Δευτέρα, 16 Ιανουαρίου 2017

Spanish deliver masterclass on imaging of peritoneum

2017_01_16_14_55_29_676_Barcelona_SagradWhat do you really need to know about imaging of peritoneal metastases? Radiologists...


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Cosmetics, Vol. 4, Pages 6: Acknowledgement to Reviewers of Cosmetics in 2016

The editors of Cosmetics would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. [...]

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Carbon cascade reveals fresh look to the element of life

Suspensions of carbon are manipulated into amazing patterns using electricity, vibration, temperature changes and infrared light

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Current and future management of the young child with early onset wheezing.

Purpose of review: In this review, we discuss current thinking in relation to available guidelines for the care of preschool-aged children with recurrent wheezing, while highlighting the gaps in our knowledge and discussing changes that could occur over the next 5 years. Recent findings: The Asthma Predictive Index as well as allergen-specific IgE, peripheral eosinophil count and exhaled nitric oxide are perhaps underutilized sources of information that can assist in predicting progression to asthma and response to therapies. Inhaled corticosteroids and leukotriene receptor antagonists decrease impairment and exacerbation frequency in wheezing children but are not disease modifying. Macrolides may be useful during acute wheezing episodes for preventing progression to more severe symptoms. Monoclonal antibodies targeting IgE and TH2 cytokines have been successful in trials of adults and older children with asthma, but trials in younger children are needed. Summary: Establishing the phenotype and endotype of young wheezing children can be useful for prognostication of future asthma risk as well as for selection of the most appropriate treatment. Primary asthma prevention strategies are needed during the critical developmental window in early life prior to the onset of irrecoverable loss of lung function. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Carbon cascade reveals fresh look to the element of life

carbon_newscientist_2016-800x533.jpg

Suspensions of carbon are manipulated into amazing patterns using electricity, vibration, temperature changes and infrared light

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Comparative RNA-Sequence Transcriptome Analysis of Phenolic Acid Metabolism in Salvia miltiorrhiza, a Traditional Chinese Medicine Model Plant

Salvia miltiorrhiza Bunge is an important traditional Chinese medicine (TCM). In this study, two S. miltiorrhiza genotypes (BH18 and ZH23) with different phenolic acid concentrations were used for de novo RNA sequencing (RNA-seq). A total of 170,787 transcripts and 56,216 unigenes were obtained. There were 670 differentially expressed genes (DEGs) identified between BH18 and ZH23, 250 of which were upregulated in ZH23, with genes involved in the phenylpropanoid biosynthesis pathway being the most upregulated genes. Nine genes involved in the lignin biosynthesis pathway were upregulated in BH18 and thus result in higher lignin content in BH18. However, expression profiles of most genes involved in the core common upstream phenylpropanoid biosynthesis pathway were higher in ZH23 than that in BH18. These results indicated that genes involved in the core common upstream phenylpropanoid biosynthesis pathway might play an important role in downstream secondary metabolism and demonstrated that lignin biosynthesis was a putative partially competing pathway with phenolic acid biosynthesis. The results of this study expanded our understanding of the regulation of phenolic acid biosynthesis in S. miltiorrhiza.

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Adaptive cone-beam CT planning improves long-term biochemical disease-free survival for 125I prostate brachytherapy

