The IGF axis in HPV associated cancers

Publication date: Available online 4 February 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Adam Pickard, Julia Durzynska, Dennis J. McCance, Elisabeth R. Barton
Human papillomaviruses (HPV) infect and replicate in stratified epithelium at cutaneous and mucosal surfaces. The proliferation and maintenance of keratinocytes, the cells which make up this epithelium, is controlled by a number of growth factor receptors such as the keratinocyte growth factor receptor (KGFR, also called fibroblast growth factor receptor 2b (FGFR2b)), the epithelial growth factor receptor (EGFR) and the insulin-like growth factor receptors 1 and 2 (IGF1R and IGF2R). In this review, we will delineate the mutation, gene transcription, translation and processing of the IGF axis within HPV associated cancers. The IGFs are key for developmental and postnatal growth of almost all tissues; we explore whether this crucial axis been hijacked by HPV.



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Transcervical ultrasonographic examination of palatine tonsil size and its correlation with age, gender and body-mass index in healthy children

Publication date: April 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 95
Author(s): Mehmet Öztürk
ObjectiveOur aim was to assess the palatine tonsil size with transcervical ultrasonography in healthy children and to analyze whether the palatine tonsil size is correlated with age, gender and body-mass index (BMI).MethodsThis series consisted of 680 healthy children (340 females, 340 males) who underwent transcervical ultrasonography for evaluation of palatine tonsil size. A total of seventeen age groups (range: 1–17 years) comprised of 40 children (20 females, 20 males) were constituted. Demographic data including gender, height, weight and BMI were noted. Correlation between baseline descriptive data and tonsil volume was investigated.ResultsThe average age was 102.51 ± 59.24 months (range: 12 to 204) and body-mass index was 17.50–5.16 kg/m2 (min: 12.4-max:25.8). The average tonsil volume was 1819.5–2023.5 mm³ (min:601, max: 4007). The tonsil volume did not differ significantly between females and males (p = 0.108). However, there was a significant difference between tonsil volumes of various age groups (p < 0.001). Tonsil size seemed to be greater in parallel with advancement of age (p < 0.001) and increased BMI (p < 0.001).ConclusionTranscervical ultrasonography can be an accurate, safe, cheap, non-invasive and accessible measure for evaluation of the size of tonsils objectively. There were strongly positive correlations between age, BMI and palatine tonsil size in healthy children and variability with respect to descriptive characteristics must be considered during diagnostic procedures and preoperative evaluation.Advances in knowledgeIn our study, we suggest that transcervical ultrasonography can be an accurate, safe, cheap, non-invasive and accessible measure for evaluation of the size of tonsils. There were positive correlations between age, BMI and palatine tonsil size in healthy children.



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Parent educational materials regarding the newborn hearing screening process

Publication date: April 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 95
Author(s): Lata A. Krishnan, Breanne Lawler, Shannon Van Hyfte
PurposeNewborn hearing screening (NHS) procedures and implementation vary from state to state in the US. The purpose of this study was to evaluate the content and nature of information provided to parents about their infant's NHS across states to answer two questions: 1) what information is included in each state's parent information brochure? and 2) do the brochures include educational information requested by parents that may help reduce parental anxiety, improve satisfaction, and decrease the potential for misunderstandings?MethodEach state's parent brochures and educational resources provided to parents were accessed via the National Center for Hearing Assessment and Management (NCHAM) website, categorized, and reviewed for content.ResultsResults indicate that the information provided to parents varies considerably across states and many brochures do not contain important information that is desired by parents.ConclusionsNHS procedures may be improved by providing standardized information regarding the process to parents in all states.



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Editorial Board

Publication date: March 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 94





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The clinical efficacy of early intervention for infected preauricular sinus

Publication date: Available online 4 February 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Oak-Sung Choo, Top Kim, Jeong Hun Jang, Yun-Hoon Choung
ObjectiveThe study was designed to evaluate the outcomes of early surgical intervention, and to suggest the accurate operation time and surgical strategies.MethodsA total of 190 cases (144 patients) of PAS excision were classified into 2 groups according to their time of surgery; early intervention group (n=53), and non-early intervention group (n=137). Early intervention was defined as excision performed within 3 weeks from their first hospital visit, and after acute infection control, surgical removal was followed regardless of their infection status. The mean age of patients was 18.3 ± 15.7 years old (62 male, 82 female). During surgery, a parallel incision was added when iatrogenic fistula due to incision and drainage (I &D) or additionally opened wounds caused by infection was present.ResultsCases of I & D history, revision cases, use of preoperative antibiotics were significantly higher in the early intervention group compared to the non-early intervention group, however, the time of surgery did not affect the complication rate (p = 0.533). Within the infected cases, only 1 patient from the non-early intervention group showed a minor complication of keloid scar. During our follow up period of minimum of 6 months, there was no recurrence in either groups.ConclusionThe early intervention of PASs does not seem to increase postoperative complication or recurrence rates. A double parallel skin incision is a simple but adequate technique to treat infected PASs.



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EEG synchronization measures are early outcome predictors in comatose patients after cardiac arrest

Publication date: Available online 5 February 2017
Source:Clinical Neurophysiology
Author(s): Frédéric Zubler, Andreas Steimer, Rebekka Kurmann, Mojtaba Bandarabadi, Jan Novy, Heidemarie Gast, Mauro Oddo, Kaspar Schindler, Andrea O. Rossetti
ObjectiveOutcome prognostication in comatose patients after cardiac arrest (CA) remains a major challenge. Here we investigated the prognostic value of combinations of linear and non-linear bivariate EEG synchronization measures.Methods94 comatose patients with EEG within 24h after CA were included. Clinical outcome was assessed at 3 months using the Cerebral Performance Categories (CPC). EEG synchronization between the left and right parasagittal, and between the frontal and parietal brain regions was assessed with 4 different quantitative measures (delta power asymmetry, cross-correlation, mutual information, and transfer entropy). 2/3 of patients were used to assess the predictive power of all possible combinations of these eight features (4 measures x 2 directions) using cross-validation. The predictive power of the best combination was tested on the remaining 1/3 of patients.ResultsThe best combination for prognostication consisted of 4 of the 8 features, and contained linear and non-linear measures. Predictive power for poor outcome (CPC 3-5), measured with the area under the ROC curve, was 0.84 during cross-validation, and 0.81 on the test set. At specificity of 1.0 the sensitivity was 0.54, and the accuracy 0.81.ConclusionCombinations of EEG synchronization measures can contribute to early prognostication after CA. In particular, combining linear and non-linear measures is important for good predictive power.Significancequantitative methods might increase the prognostic yield of currently used multi-modal approaches.



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The generator site in acquired autoimmune neuromyotonia

Publication date: Available online 5 February 2017
Source:Clinical Neurophysiology
Author(s): Miguel Oliveira Santos, Michael Swash, Mamede de Carvalho
ObjectiveTo investigate the origin of ectopic activity in neuromyotonia (NMT).MethodsWe studied two patients. In addition to routine studies, we tested synchronicity of spontaneous discharges in different motor units in simultaneous recordings made with two needle electrodes in the first dorsal interosseus muscle. Time-locked fasciculations in these double recordings would represent abnormal ectopic activity initiated in a nerve trunk with ephaptic stimulation of a nearby axon. In patient 1, this research protocol was applied once, 15 years after regular intravenous immunoglobulin (IvIg) treatment. Patient 2 was investigated before and 1 year after IvIg.ResultsBoth patients improved after IVIg, mirrored by a striking decrease in the amount of spontaneous activity on electromyography. Moreover, our technique did not detect synchronous spontaneous activity (time-locked fasciculations) on the second assessment, although this was predominant before treatment in patient 2.ConclusionsIn NMT, abnormal discharges originate both in distal axonal branches and in more proximal segments. It appears that IvIg is more effective in blocking antibody activity in proximal axonal segments, perhaps related to factors such as blood-nerve barrier, temperature or differing ion channel distributions.SignificanceTreatment effects can shed light on the origin of abnormal activity in NMT.



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Redefining Periodic Patterns on Electroencephalograms of Patients with Sporadic Creutzfeldt–Jakob Disease

Publication date: Available online 5 February 2017
Source:Clinical Neurophysiology
Author(s): Jung-Won Shin, Byeongsoo Yim, Seung Hun Oh, Nam Keun Kim, Sang kun Lee, Ok-Joon Kim
ObjectiveWe aimed to redefine various periodic patterns (PPs) observed on electroencephalography (EEG) in patients with sporadic Creutzfeldt–Jakob disease (sCJD) using the American Clinical Neurophysiology Society's (ACNS) Criteria.MethodsWe analyzed EEG data of 23 patients with sCJD were admitted to two university hospitals between August 2005 and September 2015.ResultsWe classified PPs on EEG data into three types: irregular periodic discharges (PDs) with superimposed rhythmic activities, appearing at a median of 8 weeks after onset (w.a.o.); rhythmic sharp-and-wave, at a median of 11 w.a.o.; and PDs with biphasic or triphasic morphology, at a median of 17 w.a.o. Of 16 patients presenting with PPs, 14 had widespread lesions in both cortical and subcortical areas with clinical stage III at admission, and shorter time intervals for admission to hospital from disease onset than patients without PPs (Patients with PP, 11.6 ± 12.2 weeks; without PP, 18.2 ± 8.3 weeks; p = 0.033).ConclusionsPPs largely presented as three types at different stages of disease progression, and patients who had PPs had more wide spread lesions and rapid disease progression.SignificanceOur redefinition of PPs demonstrated on EEG using the ACNS criteria may contribute to further understanding of the pathological mechanisms of sCJD, and PPs might be a predictive factor of a rapid sCJD progression.



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Vitamin D Deficiency in Mothers, Neonates and Children

Publication date: Available online 5 February 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Deena H. Elsori, Majeda S. Hammoud
Vitamin D is produced in response to the exposure of skin to sunlight through UV-B synthesis. It can also be obtained from diet and dietary supplements. Vitamin D is essential for strong bones as it helps to absorb calcium from diet. Vitamin D deficiency mainly occurs if strict vegetarian diet is followed as mostly the source of vitamin D is animal based; therefore, exposure to sunlight is restricted or having dark skin color. Low vitamin D levels results in increased possibility of gestational diabetes among pregnant women, low birth weight and pre-eclampsia in infants, and mothers may suffer bone impairment, osteoporosis, hypocalcaemia, and hypertension. Vitamin D deficiency is directly linked with severe complication in mothers and neonates, causing rickets, poor fetal growth and infantile eczema in neonates. Higher prevalence rate of vitamin D deficiency has led professionals to emphasize on development of relevant precautionary measures.



