR 1.83, P=0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR 0.50, P=0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab +/- irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P=0.033) and multivariable analyses (P=0.046). Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bev or FOLFIRI/cet. Whereas AA carriers derive a survival benefit with FOLFIRI/cet, treatment with FOLFIRI/bev is associated with a worse outcome.

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CXCR4 is a potential target for diagnostic PET/CT imaging in Barrett's dysplasia and esophageal adenocarcinoma

Introduction: Barrett's Esophagus (BE) represents an early stage in carcinogenesis leading to esophageal adenocarcinoma (EAC). Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of BE and EAC. Methods: Here we utilized a IL-1b transgenic mouse model of BE and EAC and human patient imaging to analyse the importance of CXCR4 expressing cells during esophageal carcinogenesis. Results: IL-1b overexpression induces chronic esophageal inflammation and recapitulates the progression to BE and EAC. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1b mice, and also elevated in EAC patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in esophageal cancer patients demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. Discussion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in EAC.

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Inhibition of ID1-BMPR2 intrinsic signaling sensitizes glioma stem cells to differentiation therapy

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, cancer stem cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear. Experimental Design: We performed in silico screening and in vitro validation studies through western blotting, q-RT-PCR for treatment of WNT and SHH signaling inhibitors and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice. Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through microRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating WNT and SHH signaling. Combined pharmacological blockade of WNT and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice. Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through WNT and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation.

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CD271 Confers an Invasive and Metastatic Phenotype of Head and Neck Squamous Cell Carcinoma Through the Upregulation of Slug

Purpose: Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells, and CD271 (NGFR; p75NTR) has been associated with a tumor-initiating cell subpopulation. This study assessed the role of CD271 in modulating metastatic behavior in HNSCC. Experimental Design: CD271 was overexpressed in murine and human oral squamous cell carcinoma cells to assess the impact of CD271 activation on the invasive and metastatic phenotype of these cells, using in vitro and orthotopic in vivo modeling. Treatment with human nerve growth factor (NGF) to activate CD271, as well as shRNA knockdown of the CD271-upregulated Snai2 expression, was used to assess the mechanism of the CD271-induced invasive phenotype. Relevance of CD271 expression in human HNSCC was evaluated in patient derived xenografts (PDXs) and primary human oral cancers, annotated with clinical behavior characteristics and survival data. Results: Forced expression of CD271 resulted in a more invasive and metastatic phenotype. Slug, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, encoded by Snai2, was highly expressed in MOC2-CD271 and HSC3-CD271, compared to respective parental cells. CD271 activation by NGF conferred enhanced invasiveness in CD271-overexpressing cells, which was abrogated by Snai2 knockdown. In PDXs and primary human HNSCC, CD271 expression correlated with higher Snai2 expression, greater nodal metastasis, and shorter disease-free survival. Conclusions: Activation of CD271 results in upregulation of Snai2/Slug, which, in turn, results in a more invasive phenotype and an enhanced capacity for metastasis to regional lymph nodes. These findings point to CD271 as a promising, therapeutic target for oral cancer metastasis.

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Biomarkers of primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients: the AMNESIA case-control study

Purpose: Refining the selection of HER2 positive metastatic gastric cancer patients candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. Experimental design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed. Results: AMNESIA panel alterations were significantly more frequent in resistant (11 out of 20, 55%) as compared to sensitive (0% of 17) patients (p<0.001), and in HER2 IHC 2+ (7 out of 13, 53.8%) than 3+ (4 out of 24, 16.7%) tumors (p=0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free (5.2 versus 2.6 months, HR: 0.34 [95%CI: 0.07-0.48]; p=0.001) and overall survival (16.1 versus 7.6 months, HR: 0.38 [95%CI: 0.09-0.75], p=0.015). The predictive accuracy of AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of AMNESIA panel and HER2 IHC was 84%. Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients, and should be further validated with the aim of molecularly stratifying HER2 addicted cancers for the development of novel treatment strategies.

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Vimentin is required for lung adenocarcinoma metastasis via heterotypic tumor cell-cancer-associated fibroblast interactions during collective invasion

Purpose: Vimentin is an epithelial to mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis. Experimental Design: We used the LSL-Kras G12D/Lkb1 fl/fl/Vim-/-model (KLV-/-), which incorporates a whole-body knockout of vimentin and is derived from the Cre-dependent LSL-Kras G12D/Lkb1 fl/fl model (KLV+/+). We compared the metastatic phenotypes of the GEMMs and analyzed primary tumors from the KLV models and lung adenocarcinoma patients to assess vimentin expression and function. Results: Characterization of KLV^+/+ and KLV-/- mice, show that vimentin is not required for primary lung tumor growth but is required for metastasis and vimentin loss generates lower grade primary tumors. Interestingly, in the KLV+/+ mice, vimentin was not expressed in tumor cells but in cancer-associated fibroblasts (CAFs) surrounding collective invasion packs (CIPs) of epithelial tumor cells, with significantly less CIPs in KLV-/- mice. CIPs correlate with tumor grade, and are vimentin-negative and E-cadherin-positive, indicating a lack of cancer cell EMT. Similar heterotypic staining pattern was observed in human lung adenocarcinoma samples. In vitro studies show that vimentin is required for CAF-led tumor cell invasion, supporting a vimentin-dependent model of collective invasion. Conclusions: These data show that vimentin is required for lung adenocarcinoma metastasis by maintaining heterotypic tumor cell-CAF interactions during collective invasion.

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Etk interaction with PFKFB4 modulates chemoresistance of small cell lung cancer by regulating autophagy

Purpose: Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx), was found to be critical in modulating the chemoresistance of small cell lung cancer (SCLC) in our preliminary study. However, the molecular mechanisms of Etk in SCLC chemoresistance remain poorly understood. The present study investigated the downstream factor and pathway involved. Experimental Design: We demonstrated first that knockdown of Etk by siRNAs suppressed autophagy in chemoresistant SCLC cells, and that direct inhibition of autophagy sensitized cells to chemotherapy. Our subsequent microarray, co-immunoprecipitation (co-IP) and GST-pull down experiments identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a downstream target of Etk and an Etk-interacting protein. We demonstrated knockdown of PFKFB4 suppressed autophagy in SCLC cells. Our in vitro and in vivo gain or loss-of-function analyses of PFKFB4 revealed PFKFB4 plays a critical role in SCLC chemoresistance. Our analysis of PFKFB4 expression in SCLC specimens demonstrated that high levels of PFKFB4 are associated with poor therapeutic response and prognosis. Furthermore, as Etk shares conserved domains with Btk (Bruton's tyrosine kinase) family, we explored the potential of Ibrutinib, a Btk inhibitor clinically effective in treating leukemia, in targeting Etk and found that Ibrutinib exhibited a synergistic anti-tumor effect with chemotherapy in SCLC preclinical models including a PDX model. Results: Described above Conclusions:Our results demonstrated for the first time that Etk interacts with PFKFB4 to promote SCLC chemoresistance through regulation of autophagy. Aberrant Etk and PFKFB4 can be predictive factors for the chemotherapy response as well as potential therapeutic targets in SCLC.

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Αρχειοθήκη ιστολογίου

Τρίτη 5 Δεκεμβρίου 2017

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