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Publication date: Available online 16 January 2017
Source:Brachytherapy
Author(s): M. Peters, D.A. Smit Duijzentkunst, H. Westendorp, S.M.G. van de Pol, R. Kattevilder, A. Schellekens, J.R.N. van der Voort van Zyp, M.A. Moerland, M. van Vulpen, C.J. Hoekstra
PurposeDetermining the independent effect of additional intraoperative adaptive C-arm cone-beam CT (CBCT) planning vs. transrectal ultrasound (TRUS)-guided interactive planning alone in 125I brachytherapy for prostate cancer (PCa) on biochemical disease-free survival (BDFS).Methods and materialsT1/T2-stage PCa patients receiving TRUS-guided brachytherapy from 2000 to 2014 were analyzed. From October 2006, patients received additional intraoperative adaptive CBCT planning for dosimetric evaluation and subsequent remedial seed placement in underdosed areas. Patients were stratified according to the National Comprehensive Cancer Network (NCCN) risk classification. Kaplan–Meier analysis was used to estimate BDFS (primary outcome), overall survival, and PCa-specific survival (secondary outcomes). Cox regression was used to assess the relation between CBCT use and biochemical failure (BF) and overall mortality.ResultsIn all, 1623 patients were included. Median followup was 99 months (interquartile range 70–115) for TRUS patients (n = 613) and 51 months (interquartile range 29–70) for CBCT patients (n = 1010). BF occurred 203 times and 206 patients died, 26 from PCa. For TRUS and CBCT patients, 7-year BDFS was 87.2% vs. 93.5% (log rank: p = 0.04) for low, 75.9% vs. 88.5% (p < 0.001) for intermediate, and 57.1% vs. 85.0% for high-risk patients (p < 0.001). For TRUS and CBCT patients, 7-year PCa-specific survival was 96.0% vs. 100% (p < 0.0001). After Cox regression, CBCT patients had lower hazard of BF: hazard ratio (HR) 0.25 (95% confidence interval [CI]: 0.18–0.33; p < 0.0001). Corrected for confounders, CBCT remained a predictor of BF: HR 0.51 (95% CI: 0.31–0.86; p = 0.01) but not for overall mortality: HR 0.66 (95% CI: 0.40–1.07; p = 0.09).ConclusionsAdditional intraoperative adaptive CBCT planning in 125I prostate brachytherapy leads to a significant increase in BDFS in all NCCN risk groups.



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American Brachytherapy Society Task Group Report: Use of androgen deprivation therapy with prostate brachytherapy—A systematic literature review

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Publication date: Available online 16 January 2017
Source:Brachytherapy
Author(s): M. Keyes, G. Merrick, S.J. Frank, P. Grimm, M.J. Zelefsky
PurposeProstate brachytherapy (PB) has well-documented excellent long-term outcomes in all risk groups. There are significant uncertainties regarding the role of androgen deprivation therapy (ADT) with brachytherapy. The purpose of this report was to review systemically the published literature and summarize present knowledge regarding the impact of ADT on biochemical progression-free survival (bPFS), cause-specific survival (CSS), and overall survival (OS).Methods and MaterialsA literature search was conducted in Medline and Embase covering the years 1996–2016. Selected were articles with >100 patients, minimum followup 3 years, defined risk stratification, and directly examining the role and impact of ADT on bPFS, CSS, and OS. The studies were grouped to reflect disease risk stratification. We also reviewed the impact of ADT on OS, cardiovascular morbidity, mortality, and on-going brachytherapy randomized controlled trials (RCTs).ResultsFifty-two selected studies (43,303 patients) were included in this review; 7 high-dose rate and 45 low-dose rate; 25 studies were multi-institutional and 27 single institution (retrospective review or prospective data collection) and 2 were RCTs. The studies were heterogeneous in patient population, risk categories, risk factors, followup time, and treatment administered, including ADT administration and duration (median, 3–12 months);71% of the studies reported a lack of benefit, whereas 28% showed improvement in bPFS with addition of ADT to PB. The lack of benefit was seen in low-risk and favorable intermediate-risk (IR) disease and most high–dose rate studies. A bPFS benefit of up to 15% was seen with ADT use in patients with suboptimal dosimetry, those with multiple adverse risk factors (unfavorable IR [uIR]), and most high-risk (HR) studies. Four studies reported very small benefit to CSS (2%). None of the studies showed OS advantage; however, three studies reported an absolute 5–20% OS detriment with ADT. Literature suggests that OS detriment is more likely in older patients or those with pre-existing cardiovascular disease. Four RCTs with an adequate number of patients and well-defined risk stratification are in progress. One RCT will answer the question regarding the role of ADT with PB in favorable IR patients and the other three RCTs will focus on optimal duration of ADT in the uIR and favorable HR population.ConclusionsPatients treated with brachytherapy have excellent long-term disease outcomes. Existing evidence shows no benefit of adding ADT to PB in low-risk and favorable IR patients. UIR and HR patients and those with suboptimal dosimetry may have up to 15% improvement in bPFS with addition of 3–12 months of ADT, with uncertain impact on CSS and a potential detriment on OS. To minimize morbidity, one should exercise caution in prescribing ADT together with PB, in particular to older men and those with existing cardiovascular disease. Due to the retrospective nature of this evidence, significant selection, and treatment bias, no definitive conclusions are possible. RCT is urgently needed to define the potential role and optimal duration of ADT in uIR and favorable HR disease.