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Changing Mutational and Adaptive Landscapes and the Genesis of Cancer

Publication date: Available online 4 February 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): L. Alexander Liggett, James DeGregori
By the time the process of oncogenesis has produced an advanced cancer, tumor cells have undergone extensive evolution. The cellular phenotypes resulting from this evolution have been well studied, and include accelerated growth rates, apoptosis resistance, immortality, invasiveness, and immune evasion. Yet with all of our current knowledge of tumor biology, the details of early oncogenesis have been difficult to observe and understand. Where different oncogenic mutations may work together to enhance the survival of a tumor cell, in isolation they are often pro-apoptotic, pro-differentiative or pro-senescent, and therefore often, somewhat paradoxically, disadvantageous to a cell. It is also becoming clear that somatic mutations, including those in known oncogenic drivers, are common in tissues starting at a young age. These observations raise the question: how do we largely avoid cancer for most of our lives? Here we propose that evolutionary forces can help explain this paradox. As humans and other organisms age or experience external insults such as radiation or smoking, the structure and function of tissues progressively degrade, resulting in altered stem cell niche microenvironments. As tissue integrity declines, it becomes less capable of supporting and maintaining resident stem cells. These stem cells then find themselves in a microenvironment to which they are poorly adapted, providing a competitive advantage to those cells that can restore their functionality and fitness through mutations or epigenetic changes. The resulting oncogenic clonal expansions then increase the odds of further cancer progression. Understanding how the causes of cancer, such as aging or smoking, affect tissue microenvironments to control the impact of mutations on somatic cell fitness can help reconcile the discrepancy between marked mutation accumulation starting early in life and the somatic evolution that leads to cancer at advanced ages or following carcinogenic insults. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.



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Forkhead box-P3+ regulatory T cells and toll-like receptor 2 co-expression in oral squamous cell carcinoma

Publication date: Available online 4 February 2017
Source:Acta Histochemica
Author(s): H.M. Hussaini, V.P.B. Parachuru, G.J. Seymour, A.M. Rich
BackgroundThe function of forkhead box-P3 (FoxP3) regulatory T cells (Treg) and toll-like receptor (TLR)2 protein in the oral cancer microenvironment is not fully understood, but evidence from other malignancies suggests it is likely they are involved with tumour development and progression. The aim of this study was to investigate the distribution of FoxP3⁺cells, TLR2⁺ cells and double-labelled FoxP3⁺TLR2⁺ immune cells in oral squamous cell carcinoma (OSCC), using immunohistochemistry (IHC) and immunofluorescence (IF).Methods25 archival cases of OSCC were immunostained with anti-FoxP3 and anti-TLR2 antibodies. Inflamed hyperplastic oral mucosal tissues were used as controls. The proportion of single-labelled, double-labelled and negative cells was determined.ResultsA higher frequency of double-labelled FoxP3⁺TLR2⁺ Tregs was observed within the immune cells of OSCC compared to inflamed controls using IHC (p<0.05). Cell-to-cell contact between single-stained TLR2⁺ cells and FoxP3⁺ cells was noted. Double IF studies validated demonstration of co-expression of FoxP3⁺/TLR2⁺ immune cells in OSCC.ConclusionThe presence of FoxP3⁺TLR2⁺ cells within the OSCC microenvironment may represent a dendritic cell-dependent pathway capable of inhibiting Treg suppressive activity, potentially enhancing the anti-tumour response. Modulation of TLR2-Treg interactions should be further explored to determine if they have a role in the therapeutic management of OSCC.



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Immunoreactivity pattern of calretinin in the developing human cerebellar cortex

Publication date: Available online 4 February 2017
Source:Acta Histochemica
Author(s): Valeria Pibiri, Clara Gerosa, Laura Vinci, Gavino Faa, Rossano Ambu
The immunohistochemical expression of the calcium-binding protein calretinin during human cerebellar development has been investigated in this study. Human cerebellum samples, obtained from 7 fetuses and newborns ranging from 11 to 38 weeks of gestation, were 10% formalin-fixed, routinely processed and paraffin-embedded. 3μm-tick sections were immunostained with an anti-calretinin antibody. Our study evidenced a different immunoreactivity for calretinin in Purkinje cells and in several cerebellar interneurons at different intrauterine developmental stages. Whereas at 11 weeks of gestation calretinin immunoreactivity was not detected in the developing cerebellum, from the 18th to the 24th week, calretinin expression was found in Purkinje cells migrating from the ventricular neuroepithelium and in migrating cerebellar interneurons. From the 30th to the 38th week, calretinin was expressed by most of Purkinje cells and by migrating cerebellar interneurons. Furthermore, granule cells in the internal granular layer were also immunoreactive for calretinin. Our data show that calretinin, other than for developing Purkinje cells, is a useful marker also for migrating cerebellar interneurons and for some neuronal elements related to the granular layer. Moreover, given the critical role of calcium in a great variety of neuronal processes in the central nervous system, our findings suggest that calretinin may play a pivotal role in the regulation of neuronal excitability during intrauterine cerebellar development.



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Effect of dietary zinc on morphological characteristics and apoptosis related gene expression in the small intestine of Bama miniature pigs

Publication date: Available online 4 February 2017
Source:Acta Histochemica
Author(s): Xin Zhou, Yansen Li, Zhaojian Li, Yun Cao, Fei Wang, ChunMei Li
To investigate the effects of dietary zinc (Zn) on small intestinal mucosal epithelium, 6-month-old male Bama miniature pigs were randomly allocated into three groups and treated with three levels of Zn (Control, T1, and T2 diet supplemented with 0, 50, and 1500mg/kg Zn, respectively, as zinc sulfate) for 38days. The samples of small intestine tissues, serum, and feces were collected. The results showed that Zn concentrations of small intestine in the T2 group were higher than those in the control and T1 groups (p<0.05). In the T2 group, the pharmacological dose of dietary Zn treatment caused marked damage to the small intestinal epithelium. The expression of Bax, cleaved caspase-3, and caspase-8 were increased in the duodenum and the jejunum of the T2 group (p<0.05). The mRNA transcript levels of BAX, CYCS and CASP3 genes were upregulated in the duodenum and the jejunum of the T2 group. We concluded that a diet with a pharmacological dose of Zn increased the accumulation of Zn and the expression of Bax, cleaved caspase-3, and caspase-8, which might activate the apoptosis and lead to the marked injury of porcine small intestinal epithelium.

Graphical abstract

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Ceramic strengthening by tuning the elastic moduli of resin-based luting agents

Publication date: Available online 4 February 2017
Source:Dental Materials
Author(s): Aloísio O. Spazzin, Ataís Bacchi, Rodrigo Alessandretti, Mateus B. Santos, Gabriela R. Basso, Jason Griggs, Rafael R. Moraes
ObjectiveResin-based luting agents (RBLAs) with tuned elastic moduli (E) were prepared and their influence on the strengthening, reliability, and mode of failure of luted feldspar ceramic was investigated.MethodsRBLAs with low E (2.6GPa), intermediate E (6.6GPa), and high E (13.3GPa) were prepared and used to coat acid-etched ceramic disks. Positive (untreated ceramic) and negative (acid-etched ceramic) control groups were tested. The response variables (n=30) were biaxial flexural strength (σbf, MPa), characteristic strength (σ0, MPa), and Weibull modulus at the ceramic surface (z=0) and luting agent surface (z=−t2). A 3D finite element analysis simulated the biaxial flexural test. Fractographic analysis and morphology of the bonded interfaces were analyzed using scanning electron microscopy.ResultsThe RBLAs improved σbf and σ0 at z=0, particularly those with intermediate and high E, whereas the mechanical reliability was only affected in the negative control. At z=−t2, differences between all RBLAs were observed but the structural reliability was independent of the RBLA tested. Increasing E of the RBLA was associated with increased stress concentration at the RBLA and reduced stresses reaching the ceramic. Failures originated on the ceramic surface at the ceramic-cement interface. In the high E group, failure sometimes originated from the RBLA free surface. All RBLAs completely filled the ceramic irregularities.SignificanceIncreased E of the RBLA reduced the variability of strength, the stress reaching the ceramic structure, and sometimes altered the origin of failure. The use of high E RBLAs seems beneficial for luting feldspar ceramics.



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Setting characteristics and mechanical properties of self-adhesive resin luting agents

Publication date: Available online 4 February 2017
Source:Dental Materials
Author(s): Raphael Pilo, Dimitris Papadogiannis, Spiros Zinelis, George Eliades
ObjectiveTo evaluate the degree of conversion (DC%), salt yield and mechanical properties of self-adhesive luting agents (SAA) set under dual-cure (E) and self-cure (NE) modes.MethodsThree SAA (GC LinkAce/GCLA, MaxCem Elite/MXEL, Rely-X Unicem 2/RXUN) and an adhesive resin luting agent (Rely-X Ultimate/RXUL-control) were used. The properties tested under E and NE modes were a) DC% and phosphate salt yield after 10min, 1h (h) and 3 weeks (w) storage, by infrared spectroscopy; and b) the mechanical properties of 3w-stored specimens by instrumented indentation testing (Martens hardness/HM, Elastic modulus/EIT, Elastic index/ηIT) and microscopic Vickers hardness/VH. Statistical analysis was performed by 3-way ANOVA (DC%), 2-way ANOVA (salt yield) and 1-way ANOVA (mechanical properties) at an a=0.05.ResultsSignificantly higher DC% was found in E, except from the 3w groups of GCLA and MXEL. Within E, no significant differences were found, but within NE, there were differences in the 3 w groups of GCLA (vs 10 min) and MXEL (vs 1h). All materials demonstrated increased salt yield in NE, with the highest values found in RXUL and RXUN. GCLA, RXUL showed the lowest HM in E and MXEL the highest in NE. The rankings of the significant differences in EIT were MXEL>GCLA,RXUN,RXUL (E) and RXUL,MXEL>GCLA,RXUN (NE), whereas for ηIT RXUL,RXUN>GCLA,MXEL (E) and GCLA>RXUL>MXEL,RXUN (NE). The results of VH measurements showed an overestimation ranging from 13% up to 38% in comparison with HM.SignificanceThere are significant differences in the properties tested, which may anticipate variations in the chemical, mechanical and biological performance of the products.



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Comparative analysis of the mechanical properties of fiber and stainless steel multistranded wires used for lingual fixed retention

Publication date: Available online 4 February 2017
Source:Dental Materials
Author(s): O. Annousaki, S. Zinelis, G. Eliades, T. Eliades
ObjectiveTo evaluate the effect of different resins used for the co-polymerization of EverStick fiber-reinforced fixed orthodontic retainer on its mechanical properties and to compare the mechanical properties of these configurations to commonly used multistrand wires.Materials and methodsTen 0.0175-in. WildCat (WC175), ten 0.0215-in. WildCat (WC215) three-strand twisted wires and thirty EverStick fibers were tested in this study. The EverStcik fibers were equally shared in three groups (n=10). The samples of first group (ESRE) were polymerized employing Stickresin (Light cure enamel adhesives), the second one (ESFT) employing Flow Tain (Light cured composite), whilst the specimens for the third group (ES) were not combined with resin. All samples were loaded in tensile up to fracture in a universal tensile testing machine and the modulus of elasticity, tensile strength and strain after fracture were recorded. The same groups were also tested employing Instrumented Indentation Testing (IIT) and Martens Hardness (HM), Indentation Modulus (EIT) and elastic index (ηIT) were determined. The results of tensile testing and IIT were statistically analyzed employing one way Anova and the Student Newman Keuls test (SNK) at a=0.05 level of significance.ResultsWC175 and WC215 showed higher modulus of elasticity and tensile strength but lower strain after fracture compared to Everstic groups. IIT illustrated significantly higher values for HM, EIT, and ηIT for WC groups compared to ESRE, ESFT and ES. ESFT showed higher HM and elastic index compared to ESRE and ES, a finding which is attributed to the fact the FlowTain is a filler-reinforce composite with higher hardness compared to unfilled resins.SignificanceMultistrand wires demonstrated higher values in mechanical properties compared to EverStick ones. The co-polymerization with difference resins does not affect the tensile properties of Everstic, however the use of a light cured composite has a beneficial effect on hardness.



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The therapeutic contribution of nanomedicine to treat neurodegenerative diseases via neural stem cell differentiation

Publication date: April 2017
Source:Biomaterials, Volume 123
Author(s): Dario Carradori, Joel Eyer, Patrick Saulnier, Véronique Préat, Anne des Rieux
The discovery of adult neurogenesis drastically changed the therapeutic approaches of central nervous system regenerative medicine. The stimulation of this physiologic process can increase memory and motor performances in patients affected by neurodegenerative diseases. Neural stem cells contribute to the neurogenesis process through their differentiation into specialized neuronal cells. In this review, we describe the most important methods developed to restore neurological functions via neural stem cell differentiation. In particular, we focused on the role of nanomedicine. The application of nanostructured scaffolds, nanoparticulate drug delivery systems, and nanotechnology-based real-time imaging has significantly improved the safety and the efficacy of neural stem cell-based treatments. This review provides a comprehensive background on the contribution of nanomedicine to the modulation of neurogenesis via neural stem cell differentiation.

Graphical abstract

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Biodegradable scaffolds promote tissue remodeling and functional improvement in non-human primates with acute spinal cord injury

Publication date: April 2017
Source:Biomaterials, Volume 123
Author(s): Jonathan R. Slotkin, Christopher D. Pritchard, Brian Luque, Janice Ye, Richard T. Layer, Mathew S. Lawrence, Timothy M. O'Shea, Roland R. Roy, Hui Zhong, Isabel Vollenweider, V. Reggie Edgerton, Grégoire Courtine, Eric J. Woodard, Robert Langer
Tissue loss significantly reduces the potential for functional recovery after spinal cord injury. We previously showed that implantation of porous scaffolds composed of a biodegradable and biocompatible block copolymer of Poly-lactic-co-glycolic acid and Poly-l-lysine improves functional recovery and reduces spinal cord tissue injury after spinal cord hemisection injury in rats. Here, we evaluated the safety and efficacy of porous scaffolds in non-human Old-World primates (Chlorocebus sabaeus) after a partial and complete lateral hemisection of the thoracic spinal cord. Detailed analyses of kinematics and muscle activity revealed that by twelve weeks after injury fully hemisected monkeys implanted with scaffolds exhibited significantly improved recovery of locomotion compared to non-implanted control animals. Twelve weeks after injury, histological analysis demonstrated that the spinal cords of monkeys with a hemisection injury implanted with scaffolds underwent appositional healing characterized by a significant increase in remodeled tissue in the region of the hemisection compared to non-implanted controls. The number of glial fibrillary acidic protein immunopositive astrocytes was diminished within the inner regions of the remodeled tissue layer in treated animals. Activated macrophage and microglia were present diffusely throughout the remodeled tissue and concentrated at the interface between the preserved spinal cord tissue and the remodeled tissue layer. Numerous unphosphorylated neurofilament H and neuronal growth associated protein positive fibers and myelin basic protein positive cells may indicate neural sprouting inside the remodeled tissue layer of treated monkeys. These results support the safety and efficacy of polymer scaffolds in a primate model of acute spinal cord injury. A device substantially similar to the device described here is the subject of an ongoing human clinical trial.



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Silk-based anisotropical 3D biotextiles for bone regeneration

Publication date: April 2017
Source:Biomaterials, Volume 123
Author(s): Viviana P. Ribeiro, Joana Silva-Correia, Ana I. Nascimento, Alain da Silva Morais, Alexandra P. Marques, Ana S. Ribeiro, Carla J. Silva, Graça Bonifácio, Rui A. Sousa, Joaquim M. Oliveira, Ana L. Oliveira, Rui L. Reis
Bone loss in the craniofacial complex can been treated using several conventional therapeutic strategies that face many obstacles and limitations. In this work, novel three-dimensional (3D) biotextile architectures were developed as a possible strategy for flat bone regeneration applications. As a fully automated processing route, this strategy as potential to be easily industrialized. Silk fibroin (SF) yarns were processed into weft-knitted fabrics spaced by a monofilament of polyethylene terephthalate (PET). A comparative study with a similar 3D structure made entirely of PET was established. Highly porous scaffolds with homogeneous pore distribution were observed using micro-computed tomography analysis. The wet state dynamic mechanical analysis revealed a storage modulus In the frequency range tested, the storage modulus values obtained for SF-PET scaffolds were higher than for the PET scaffolds. Human adipose-derived stem cells (hASCs) cultured on the SF-PET spacer structures showed the typical pattern for ALP activity under osteogenic culture conditions. Osteogenic differentiation of hASCs on SF-PET and PET constructs was also observed by extracellular matrix mineralization and expression of osteogenic-related markers (osteocalcin, osteopontin and collagen type I) after 28 days of osteogenic culture, in comparison to the control basal medium. The quantification of convergent macroscopic blood vessels toward the scaffolds by a chick chorioallantoic membrane assay, showed higher angiogenic response induced by the SF-PET textile scaffolds than PET structures and gelatin sponge controls. Subcutaneous implantation in CD-1 mice revealed tissue ingrowth's accompanied by blood vessels infiltration in both spacer constructs. The structural adaptability of textile structures combined to the structural similarities of the 3D knitted spacer fabrics to craniofacial bone tissue and achieved biological performance, make these scaffolds a possible solution for tissue engineering approaches in this area.



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Perivascular extracellular matrix hydrogels mimic native matrix microarchitecture and promote angiogenesis via basic fibroblast growth factor

Publication date: April 2017
Source:Biomaterials, Volume 123
Author(s): George R. Fercana, Saigopalakrishna Yerneni, Marie Billaud, Jennifer C. Hill, Paul VanRyzin, Tara D. Richards, Brian M. Sicari, Scott A. Johnson, Stephen F. Badylak, Phil G. Campbell, Thomas G. Gleason, Julie A. Phillippi
Extracellular matrix (ECM)-derived bioscaffolds have been shown to elicit tissue repair through retention of bioactive signals. Given that the adventitia of large blood vessels is a richly vascularized microenvironment, we hypothesized that perivascular ECM contains bioactive signals that influence cells of blood vessel lineages. ECM bioscaffolds were derived from decellularized human and porcine aortic adventitia (hAdv and pAdv, respectively) and then shown have minimal DNA content and retain elastin and collagen proteins. Hydrogel formulations of hAdv and pAdv ECM bioscaffolds exhibited gelation kinetics similar to ECM hydrogels derived from porcine small intestinal submucosa (pSIS). hAdv and pAdv ECM hydrogels displayed thinner, less undulated, and fibrous microarchitecture reminiscent of native adventitia, with slight differences in ultrastructure visible in comparison to pSIS ECM hydrogels. Pepsin-digested pAdv and pSIS ECM bioscaffolds increased proliferation of human adventitia-derived endothelial cells and this effect was mediated in part by basic fibroblast growth factor (FGF2). Human endothelial cells cultured on Matrigel substrates formed more numerous and longer tube-like structures when supplemented with pAdv ECM bioscaffolds, and FGF2 mediated this matrix signaling. ECM bioscaffolds derived from pAdv promoted FGF2-dependent in vivo angiogenesis in the chick chorioallantoic membrane model. Using an angiogenesis-focused protein array, we detected 55 angiogenesis-related proteins, including FGF2 in hAdv, pAdv and pSIS ECMs. Interestingly, 19 of these factors were less abundant in ECMs bioscaffolds derived from aneurysmal specimens of human aorta when compared with non-aneurysmal (normal) specimens. This study reveals that Adv ECM hydrogels recapitulate matrix fiber microarchitecture of native adventitia, and retain angiogenesis-related actors and bioactive properties such as FGF2 signaling capable of influencing processes important for angiogenesis. This work supports the use of Adv ECM bioscaffolds for both discovery biology and potential translation towards microvascular regeneration in clinical applications.



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Engineering of a hybrid nanoparticle-based nicotine nanovaccine as a next-generation immunotherapeutic strategy against nicotine addiction: A focus on hapten density

Publication date: April 2017
Source:Biomaterials, Volume 123
Author(s): Zongmin Zhao, Kristen Powers, Yun Hu, Michael Raleigh, Paul Pentel, Chenming Zhang
Although vaccination is a promising way to combat nicotine addiction, most traditional hapten-protein conjugate nicotine vaccines only show limited efficacy due to their poor recognition and uptake by immune cells. This study aimed to develop a hybrid nanoparticle-based nicotine vaccine with improved efficacy. The focus was to study the impact of hapten density on the immunological efficacy of the proposed hybrid nanovaccine. It was shown that the nanovaccine nanoparticles were taken up by the dendritic cells more efficiently than the conjugate vaccine, regardless of the hapten density on the nanoparticles. At a similar hapten density, the nanovaccine induced a significantly stronger immune response against nicotine than the conjugate vaccine in mice. Moreover, the high- and medium-density nanovaccines resulted in significantly higher anti-nicotine antibody titers than their low-density counterpart. Specifically, the high-density nanovaccine exhibited better immunogenic efficacy, resulting in higher anti-nicotine antibody titers and lower anti-carrier protein antibody titers than the medium- and low-density versions. The high-density nanovaccine also had the best ability to retain nicotine in serum and to block nicotine from entering the brain. These results suggest that the hybrid nanoparticle-based nicotine vaccine can elicit strong immunogenicity by modulating the hapten density, thereby providing a promising next-generation immunotherapeutic strategy against nicotine addiction.

Graphical abstract

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Investigation and Diagnosis of an Immediate Allergy to Amide Local Anaesthetic in a Paediatric Dental Patient

Abstract

Local anaesthetics remain the most common prescription medication utilised in dental practice. Adverse reactions following administration of local anaesthetic are somewhat common and are frequently reported as 'allergies'. However, of these events, it is estimated that only 1% are confirmed allergies to the local anaesthetic. This case presents the process of referral for investigation and testing to confirm an amide local anaesthetic allergy in a paediatric patient. Testing for a safe alternative was also completed to identify local anaesthetic agents also of the amide variety that can be utilised safely on this individual. Following skin testing of alternative agents intraoral challenges were completed. Finally, restorative dental treatment was provided safely for the patient with the use of an alternative amide local anaesthetic on a number of occasions with no further adverse outcomes.

This article is protected by copyright. All rights reserved.