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The UPR reduces glucose metabolism via IRE1 signaling

Publication date: Available online 16 January 2017
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): Judith M. van der Harg, Jessica C. van Heest, Fabian N. Bangel, Sanne Patiwael, Jan R.T. van Weering, Wiep Scheper
Neurons are highly dependent on glucose. A disturbance in glucose homeostasis therefore poses a severe risk that is counteracted by activation of stress responses to limit damage and restore the energy balance. A major stress response that is activated under conditions of glucose deprivation is the unfolded protein response (UPR) that is aimed to restore proteostasis in the endoplasmic reticulum. The key signaling of the UPR involves the transient activation of a transcriptional program and an overall reduction of protein synthesis. Since the UPR is strategically positioned to sense and integrate metabolic stress signals, it is likely that - apart from its adaptive response to restore proteostasis - it also directly affects metabolic pathways. Here we investigate the direct role of the UPR in glucose homeostasis. O-GlcNAc is a post-translational modification that is highly responsive to glucose fluctuations. We find that UPR activation results in decreased O-GlcNAc modification, in line with reduced glucose metabolism. Our data indicate that UPR activation has no direct impact on the upstream processes in glucose metabolism; glucose transporter expression, glucose uptake and hexokinase activity. In contrast, prolonged UPR activation decreases glycolysis and mitochondrial metabolism. Decreased mitochondrial respiration is not accompanied by apoptosis or a structural change in mitochondria indicating that the reduction in metabolic rate upon UPR activation is a physiological non-apoptotic response. The metabolic decrease is prevented if the IRE1 pathway of the UPR is inhibited. This indicates that activation of IRE1 signaling induces a reduction in glucose metabolism, as part of an adaptive response.



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Coronary-Cameral Fistula Connecting the Left Anterior Descending Artery and the First Obtuse Marginal Artery to the Left Ventricle: A Rare Finding

Coronary-cameral fistulas are rare congenital malformations, often incidentally found during cardiac catheterizations. The majority of these fistulas are congenital in nature but can be acquired secondary to trauma or invasive cardiac procedures. These fistulas most commonly originate in the right coronary artery and terminate into the right ventricle and least frequently drain into the left ventricle. Depending upon their size and location, coronary-cameral fistulas can lead to congestive heart failure, myocardial infarction, and bacterial endocarditis. We describe a case of 49-year-old woman who presented with worsening exertional dyspnea and leg swelling. Transthoracic echocardiogram revealed an ejection fraction of 35%. Cardiac catheterization demonstrated a fistula connecting the left anterior descending artery and the first obtuse marginal artery to the left ventricle. In this report, the authors provide a concise review on coronary fistulas, complications, and management options.

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A Removal of Eye Movement and Blink Artifacts from EEG Data Using Morphological Component Analysis

EEG signals contain a large amount of ocular artifacts with different time-frequency properties mixing together in EEGs of interest. The artifact removal has been substantially dealt with by existing decomposition methods known as PCA and ICA based on the orthogonality of signal vectors or statistical independence of signal components. We focused on the signal morphology and proposed a systematic decomposition method to identify the type of signal components on the basis of sparsity in the time-frequency domain based on Morphological Component Analysis (MCA), which provides a way of reconstruction that guarantees accuracy in reconstruction by using multiple bases in accordance with the concept of “dictionary.” MCA was applied to decompose the real EEG signal and clarified the best combination of dictionaries for this purpose. In our proposed semirealistic biological signal analysis with iEEGs recorded from the brain intracranially, those signals were successfully decomposed into original types by a linear expansion of waveforms, such as redundant transforms: UDWT, DCT, LDCT, DST, and DIRAC. Our result demonstrated that the most suitable combination for EEG data analysis was UDWT, DST, and DIRAC to represent the baseline envelope, multifrequency wave-forms, and spiking activities individually as representative types of EEG morphologies.