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Biophysical characterization of Acacia caesia- fabricated silver nanoparticles: effectiveness on mosquito vectors of public health relevance and impact on non-target aquatic biocontrol agents

Abstract

Mosquito-borne diseases lead to serious public health concerns in tropical and sub-tropical countries worldwide, due to development of mosquito resistance to synthetic pesticides, non-target effects of pesticides, and socioeconomic reasons. Currently, green nanotechnology is a promising research field, showing a wide range of potential applications in vector control programs. The employ of natural products as reducing agents to fabricate insecticidal nanocomposites is gaining research attention worldwide, due to low costs and high effectiveness. Interestingly, biophysical features of green-synthesized nanoparticles strongly differ when different botanicals are employed for nanosynthesis. In this study, a cheap Acacia caesia leaf extract was employed to fabricate silver nanoparticles (Ag NPs) with ovicidal, larvicidal, and adulticidal toxicity against three mosquito vectors, Anopheles subpictus, Aedes albopictus, and Culex tritaeniorhynchus. Ag NPs were analyzed by various biophysical methods, including spectroscopy (UV-visible spectrophotometry, XRD, FTIR, EDX) and microscopy (SEM, TEM, AFM) techniques. High acute larvicidal potential was observed against larvae of An. subpictus (LC₅₀ = 10.33 μg/ml), Ae. albopictus (LC₅₀ = 11.32 μg/ml), and Cx. tritaeniorhynchus (LC₅₀ = 12.35 μg/ml). Ag NPs completely inhibited egg hatchability on three vectors at 60, 75, and 90 μg/ml, respectively. In adulticidal assays, LD₅₀ values were 18.66, 20.94, and 22.63 μg/ml. If compared to mosquito larvae, Ag NPs were safer to three non-target aquatic biocontrol agents, with LC₅₀ ranging from 684 to 2245 μg/ml. Overall, our study highlights the potential of A. caesia as an abundant and cheap bioresource to fabricate biogenic Ag NPs effective against mosquito young instars and adults, with moderate impact on non-target aquatic biocontrol agents.

http://ift.tt/2keomYd

Hyper-cell-permeable micelles as a drug delivery carrier for effective cancer therapy

Publication date: April 2017
Source:Biomaterials, Volume 123
Author(s): Phei Er Saw, Mikyung Yu, Minsuk Choi, Eunbeol Lee, Sangyong Jon, Omid C. Farokhzad
Although PEGylated liposomes (PEG-LS) have been intensively studied as drug-delivery vehicles, the rigidity and the hydrophilic PEG corona of liposomal membranes often limits cellular uptake, resulting in insufficient drug delivery to target cells. Thus, it is necessary to develop a new type of lipid-based self-assembled nanoparticles capable of enhanced cellular uptake, tissue penetration, and drug release than conventional PEGylated liposomes. Herein, we describe a simple modification of bicellar formulation in which the addition of a PEGylated phospholipid produced a dramatic physicochemical change in morphology, i.e., the disc-shaped bicelle became a uniformly distributed ultra-small (∼12 nm) spherical micelle. The transformed lipid-based nanoparticles, which we termed hyper-cell-permeable micelles (HCPMi), demonstrated not only prolonged stability in serum but also superior cellular and tumoral uptake compared to a conventional PEGylated liposomal system (PEG-LS). In addition, HCPMi showed rapid cellular uptake and subsequent cargo release into the cytoplasm of cancer cells. Cells treated with HCPMi loaded with docetaxel (DTX) had an IC50 value of 0.16 μM, compared with 0.78 μM with PEG-LS loaded with DTX, a nearly five-fold decrease in cell viability, indicating excellent efficiency in HCPMi uptake and release. In vivo tumor imaging analysis indicated that HCPMi penetrated deep into the tumor core and achieved greater uptake than PEG-LS. Results of HCPMi (DTX) treatment of allograft and xenograft mice in vivo showed high tumoral uptake and appreciable tumor retardation, with ∼70% tumor weight reduction in the SCC-7 allograft model. Taken together, these findings indicate that HCPMi could be developed further as a highly competent lipid-based drug-delivery system.

Graphical abstract

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Increased ratio of high sensitivity C-reactive protein to interleukin-10 as a potential peripheral biomarker of schizophrenia and aggression

Publication date: Available online 4 February 2017
Source:International Journal of Psychophysiology
Author(s): Qinting Zhang, Wu Hong, Haozhe Li, Fanglan Peng, Fan Wang, Ningning Li, Hui Xiang, Zongfeng Zhang, Yousong Su, Yueqi Huang, Shengyu Zhang, Guoqin Zhao, Rubai Zhou, Ling Mao, Zhiguang Lin, Weixiong Cai, Yiru Fang, Bin Xie, Min Zhao
BackgroundMany studies have indicated that immune dysfunction might be involved in the physiopathology of schizophrenia and aggression. This study aimed to investigate the correlation between high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-10 and clinical characteristics, especially aggression, and to explore the potential role of hsCRP and IL-10 as plasma biomarkers of schizophrenia.MethodsForty-one patients with schizophrenia and forty healthy individuals were enrolled. Psychopathological severity and aggression were assessed using the Positive and Negative Syndrome Scale (PANSS) and Modified Overt Aggression Scale (MOAS). Plasma concentrations of hsCRP and IL-10 were assessed by enzyme-linked immunosorbent assay (ELISA).Results(1) Higher levels of hsCRP (p<0.001), lower levels of logIL-10 (p<0.001) and higher ratio of hsCRP to IL-10 (p<0.001) were observed in the plasma of patients with schizophrenia, compared to healthy controls; (2) ROC (receiver operating characteristic) curve analysis revealed that ratio of hsCRP/IL-10 (predictive value: 0.783, p<0.01; sensitivity: 85.4%; specificity: 67.5%) was more applicable as a biomarker to distinguish patients with schizophrenia from the control group than hsCRP and IL-10 alone (predictive value: 0.718, p<0.01; 0.275, p<0.001, respectively); (3) we found positive correlations between hsCRP and the total score and verbal aggression score of MOAS (r=0.654, p<0.01; r=0.678, p<0.05), and between hsCRP/IL-10 and the total score of MOAS (r=0.636, p<0.01).ConclusionsOur results suggest the possible function of hsCRP and IL-10 in the pathogenesis of schizophrenia and the possible value of hsCRP/IL-10 as a potential peripheral biomarker of schizophrenia. This finding also suggests a relationship between hsCRP, IL-10 and their ratio with aggression in patients with schizophrenia.



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Cortical and cardiovascular responses to acute stressors and their relations with psychological distress

Publication date: Available online 4 February 2017
Source:International Journal of Psychophysiology
Author(s): Agostino Brugnera, Cristina Zarbo, Roberta Adorni, Giorgio A. Tasca, Massimo Rabboni, Emi Bondi, Angelo Compare, Kaoru Sakatani
The purpose of this study was to assess the interrelation between cortical, cardiovascular, behavioural, and psychological responses to acute stressors in a large sample of healthy individuals. To date, there are only preliminary evidences for a significant association among these psychophysiological indexes during a stress task.65 participants completed psychological questionnaires (Beck Depression Inventory and State-Trait Anxiety Inventory) and underwent a psychosocial math stress task, consisting of a control and an experimental (i.e. stressful) condition. Prefrontal and autonomic activities were recorded using respectively a 2-channel near-infrared spectroscopy (NIRS) device and a portable ECG monitoring system.Results evidenced an increased activation of both frontal areas assessed by NIRS, and a positive association between the right NIRS channel and heart rate changes from baseline, during both control and experimental conditions. Subjective stress increased during the procedure, reaching its maximum during the experimental condition. Behavioural performances during the task (e.g. response time) did not correlate with anxiety or depression. Autonomic data evidenced, as expected, an overall reduction of vagal tone during the experimental condition. Finally, severity of depressive and anxious symptoms predicted an increase in parasympathetic activity both at rest and during the task, even when controlling for respiration rate.Results support the hypothesis of an integration between right sectors of frontopolar or dorsolateral PFC and cardiac regulation. Trait anxiety and depression predicted an increase in vagal tone during the entire procedure. The implication of these findings is discussed.



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In vitro enamel erosion and abrasion-inhibiting effect of different fluoride varnishes

Publication date: May 2017
Source:Archives of Oral Biology, Volume 77
Author(s): Adílis Kalina Alexandria, Thiago Isidro Vieira, Matheus Melo Pithon, Tatiana Kelly da Silva Fidalgo, Andréa Fonseca-Gonçalves, Ana Maria Gondim Valença, Lúcio Mendes Cabral, Lucianne Cople Maia
ObjectiveTo investigate the erosion and abrasion inhibiting effect of CPP-ACP/NaF and xylitol/NaF varnishes.MethodsBovine enamel samples (n=40) were exposed to the following treatments (n=10): NaF varnish (Duraphat^®, positive control); CPP-ACP/NaF varnish (MI varnishTM); xylitol/NaF (Profluorid^®) or distilled and deionized water (MilliQ^®, negative control). The samples were submitted for 3days to 4 cycles/day of erosion (5min in Sprite Zero) and 2 cycles of abrasion/day after the first and last erosive challenge, with a toothbrush machine and slurries of a placebo toothpaste for 15s (50 strokes/s). Among the cycles and after the last daily cycle, the specimens remained in artificial saliva. The change in the enamel surface was evaluated by using 3D non-contact optical profilometry with surface roughness (Ra and Sa values) and tooth structure loss (TSL) measurements. Scanning electron microscopy (SEM) assessed the enamel topographic characteristics. Differences in the Ra, Sa and TSL among treatments were tested using one-way ANOVA followed by the Tukey test.ResultsAll varnishes promoted better results for Ra and Sa values than the negative control (p=0.0001), without difference among them (p>0.05). However, CPP-ACP/NaF varnish stimulated fewer TSL (7.09±0.70μm) compared to NaF varnish (10.33±1.36μm, p=0.002), xylitol/NaF varnish (9.96±0.41μm, p=0.007) and the negative control (18.38±3.32μm, p=0.0001).ConclusionA single-application of fluoride topical varnishes was effective in reducing enamel wear. The CPP-ACP/NaF varnish had the best effect against enamel loss from an erosion-abrasion challenge.



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Live and heat-killed Lactobacillus spp. interfere with Streptococcus mutans and Streptococcus oralis during biofilm development on titanium surface

Publication date: Available online 4 February 2017
Source:Archives of Oral Biology
Author(s): E. Ciandrini, R. Campana, W. Baffone
ObjectivesThis research investigates the ability of live and heat-killed (HK) Lactic Acid Bacteria (LAB) to interfere with Streptococcus mutans ATCC 25175 and Streptococcus oralis ATCC 9811 during biofilm formation.DesignEight Lactobacillus spp. and two oral colonizers, pathogenic Streptococcus mutans and resident Streptococcus oralis, were characterized for their aggregation abilities, cell surface properties and biofilm formation ability on titanium surface. Then, the interference activity of selected live and HK Lactobacillus spp. during S. mutans and S. oralis biofilm development were performed. The cell-free culture supernatants (CFCS) anti-biofilm activity was also determined.ResultsLAB possess good abilities of auto-aggregation (from 14.19 to 28.97%) and of co-aggregation with S. oralis. The cell-surfaces characteristics were most pronounced in S. mutans and S. oralis, while the highest affinities to xylene and chloroform were observed in Lactobacillus rhamnosus ATCC 53103 (56.37%) and Lactobacillus paracasei B21060 (43.83%). S. mutans and S. oralis developed a biofilm on titanium surface, while LAB showed a limited or no ability to create biofilm. Live and HK L. rhamnosus ATCC 53103 and L. paracasei B21060 inhibited streptococci biofilm formation by competition and displacement mechanisms with no substantial differences. The CFCSs of both LAB strains, particularly the undiluted one of L. paracasei B21060, decreased S. mutans and S. oralis biofilm formation.ConclusionsThis study evidenced the association of LAB aggregation abilities and cell-surface properties with the LAB-mediated inhibition of S. mutans and S. oralis biofilm formation. Lactobacilli showed different mechanisms of action and peculiar strain-specific characteristics, maintained also in the heat-killed LAB.

Graphical abstract

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Relationships between Oral MUC1 Expression and Salivary Hormones in Burning Mouth Syndrome

Publication date: Available online 4 February 2017
Source:Archives of Oral Biology
Author(s): Jeong-Hyun Kang, Yoon-Young Kim, Ji-Youn Chang, Hong-Seop Kho
ObjectivesTo investigate possible relationships among oral mucosal epithelial MUC1 expression, salivary female gonadal hormones and stress markers, and clinical characteristics in patients with burning mouth syndrome (BMS).DesignThirty post-menopausal female patients with BMS (60.0±5.0 years) were included. Clinical and psychological evaluations were performed and the expression level of oral mucosal epithelial MUC1 was analyzed. The levels of cortisol, dehydroepiandrosterone (DHEA), 17β-estradiol, progesterone, chromogranin A, and blood contamination were determined from unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) samples.ResultsSalivary progesterone level had significant positive correlations with oral mucosal epithelial MUC1 expression level and with salivary cortisol and DHEA levels. The salivary level of 17β-estradiol showed significant positive correlations with period of symptom duration, severity of effects of oral complaints on daily life, and results from psychological evaluations. Cortisol level in UWS and cortisol/DHEA ratio in UWS and SWS had negative correlations with severity of oral burning sensation significantly. The severity of taste disturbance had positive correlations with results from psychometry significantly.ConclusionDysregulated psychoendocrinological interactions might affect oral mucosal MUC1 expression and severity of oral burning sensation in post-menopausal BMS patients.



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Rate of Regional Nodal Metastases of Cutaneous Squamous Cell Carcinoma in the Immunosuppressed Patient

Immunosuppressed solid organ transplant recipients (SOTRs) have an increased risk of developing cutaneous squamous cell carcinomas (cSCCs) with metastatic potential. This study sought to determine the rate of regional lymph node involvement in a large cohort of solid organ transplant patients with cutaneous head and neck squamous cell carcinoma.

http://ift.tt/2kel3Ac

The experience of treatment of coblation assisted surgical approach to Eagle’s syndrome

This article aimed to Summarize our therapeutic experience with Transoral coblation assisted surgical approach used for treatment of Eagle's syndrome.

http://ift.tt/2kuad7Q

Melanoma of the external ear: A population-based study

Primary melanoma of the external ear (PMEE) is rare and therefore well-suited for large population-based registry analysis. The objective of this study was to utilize the Surveillance, Epidemiology, and End Results (SEER) set of cancer registries to determine the incidence, treatment, and survival characteristics of PMEE.

http://ift.tt/2keuVKn

Rate of Regional Nodal Metastases of Cutaneous Squamous Cell Carcinoma in the Immunosuppressed Patient

Immunosuppressed solid organ transplant recipients (SOTRs) have an increased risk of developing cutaneous squamous cell carcinomas (cSCCs) with metastatic potential. This study sought to determine the rate of regional lymph node involvement in a large cohort of solid organ transplant patients with cutaneous head and neck squamous cell carcinoma.

http://ift.tt/2kel3Ac

The experience of treatment of coblation assisted surgical approach to Eagle’s syndrome

This article aimed to Summarize our therapeutic experience with Transoral coblation assisted surgical approach used for treatment of Eagle's syndrome.

http://ift.tt/2kuad7Q

Melanoma of the external ear: A population-based study

Primary melanoma of the external ear (PMEE) is rare and therefore well-suited for large population-based registry analysis. The objective of this study was to utilize the Surveillance, Epidemiology, and End Results (SEER) set of cancer registries to determine the incidence, treatment, and survival characteristics of PMEE.

http://ift.tt/2keuVKn

International Consensus Guidelines for the Diagnosis and Management of Food Protein-Induced Enterocolitis Syndrome

Publication date: Available online 4 February 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): A. Nowak-Węgrzyn, M. Chehade, M. Groetch, J.M. Spergel, R.A. Wood, K. Allen, D. Atkins, S. Bahna, A. Barad, C. Berin, T. Brown Whitehorn, A.W. Burks, J.C. Caubet, A. Cianferoni, M. Conte, C. Davis, A. Fiocchi, K. Grimshaw, R. Gupta, B. Hofmeister, J.B. Hwang, Y. Katz, G.N. Konstantinou, S.A. Leonard, J. Lightdale, S. McGhee, S. Mehr, S. Miceli Sopo, G. Monti, A. Muraro, S. Noel, I. Nomura, S. Noone, H.A. Sampson, F. Schultz, S.H. Sicherer, C. Thompson, P. Turner, C. Venter, A. Westcott-Chavez, M. Greenhawt




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Probing the confining effect of clay particles on an amorphous intercalated dendritic polyester

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): Kevin P. Meyers, Jeremy J. Decker, Brian G. Olson, Jun Lin, Alexander M. Jamieson, Sergei Nazarenko
The fourth generation of a hydroxylated dendritic hyperbranched polyester (HBP) was combined with sodium montmorillonite clay (Na⁺MMT) using water to generate a broad range of polymer clay nanocomposites from 0 to 100% wt/wt Na⁺MMT. Analysis with differential scanning calorimetry (DSC) showed a deviation in heat capacity, ΔCp, with clay content at the Tg from a two-phase trend which was attributed to the formation of an immobilized rigid amorphous fraction (RAF) in the interlayer spacing of the intercalated system. This deviation occurred in a step-like fashion which we attributed to 0.5 nm incremental changes in the interlayer spacing, previously observed through X-ray diffraction analysis. A simple series model was utilized to quantify these interlayer spacings based on the ΔCp values and showed good correspondence with the X-ray results. The RAF was quantified from changes in heat capacity with clay content and was verified by an alternative novel positron annihilation lifetime spectroscopy (PALS) approach. The PALS quantification of the RAF was possible through an analysis of changes in the hole size thermal expansivity of the nanocomposites as a function of clay composition. Results indicated that as much as 32% by weight of the system is made up of the RAF at its maximum.

Graphical abstract

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Genome-wide interaction study of dust mite allergen on lung function in children with asthma

Publication date: Available online 4 February 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Erick Forno, Joanne Sordillo, John Brehm, Wei Chen, Takis Benos, Qi Yan, Lydiana Avila, Manuel Soto-Quirós, Michelle M. Cloutier, Angel Colón-Semidey, Maria Alvarez, Edna Acosta-Pérez, Scott T. Weiss, Augusto A. Litonjua, Glorisa Canino, Juan C. Celedón
BackgroundChildhood asthma is likely the result of gene-by-environment (GxE) interactions. Dust mite is a known risk factor for asthma morbidity. Yet, there have been no genome-wide GxE studies of dust mite allergen on asthma-related phenotypes.ObjectiveTo identify genetic variants whose effects on lung function in children with asthma are modified by level of dust mite allergen exposure.MethodsA genome-wide interaction analysis of dust mite allergen level and lung function was performed in a cohort of Puerto Rican children with asthma (PRGOAL). Replication was attempted in two independent cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study.ResultsSNP rs117902240 showed a significant interaction with dust mite allergen level on FEV1 in PRGOAL (interaction P=3.1x10^-8), and replicated in the same direction in CAMP White children and CAMP Hispanic children (combined interaction P=0.0065 for replication cohorts and 7.4 x10^-9 for all cohorts). Rs117902240 was positively associated with FEV1 in children exposed to low dust mite allergen levels, but negatively associated with FEV1 in children exposed to high levels. This SNP is on chromosome 8q24, adjacent to a binding site for CEBPβ, a transcription factor that forms part of the IL-17 signaling pathway. None of the SNPs identified for FEV1/FVC replicated in the independent cohorts.ConclusionsDust mite allergen exposure modifies the estimated effect of rs117902240 on FEV1 in children with asthma. Analysis of existing data suggests this SNP may have transcription factor regulatory functions.Capsule SummaryDust mite allergen exposure modifies the effect of certain genetic polymorphisms on lung function in children with asthma.Clinical ImplicationsThe effect of certain genetic polymorphisms on lung function in children with asthma varies depending on their dust mite allergen exposure level. Future studies should assess whether personalized interventions for these children have a greater impact on lung function.



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PLA with high elongation induced by multi-branched poly(ethylene imine) (mPEI) containing poly(l-lactic acid) (PLLA) terminals

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): Thammanoon Khamsarn, Raksit Supthanyakul, Masahiro Matsumoto, Suwabun Chirachanchai
The present work demonstrates the function of multi-branched poly(l-lactide) based on polyethylenimine cores (mPEI-PLLA) as an additive to drastically enhance the elongation of PLA resin. By simply applying mPEI as the core molecule with a catalytic amount of tin octoate, LLA ring-opening polymerization is accomplished to result in multi-branched PLLA, i.e. mPEI-PLLA. The blend of mPEI-PLLA with PLA in the film form represents the significant increase of elongation at break for as high as 280% without significant changes in Tg, indicating the role of branching PLLA to induce amorphous phase in the packing structure of PLA. The ease of mPEI-PLLA preparation and the superb elongation at break provided to PLA convince us that mPEI-PLLA is a practical miscible additive to solve the brittleness of PLA.

Graphical abstract

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Effect of cue timing and modality on gait initiation in Parkinson's disease with freezing of gait

Publication date: Available online 4 February 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Chiahao Lu, Sommer L. Amundsen Huffmaster, Paul J. Tuite, Jacqueline M. Vachon, Colum D. MacKinnon
ObjectiveTo examine the effects of cue timing, across three sensory modalities, on anticipatory postural adjustments (APAs) during gait initiation in people with Parkinson's disease (PD).DesignObservational study.SettingBiomechanics research laboratory.ParticipantsTwenty-five individuals with idiopathic PD (11 with freezing of gait, FOG) were studied in the off-levodopa state (12-hour overnight withdrawal).InterventionsGait initiation was tested without cueing (self-initiated) and with three cue timing protocols: fixed delay (3 s), random delay (4-12 s) and countdown (3-2-1-go, 1 s intervals) across three sensory modalities (acoustic, visual and vibrotactile).Main Outcome MeasuresThe incidence and spatiotemporal characteristics of APAs during gait initiation were analyzed, including vertical ground reaction forces and center of pressure.ResultsAll cue timings and modalities increased the incidence and amplitude of APAs compared to self-initiated stepping. Acoustic and visual cues, but not vibrotactile stimulation, improved the timing of APAs. Fixed delay or countdown timing protocols were more effective at decreasing APA durations compared to random delay cues. Cue-evoked improvements in APA timing, but not amplitude, correlated with the level of impairment during self-initiated gait. Cues did not improve the late push-off phase in the FOG group.ConclusionsExternal cueing improves gait initiation in PD regardless of cue timing, modality, or clinical phenotype (with and without FOG). Acoustic or visual cueing with predictive timing provided the greatest improvements in gait initiation thus these protocols may provide the best outcomes when applied by caregivers or devices.



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Mediator of DNA damage checkpoint protein 1 (MDC1) as a prognostic marker for patients with oral squamous cell carcinoma

Abstract

Background

The mediator of DNA damage checkpoint protein 1 (MDC1) is involved in the regulation of cell cycle check points and recruitment of several repair proteins to the site of DNA double stranded breaks (DSBs). The present study aims to correlate the expression of MDC1 protein with clinicopathological parameters and to evaluate its prognostic significance in patients with oral squamous cell carcinoma (OSCC).

Methods

MDC1 protein expression was evaluated immunohistochemically from untreated 100 patients with OSCC using modified H-score method. The association of MDC1 immunostaining was evaluated with clinicopathological parameters and disease outcome using univariate and multivariate survival analysis for relapse free survival (RFS) and overall survival (OS).

Results

Incidence of nuclear and cytoplasmic expression of MDC1 protein was 85% & 92%, respectively. Strong nuclear MDC1 protein expression was found to be significantly correlated with lymphnode metastasis (p=0.032). For RFS, Kaplan-Meier survival analysis demonstrated that presence of metastatic lymphnode (p=0.001), lymphatic permeation (p=0.020) and nuclear MDC1 (p=0.005) remained significant risk predictors. In multivariate survival analysis, nuclear MDC1 (p=0.027) entered at step 2 after presence of metastatic lymphnode (p=0.002) at step 1 for predicting reduced RFS. In relation to treatment, OSCC patients exhibiting weak expression of nuclear MDC1 protein were benefited significantly when treated with surgery followed by radiation therapy (p=0.001)

Conclusion

Thus, present study showed that MDC1 protein expression could be used as a prognostic marker in predicting relapse free survival in patients with OSCC. OSCC patients expressing weak MDC1 protein could be benefited by adjuvant radiotherapy instead chemo-radiotherapy.

This article is protected by copyright. All rights reserved.

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Reduced Chromatin acetylation of malignant salivary gland tumors correlates with enhanced proliferation

Abstract

Background

Epigenetic changes refer to any heritable modification in gene expression independent of alterations in the DNA sequence. Currently, it is well established that epigenetics represents a crucial player for tumor development. Nevertheless, the epigenetic mechanisms involved in the development and progression of salivary gland tumors (SGTs) remain poorly understood.

Methods

In the present study, we analyzed the pattern of acetyl-histone H3 (lys9) expression in benign and malignant SGTs and further correlate our results with tumors' proliferative activity and clinical outcomes. We assembled tissue microarrays (TMAs) of 84 cases of SGTs and analyzed for acetyl-histone H3 (lys9) and Ki-67 using immunohistochemistry. The study comprised 42 benign and 42 malignant SGTs.

Results

All cases included in the present study were positive to acetyl-H3 (lys9). We observed that malignant SGTs were hypoacetylated compared to benign (p=0.04). Moreover, acetyl-H3 (lys9) expression was inversely correlated with Ki67 (** p=0.02).

Conclusion

This study provides the first insight regarding histone modifications in SGTs. Our results suggest that epigenetic mechanism, particular hypoacetylation of histone H3 (lys9) might play a role in the behavior of salivary gland tumors. Also, our findings suggest that interfering with the acetylation pattern of tumor histones represents a potential novel therapeutic strategy for the treatment of SGTs.

This article is protected by copyright. All rights reserved.

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The incidence of concha bullosa, unusual anatomic variation and its relationship to nasal septal deviation: A retrospective radiologic study

Publication date: Available online 4 February 2017
Source:Auris Nasus Larynx
Author(s): Soo Kweon Koo, Jong Deok Kim, Ji Seung Moon, Sung Hoon Jung, Sang Hoon Lee
ObjectiveIdentifying anatomical variations associated with pathological findings is very useful for diagnoses and therapeutics. We conducted a study to detect various anatomical variations (superior, middle, inferior turbinate concha bullosa, uncinate bulla and nasal swell body [NSB]) in connection with nasal septal deviation.MethodsThis study used a retrospective radiological design to analyze 594 (1188 sides) osteomeatal computed tomography scans from 494 male patients and 100 female patients aged between 17 and 75 years. We randomly selected 100 male and 100 female patients as controls; we compared the groups and performed a statistical analysis. All patients in the control group had sinusitis only (i.e., they lacked nasal septal deviations).ResultsLeft-sided septal deviation was found to be slightly more prevalent than right-sided deviation (43.9% and 36.4%, respectively). The incidence of S-curved septal deviation was 18.5%, that of dorso-ventral deviation was 10.9%, and that of caudal-rostral deviation was 7.6%. The incidence of only septal spur was 1.2%. In the case of middle turbinate concha bullosa, the incidence of the unilateral type was 17.3% and that of the bilateral type was 36.4%. In superior turbinate concha bullosa, the incidence of the unilateral type was 11.3% and that of the bilateral type was 27.4%. The incidence of inferior turbinate concha bullosa was 1.0% and that of uncinate bulla was 1.7%. NSB was found in 25.1% of patients, 24.7% of males and 27.0% of females. The frequencies of middle and superior concha bullosa were about 10–12 fold higher on the concave side. The nasal septal deviation group exhibited a higher incidence of most anatomical variants than the non-deviated group; differences in the middle turbinate concha bullosa attained statistical significance.ConclusionThe radiologist must focus on anatomical variants in the preoperative evaluation. It is important for surgeons to be aware of these variations.



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The clinical efficacy of early intervention for infected preauricular sinus

The study was designed to evaluate the outcomes of early surgical intervention, and to suggest the accurate operation time and surgical strategies.

http://ift.tt/2jNkfnp

Unusual cause acute airway obstruction

Publication date: Available online 4 February 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): R. Vengatesh, N. Sanjeevan, Nik Fariza Husna Nik Hassan
Upper airway obstruction is one the most feared condition in Otolaryngology.Acute upper airway obstruction usually requires prompt tracheostomy as a lifesaving act. Through assessment and appropriate diagnosis and management of underlying cause are mandatory and at times even can avoid tracheostomy and its potential complications. We describe a case of severe laryngopharyngeal reflux (LPR) in 63-year-old man, causing acute stridor and airway obstruction lead to emergency tracheostomy. According to our literature review this may be the first case of LPR implicated in acute airway obstruction.



http://ift.tt/2jNjlY3

Unusual cause acute airway obstruction

Publication date: Available online 4 February 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): R. Vengatesh, N. Sanjeevan, Nik Fariza Husna Nik Hassan
Upper airway obstruction is one the most feared condition in Otolaryngology.Acute upper airway obstruction usually requires prompt tracheostomy as a lifesaving act. Through assessment and appropriate diagnosis and management of underlying cause are mandatory and at times even can avoid tracheostomy and its potential complications. We describe a case of severe laryngopharyngeal reflux (LPR) in 63-year-old man, causing acute stridor and airway obstruction lead to emergency tracheostomy. According to our literature review this may be the first case of LPR implicated in acute airway obstruction.



http://ift.tt/2jNjlY3

Over-Analysis of Minimal Data gives Misleading Conclusions: Response to Article by Benedetti-Pinto et al

Benedetti-Pinto et al have raised an interesting and current topic and report observations of possible associations between average h-indices of the editorial boards of plastic surgery journals and the impact factors of their journals1. However, whilst their analysis was valid, their conclusions were badly overstated, in light of the severe limitations of the data.

http://ift.tt/2keoC9F

Molecular Characterization and Functional Analyses of a Diapause Hormone Receptor-like Gene in Parthenogenetic Artemia

Publication date: Available online 4 February 2017
Source:Peptides
Author(s): Hui-Li Ye, Dong-Rui Li, Jin-Shu Yang, Dian-Fu Chen, Stephanie De Vos, Marnik Vuylsteke, Patrick Sorgeloos, Gilbert Van Stappen, Peter Bossier, Hiromichi Nagasawa, Wei-Jun Yang
In arthropods, mature females under certain conditions produce and release encysted gastrula embryos that enter diapause, a state of obligate dormancy. The process is presumably regulated by diapause hormone (DH) and diapause hormone receptor (DHR) that were identified in the silkworm, Bombyx mori and other insects. However, the molecular structure and function of DHR in crustaceans remains unknown. Here, a DHR-like gene from parthenogenetic Artemia (Ar-DHR) was isolated and sequenced. The cDNA sequence consists of 1410bp with a 1260-bp open reading frame encoding a protein consisting of 420 amino acid residues. The results of real-time PCR (qRT-PCR) and Western blot analysis showed that the mRNA and protein of Ar-DHR were mainly expressed at the diapause stage. Furthermore, we found that Ar-DHR was located on the cell membrane of the pre-diapause cyst but in the cytoplasm of the diapause cyst by analysis of immunofluorescence. In vivo knockdown of Ar-DHR by RNA interference (RNAi) and antiserum neutralization consistently inhibited diapause cysts formation. The results indicated that Ar-DHR plays an important role in the induction and maintenance of embryonic diapause in Artemia. Thus, our findings provide an insight into the regulation of diapause formation in Artemia and the function of Ar-DHR.



http://ift.tt/2jNd7aA

Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients

Publication date: March 2017
Source:European Journal of Cancer, Volume 73
Author(s): Kilian Wistuba-Hamprecht, Alexander Martens, Florian Heubach, Emanuela Romano, Marnix Geukes Foppen, Jianda Yuan, Michael Postow, Phillip Wong, Domenico Mallardo, Bastian Schilling, Anna Maria Di Giacomo, Amir Khammari, Brigitte Dreno, Michele Maio, Dirk Schadendorf, Paolo A. Ascierto, Jedd D. Wolchok, Christian U. Blank, Claus Garbe, Graham Pawelec, Benjamin Weide
The role of the assessment of peripheral T-cell phenotypes in predicting overall survival (OS) after ipilimumab treatment is unclear. Here, we analysed mononuclear cells in the blood before and at different time points during treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of baseline naïve and memory T-cells were measured by flow cytometry and correlated with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p = 0.029) and higher clinical response rates (p = 0.01). The frequency of these EM1 cells and the M category had independent impacts on OS (hazard ratio = 1.5, p = 0.033; and hazard ratio = 1.9, p = 0.007). In contrast, high baseline frequencies of late stage-differentiated effector memory CD8 cells (>23.8%) were negatively associated with OS (p = 0.034) but did not correlate with clinical response. Following treatment, a decrease of CD8 cells from baseline to the time of the second drug dose and at later time points was strongly and consistently correlated with a high clinical response rate. Our observations thus suggest an important predictive role of baseline CD8 EM1 cells and changes in CD8 cells for clinical response of ipilimumab. Further validation of these biomarker candidates is warranted.



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Cephalometric evaluation after two-stage palatoplasty combined with a Hotz plate: a comparative study between the modified Furlow and Widmaier–Perko methods

The effects on craniofacial growth of two different soft palate repair techniques in two-stage palatoplasty were investigated. This was a retrospective, cross-sectional cohort study of 68 children with non-syndromic, complete unilateral cleft lip and palate. Thirty-four patients were treated with the modified Furlow method (F-group) and the remaining 34 with the Widmaier–Perko method (P-group). Craniofacial growth was assessed by analyzing 12 angular and 12 linear measurements on lateral cephalograms.

http://ift.tt/2l5Gl4S

The effect of orthognathic surgery on the temporomandibular joint and oral function: a systematic review

The objective of this systematic review was to examine the effect of orthognathic surgery (OS) on the temporomandibular joint and oral function. Electronic databases were systematically searched for studies published until October 2015. Articles were assessed against predefined inclusion criteria. The included papers were divided into four groups based on the type of OS performed. The following items were recorded: quality of evidence using the Oxford Centre for Evidence-Based medicine (CEBM) criteria, number of patients, presence/absence of controls, mean age at treatment, follow-up time, clinical examination findings, bite force, use of the Helkimo Index and Research Diagnostic Criteria for Temporomandibular Disorders, imaging findings, and patient questionnaire results.

http://ift.tt/2l9Y8Vo

Does additional cone beam computed tomography decrease the risk of inferior alveolar nerve injury in high-risk cases undergoing third molar surgery?Does CBCT decrease the risk of IAN injury?

The objectives of this study were to evaluate the efficacy of additional cone beam computed tomography (CBCT) imaging on decreasing the risk of inferior alveolar nerve (IAN) injury during third molar removal in patients at high risk and to assess the surgical outcomes. The study sample included patients considered at high risk for IAN injury based on panoramic radiography (PAN) evaluation. The primary predictor was the type of imaging method (PAN only or with additional CBCT). The other variables were demographic and anatomical/radiographic factors.

http://ift.tt/2l5FaCq

Exploratory efficacy endpoints in the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA)

Publication date: Available online 4 February 2017
Source:Vaccine
Author(s): Chris Webber, Michael Patton, Scott Patterson, Beate Schmoele-Thoma, Susanne M. Huijts, Marc J.M. Bonten
BackgroundThe Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) assessed vaccine-type community-acquired pneumonia (VT-CAP) and vaccine-type invasive pneumococcal disease (VT-IPD) prevention with 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ⩾65years. We report vaccine efficacy (VE) of PCV13 for the remaining 23 exploratory endpoints and serotype distributions for pneumococcal CAP and IPD.MethodsThis was a parallel-group, randomised, placebo-controlled, double-blind trial comparing single-dose PCV13 with placebo. Exploratory CAP endpoints included first episode of confirmed non-VT (NVT) pneumococcal CAP; all confirmed episodes of NVT pneumococcal CAP, pneumococcal CAP, nonbacteraemic/noninvasive (NB/NI) VT pneumococcal CAP, and NB/NI pneumococcal CAP; and first and all episodes of culture-confirmed VT pneumococcal CAP, culture-confirmed pneumococcal CAP, culture-confirmed NVT pneumococcal CAP, probable VT pneumococcal CAP, probable NVT pneumococcal CAP, and probable and possible pneumococcal CAP. Exploratory IPD endpoints included all episodes of VT-IPD and IPD, and first and all episodes of NVT-IPD. The per-protocol and modified intent-to-treat (mITT) populations were evaluated.ResultsIn total, 84,496 participants were enrolled. Eight of 23 exploratory CAP and IPD endpoints were statistically significant in both populations. In the per-protocol population, these included VE of 29% for all episodes of confirmed pneumococcal CAP, 43% for all NB/NI episodes of VT pneumococcal CAP, 52% for all episodes of culture-confirmed pneumococcal CAP, and 53% for all episodes of IPD. Comparable VE estimates were observed in the mITT population. The most common VT serotypes were 1 (10 first episodes of confirmed pneumococcal CAP; 2 first episodes of IPD) and 7F (22; 7) among PCV13 and placebo recipients, respectively.ConclusionsThe results of this analysis yielded statistically significant PCV13 VE for all episodes of confirmed pneumococcal CAP (including NB/NI and culture-confirmed episodes) and for all episodes of IPD in adults aged ⩾65years. These findings are consistent with the primary efficacy analysis. ClinicalTrials.gov identifier: NCT00744263.



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Phenytoin-induced gingival overgrowth caused by death receptor pathway malfunction

Abstract

Objective

In this study, we investigated the role of phenytoin (PHT) in death receptor-induced apoptosis of gingival fibroblasts to clarify the mechanism of PHT-induced gingival overgrowth.

Methods

Human gingival fibroblasts were cultured to semi-confluence and treated with PHT (0.025, 0.1, 0.25, and 1.0 μM) for 48 h, and then the apoptotic cell numbers were relatively determined by absorptiometry. After 24 h of 0.25 μM PHT treatment, caspase activity was measured by absorptiometry, apoptotic and cell cycle phase distribution was analyzed by flow cytometry, expression levels of apoptotic genes were quantified by real-time qPCR, and expression of apoptotic proteins was detected by western blot analysis. After 48 h of 0.25 μM PHT treatment, appearance of apoptotic cells were detected by TUNEL assay.

Results

PHT treatment decreased the proportion of apoptotic cells in gingival fibroblasts compared to a serum-free control culture in response to the protein changes as follows: PHT upregulated c-FLIP and, in turn, downregulated FADD, caspase-8, and caspase-3; PHT upregulated c-IAP2 and downregulated TRAF2; PHT downregulated caspase-9 and caspase-3 via decreased RIPK1 activity and increased Bcl-2 activity.

Conclusions

PHT-induced gingival overgrowth may result from the above-mentioned mechanisms involving apoptosis inhibition in gingival fibroblasts.

This article is protected by copyright. All rights reserved.

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The incidence of concha bullosa, unusual anatomic variation and its relationship to nasal septal deviation: A retrospective radiologic study

Identifying anatomical variations associated with pathological findings is very useful for diagnoses and therapeutics. We conducted a study to detect various anatomical variations (superior, middle, inferior turbinate concha bullosa, uncinate bulla and nasal swell body [NSB]) in connection with nasal septal deviation.

http://ift.tt/2kF75Ic

The incidence of concha bullosa, unusual anatomic variation and its relationship to nasal septal deviation: A retrospective radiologic study

Identifying anatomical variations associated with pathological findings is very useful for diagnoses and therapeutics. We conducted a study to detect various anatomical variations (superior, middle, inferior turbinate concha bullosa, uncinate bulla and nasal swell body [NSB]) in connection with nasal septal deviation.

http://ift.tt/2kF75Ic

Oxidized and degraded mitochondrial polynucleotides (DeMPs), especially RNA, are potent immunogenic regulators in primary mouse macrophages

Publication date: Available online 4 February 2017
Source:Free Radical Biology and Medicine
Author(s): Abhinav R Saxena, Linda Y Gao, Shachi Srivatsa, Elizabeth Z Bobersky, Sivakumar Periasamy, Danielle T Hunt, Kyle E Altman, Dana R. Crawford
Certain mitochondrial components can act as damage-associated molecular patterns (DAMPs) or danger signals, triggering a proinflammatory response in target (usually immune) cells. We previously reported the selective degradation of mitochondrial DNA and RNA in response to cellular oxidative stress, and the immunogenic effect of this DNA in primary mouse astrocytes. Here, we extend these studies to assess the immunogenic role of both mitochondrial DNA and RNA isolated from hydrogen peroxide (HP) treated HA1 cells (designated "DeMPs" for degraded mitochondrial polynucleotides) using mouse bone marrow derived macrophages (BMDMs), a conventional immune cell type. DeMPs and control mitochondrial DNA (cont mtDNA) and RNA (cont mtRNA) were transfected into BMDMs and cell-free media analyzed for the presence of proinflammatory cytokines (IL-6, MCP-1, and TNFα) and Type I interferon (IFN-α and IFN-β). Cont mtDNA induced IL-6 and MCP-1 production, and this effect was even greater with DeMP DNA. A similar response was observed for Type I interferons. An even stronger induction of proinflammatory cytokine and type 1 interferons was observed for cont mtRNA. However, contrary to DeMP DNA, DeMP RNA attenuated rather than potentiated the cont mtRNA cytokine inductions. This attenuation effect was not accompanied by an IL-10 or TGFβ anti-inflammatory response. All DeMP effects were observed at multiple oxidant concentrations. Finally, DeMP production and immunogenicity overlaps with cellular adaptive response and so may contribute to cellular oxidant protection. These results provide new insight into the immunogenicity of mitochondrial polynucleotides, and identify new roles and selective consequences of cellular oxidation.



http://ift.tt/2kAUq9T

Mechanisms of defense against products of cysteine catabolism in the nematode Caenorhabditis elegans

Publication date: Available online 4 February 2017
Source:Free Radical Biology and Medicine
Author(s): Leonid Livshits, Arijit Kumar Chatterjee, Netanel Karbian, Rachel Abergel, Zohar Abergel, Einav Gross
Cysteine catabolism presents cells with a double-edged sword. On the one hand, cysteine degradation provides cells with essential molecules such as taurine and sulfide. The formation of sulfide in cells is thought to regulate important and diverse physiological processes including blood circulation, synaptic activity and inflammation. On the other hand, the catabolism of cysteine by gut microbiota can release high levels of sulfide that may underlie the development or relapse of ulcerative colitis, an inflammatory bowel disease affecting millions of people worldwide. Here, we have used the nematode C. elegans to explore how cells tolerate high levels of sulfide produced by cysteine degradation in bacteria. We have identified mutations in genes coding for thioredoxin family proteins, mitochondrial proteins, and collagens that confer tolerance to sulfide toxicity. Exposure to sulfide induces the unfolded protein response in the endoplasmic reticulum and mitochondria. Moreover, our results suggest that sulfide toxicity is mediated by reactive oxygen species (ROS). Indeed, pre-treatment of worms with antioxidants increases their tolerance to sulfide toxicity. Intriguingly, sub-toxic levels of the superoxide generator paraquat can also increase the tolerance of worms to sulfide. Therefore, it appears that activation of ROS detoxification pathway prior to the exposure to sulfide, can increase the tolerance to sulfide toxicity. Our results suggest that these detoxification pathways are mediated by the hypoxia inducible factor HIF-1. Finally, we show that sulfide resistance varies among wild C. elegans and other nematode species, suggesting that tolerance to sulfide was naturally selected in certain habitats.

Graphical abstract

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Role of the oxidized form of XRCC1 in protection against extreme oxidative stress

Publication date: Available online 4 February 2017
Source:Free Radical Biology and Medicine
Author(s): Julie K. Horton, Hannah J. Seddon, Ming-Lang Zhao, Natalie R. Gassman, Agnes K. Janoshazi, Donna F. Stefanick, Samuel H. Wilson
The multi-domain protein XRCC1 is without catalytic activity, but can interact with a number of known repair proteins. The interaction between the N-terminal domain (NTD) of XRCC1 and DNA polymerase β (pol β) is critical for recruitment of pol β to sites of DNA damage and repair. Crystallographic and NMR approaches have identified oxidized and reduced forms of the XRCC1 NTD, and the corresponding forms of XRCC1 have been identified in cultured mouse fibroblast cells. Both forms of NTD interact with pol β, but the interaction is much stronger with the oxidized form. The potential for formation of the C12-C20 oxidized conformation can be removed by alanine substitution at C12 (C12A) leading to stabilized reduced XRCC1 with a lower pol β binding affinity. Here, we compare cells expressing C12A XRCC1 (XRE8) with those expressing wild-type XRCC1 (XC5). Reduced C12A XRCC1 is detected at sites of micro-irradiation DNA damage, but provides slower recruitment of pol β. Expression of reduced XRCC1 does not affect sensitivity to MMS or H2O2. In contrast, further oxidative stress imposed by glutathione depletion results in increased sensitization of reduced XRCC1-expressing cells to H2O2 compared with wild-type XRCC1-expressing cells. There is no indication of enhanced H2O2-generated free radicals or DNA strand breaks in XRE8 cells. However, elevated cellular PAR is found following H2O2 exposure, suggesting BER deficiency of H2O2-induced damage in the C12A expressing cells.



http://ift.tt/2jPGkN6

Glucose-6-phosphate dehydrogenase and Trypanothione reductase interaction protects Leishmania donovani from metalloid mediated oxidative stress

Publication date: Available online 4 February 2017
Source:Free Radical Biology and Medicine
Author(s): Ayan Kumar Ghosh, Savita Saini, Sushmita Das, Abhishek Mandal, Abul Hasan Sardar, Md. Yousuf Ansari, Kumar Abhishek, Ajay Kumar, Ruby Singh, Sudha Verma, Asif Equbal, Vahab Ali, Pradeep Das
Exploration of metabolons as viable drug target is rare in kinetoplastid biology. Here we present a novel protein-protein interaction among Glucose-6-phosphate dehydrogenase (LdG6PDH) and Trypanothione reductase (LdTryR) of Leishmania donovani displaying interconnection between central glucose metabolism and thiol metabolism of this parasite. Digitonin fractionation patterns observed through immunoblotting indicated localisation of both LdG6PDH and LdTryR in cytosol. In-silico and in-vitro interaction observed by size exclusion chromatography, co-purification, pull-down assay and spectrofluorimetric analysis revealed LdG6PDH and LdTryR physically interact with each other in a NADPH dependent manner. Coupled enzymatic assay displayed that NADPH generation was severely impaired by addition of Sb^III, As^III and Te^IV extraneously, which hint towards metalloid driven structural changes of the interacting proteins. Co-purification patterns and pull-down assays also depicted that metalloids (Sb^III, As^III and Te^IV) hinder the in-vitro interaction of these two enzymes. Surprisingly, metalloids at sub-lethal concentrations induced the in-vivo interaction of LdG6PDH and LdTryR, as analysed by pull-down assays and fluorescence microscopy signifying protection against metalloid mediated ROS. Inhibition of LdTryR by thioridazine in LdG6PDH^-/- parasites resulted in metalloid induced apoptotic death of the parasites due to abrupt fall in reduced thiol content, disrupted NADPH/NADP⁺ homeostasis and lethal oxidative stress. Interestingly, clinical isolates of L.donovani resistant to SAG exhibited enhanced interaction between LdG6PDH and LdTryR and showed cross resistivity towards As^III and Te^IV. Thus, our findings propose the metabolon of LdG6PDH and LdTryR as an alternate therapeutic target and provide mechanistic insight about metalloid resistance in Visceral Leishmaniasis.

Graphical abstract

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Aspirin is Associated with Improved Survival in Severely Thrombocytopenic Cancer Patients with Acute Myocardial Infarction

Background.

Patients with hematologic malignancies are at risk for severe thrombocytopenia (sTP). The risk and benefit of aspirin are not known in thrombocytopenic cancer patients experiencing acute myocardial infarction (AMI).

Materials and Methods

Medical records of patients with hematologic malignancies diagnosed with AMI at Memorial Sloan Kettering Cancer Center during 2005–2014 were reviewed. sTP was defined as a platelet count <50,000 cells per µL within 7 days of AMI.

Results.

Of 118 patients with hematologic malignancies who had AMI, 58 (49%) had sTP. Twenty-five patients (43%) with sTP received aspirin as a treatment for AMI. Compared with patients without sTP with AMI, patients with sTP with AMI were less likely to receive aspirin (83% vs. 43%; p = .0001) and thienopyridine treatment (27% vs. 3%; p = .0005). During median follow-up of 3.7 years after AMI, survival was lower in patients with sTP than in those with no sTP (23% vs. 50% at 1 year; log rank p = .003). Patients with sTP who received aspirin for AMI had improved survival compared with those who did not (92% vs. 70% at 7 days, 72% vs. 33% at 30 days, and 32% vs. 13% at 1 year; log rank p = .008). In multivariate regression models, aspirin use was associated with improved 30-day survival both in the overall patient cohort and in sTP patients. No fatal bleeding events occurred. Major bleeding was not associated with sTP or aspirin use.

Conclusion.

Treatment of AMI with aspirin in patients with hematologic malignancies and sTP is associated with improved survival without increase in major bleeding. The Oncologist 2017;22:000–000

Implications for Practice: In patients with hematologic malignancies and acute myocardial infarction with severe thrombocytopenia (platelet count < 50,000 cells/µL), guideline-recommended medical therapy is often withheld because of the fear of major bleeding. In this study, aspirin therapy was associated with improved survival without an increase in major bleeding in this high-risk patient cohort.

http://ift.tt/2ktMHrB

The synergistic effect of radiotherapy and immunotherapy: A promising but not simple partnership

Publication date: Available online 4 February 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Enrique Chajon, Joël Castelli, Hugo Marsiglia, Renaud de Crevoisier
Radiotherapy (RT) is one of the main components in the treatment of cancer. The better understanding of the immune mechanisms associated with tumor establishment and how RT affects inflammation and immunity has led to the development of novel treatment strategies. Several preclinical studies support the use of RT in combination with immunotherapy obtaining better local and systemic tumor control. Current ongoing studies will provide information about the optimal RT approach, but the development of reliable predictors of the response from the preclinical and the early phases of clinical studies is necessary to avoid discarding treatment strategies with significant clinical benefit. This review summarize the current concepts of the synergism between RT and immunotherapy, the molecular effects of RT in the tumor microenvironment, their impact on immune activation and its potential clinical applications in trials exploring this important therapeutic opportunity. Finally, the potential predictors of clinical response are discussed.



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Epigenetic control of gene expression: Potential implications for cancer treatment

Publication date: Available online 4 February 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): F. Perri, F. Longo, M. Giuliano, F. Sabbatino, G. Favia, F. Ionna, R. Addeo, G. Della Vittoria Scarpati, G. Di Lorenzo, S. Pisconti S
Epigenetic changes are defined as inherited modifications that are not present in DNA sequence. Gene expression is regulated at various levels and not only in response to DNA modifications. Examples of epigenetic control are: DNA methylation, histone deacetylation and mi-RNA expression. Methylation of several tumor suppressor gene promoters is responsible for their silencing and thus potentially sustain cancerogenesis. Similarly, histone deacetylation can lead to oncogene activation. Mi-RNA are small (18-20 nucleotides) non-coding RNA fragments capable of inhibiting other m-RNA, ultimately altering the balance in oncogene and tumor suppressor gene expression. It has been shown that growth of several tumor types can be stimulated by epigenetic changes in various phases of cancerogenesis, and drugs able to interfere with these mechanisms can have a positive impact on tumor progression. As matter of fact, epigenetic changes are dynamic and can be reversed by epigenetic inhibitors. Recently, methyltransferase and histone deacetylase inhibitors have attracted the attention of researchers and clinicians as they potentially provide alternative therapeutic options in some cancers. Drugs that inhibit DNA methylation or histone deacetylation have been studied for the reactivation of tumor suppressor genes and repression of cancer cell growth. Epigenetic inhibitors work alone or in combination with other therapeutic agents. To date, a number of epigenetic inhibitors have been approved for cancer treatment. The main challenge in the field of epigenetic inhibitors is their lack of specificity. In this review article we describe their mechanisms of action and potential in cancer treatment.



http://ift.tt/2l9wpnr

Multimodal treatment of resectable pancreatic ductal adenocarcinoma

Publication date: Available online 4 February 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Nicola Silvestris, Oronzo Brunetti, Enrico Vasile, Francesco Cellini, Ivana Cataldo, Valeria Pusceddu, Monica Cattaneo, Stefano Partelli, Mario Scartozzi, Giuseppe Aprile, Andrea Casadei Gardini, Alessio Giuseppe Morganti, Vincenzo Valentini, Aldo Scarpa, Massimo Falconi, Angela Calabrese, Vito Lorusso, Michele Reni, Stefano Cascinu
After a timing preoperative staging, treatment of resectable pancreatic adenocarcinoma (PDAC) includes surgery and adjuvant therapies, the former representing the initial therapeutic option and the latter aiming to reduce the incidence of both distant metastases (chemotherapy) and locoregional failures (chemoradiotherapy). Herein, we provide a critical overview on the role of multimodal treatment in PDAC and on new opportunities related to current more active poli-chemotherapy regimens, targeted therapies, and the more recent immunotherapy approaches. Moreover, an analysis of pathological markers and clinical features able to help clinicians in the selection of the best therapeutic strategy will be discussed. Lastly, the role of neoadjuvant treatment of initially resectable disease will be considered mostly in patients whose malignancy shows morphological but not clinical or biological criteria of resectability. Depending on the results of these investigational studies, today a multidisciplinary approach can offer the best address therapy for these patients.



http://ift.tt/2kdxhZS

Oropharyngeal cancer prognosis by tumour HPV status in France: The multicentric Papillophar study

Human-papillomavirus-positive (HPV-pos) and HPV-negative (HPV-neg) oropharyngeal cancer (OPC) differ with respect to many biological [1], clinical [2,3], and epidemiological aspects [4,5]. The survival advantage among HPV-pos OPC patients has been attributed to less severe genetic alterations, e.g., lower rates of TP53 mutations [1] and, possibly, better response to radio- and chemo-therapy than in HPV-neg OPC that are mainly caused by the use of tobacco and alcohol [5]. However, most previous reports on OPC prognosis by HPV status were conducted in populations (mainly the United States, [5], Australia [6]) and/or among selected clinical trial patients [2] in whom markers of HPV-positivity were more prevalent and heavy tobacco exposure less frequent than in Southern Europe and low and middle-income countries [7].

http://ift.tt/2l5jndS

Phosphate and ammonium adsorption of the modified biochar based on Phragmites australis after phytoremediation

Abstract

To effectively remove N and P from eutrophic water, the Phragmites australis after phytoremediation was harvested for preparation of modified biochar. The MgCl₂-modified biochar (MPB) was successfully synthesized at 600 °C under N₂ circumstance. The physiochemical characteristics, the adsorption capacity for N and P in the simulated solution, and their adsorption mechanism of MPB were then determined, followed by the treatment of eutrophic water of Tai lake and its inflow river from agricultural source. The results demonstrated that the MPB presented high adsorption capacity to both simulated NH₄-N and PO₄-P with the maximum adsorption capacity exceeding 30 and 100 mg g⁻¹, respectively. The entire ammonium adsorption process could be described by a pseudo-second-order kinetic model whereas the phosphate adsorption process could be divided into three phases, as described by both intra-particle diffusion model and the pseudo-first-order kinetic. It was further found that the dominant mechanism for ammonium adsorption was Mg²⁺ exchange instead of functional groups and surface areas and the Mg-P precipitation was the main mechanism for phosphate adsorption. The MPB also showed high removal ratio of practical TP which reached nearly 90% for both the water in Tai lake and its agricultural source. It suggested that MPB based on harvested P. australis was a promising composite for eutrophic water treatment and it could deliver multiple benefits.

Graphic abstract

http://ift.tt/2ktAJye

Comparative Columellar Scar Analysis Between W Incisions and Inverted-V Incision in Open Technique Nasal Surgery

Abstract

A visible scar on the columella is undesirable result for both patient and surgeon. So it is one of the major disadvantage of open nose surgery. Different columellar incision types have been used in open technique of nasal surgery. In this prospective study, we compare W incisions and inverted-V columellar incisions with a scar assessment scale. In this prospective randomized study, open nasal surgery (open rhinoplasty and open technique septoplasty) were performed on 93 patients between November 2009 and July 2012. The inverted-V incision was used on 31 patients (24 males, 7 females). The "W" incision was used on 62 patients (40 males, 22 females). The entire surgical procedure was performed by a single surgeon. The columellar incision was closed using 6–0 interrupted polypropylene sutures. All sutures were removed on the seventh postoperative day. Scars were assessed at 6 moths, with 3 items scar assessment scale, we observed satisfactory scar, pigmentation, and notching. We compared both groups and found that the scar pigmentation, notching and scar formation are similar to each other. As a result of this study we concluded that the inverted-V incision or "W" incision might be a similar choice in open nasal surgery.

http://ift.tt/2l8ULh4