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Enhancement of the Pitting Corrosion Resistance of AISI 316LVM Steel with Ta-Hf-C/Au Bilayers for Biomedical Applications

Tantalum carbide (TaC), hafnium carbide (HfC), and Ta-Hf-C mixed coatings with and without a gold (Au) interlayer were deposited on 316LVM steel substrates by the magnetron cosputtering technique in order to improve the corrosion resistance of steel substrates in a simulated biological fluid. To study the effect of the gold interlayer on pitting corrosion, the different systems were placed in contact with Ringer’s solution at pH 7.4 and a temperature of 37°C. The electrochemical properties of the coatings were determined using polarization curves. Subsequently, the surface morphologies were observed using scanning electron microscopy (SEM) in order to analyze the corrosion processes on the different surfaces. The gold interlayer was found to significantly improve the electrochemical properties of the system, showing a decrease in the pitting corrosion and deterioration rate, while it is expected that the binary and ternary carbides provide mechanical stability to the bilayers protecting the gold.

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Molecular Cloning, Bioinformatic Analysis, and Expression of Bombyx mori Lebocin 5 Gene Related to Beauveria bassiana Infection

A full-length cDNA of lebocin 5 (BmLeb5) was first cloned from silkworm, Bombyx mori, by rapid amplification of cDNA ends. The BmLeb5 gene is 808 bp in length and the open reading frame encodes a 179-amino acid hydroxyproline-rich peptide. Bioinformatic analysis results showed that BmLeb5 owns an O-glycosylation site and four RXXR motifs as other lebocins. Sequence similarity and phylogenic analysis results indicated that lebocins form a multiple gene family in silkworm as cecropins. Quantitative real-time PCR analysis revealed that BmLeb5 was highest expressed in the fat body. In the silkworm larvae infected by Beauveria bassiana, the expression level of BmLeb5 was upregulated in the fat body and hemolymph which are the most important immune tissues in silkworm. The recombinant protein of BmLeb5 was for the first time successfully expressed with prokaryotic expression system and purified. There are no reports so far that the expression of lebocins could be induced by entomopathogenic fungus. Our study suggested that BmLeb5 might play an important role in the immune response of silkworm to defend B. bassiana infection. The results also provided helpful information for further studying the lebocin family functioned in antifungal immune response in the silkworm.

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Antineoplastic Effects of Honokiol on Melanoma

Honokiol, a plant lignan has been shown to have antineoplastic effects against nonmelanoma skin cancer developments in mice. In this study, antineoplastic effects of honokiol were investigated in malignant melanoma models. In vitro effects of honokiol treatment on SKMEL-2 and UACC-62 melanoma cells were evaluated by measuring the cell viability, proliferation, apoptosis, cell cycle analysis, and expressions of various proteins associated with cell cycle progression and apoptosis. For the in vivo study, male nude mice inoculated with SKMEL-2 or UACC-62 cells received injections of sesame oil or honokiol for two to seven weeks. In vitro honokiol treatment caused significant decrease in cell viability, proliferation, cell cycle arrest, increased apoptosis, and modulation of apoptotic and cell cycle regulatory proteins. Honokiol caused an accumulation of cells in the G2/M phase of the cell cycle in SKMEL-2 and G0/G1 phase in UACC-62 cells. An elevated level of caspases and PARP were observed in both cell lines treated with honokiol. A decrease in the expression of various cell cycle regulatory proteins was also observed in honokiol treated cells. Honokiol caused a significant reduction of tumor growth in SKMEL-2 and UACC-62 melanoma xenografts. These findings suggest that honokiol is a good candidate for further studies as a possible treatment for malignant melanoma.

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In-Depth Investigation of Statistical and Physicochemical Properties on the Field Study of the Intermittent Filling of Large Water Tanks

Large-demand customers, generally high-density dwellings and buildings, have dedicated ground or elevated water tanks to consistently supply drinking water to residents. Online field measurement for Nonsan-2 district meter area demonstrated that intermittent replenishment from large-demand customers could disrupt the normal operation of a water distribution system by taking large quantities of water in short times when filling the tanks from distribution mains. Based on the previous results of field measurement for hydraulic and water quality parameters, statistical analysis is performed for measured data in terms of autocorrelation, power spectral density, and cross-correlation. The statistical results show that the intermittent filling interval of 6.7 h and diurnal demand pattern of 23.3 h are detected through autocorrelation analyses, the similarities of the flow-pressure and the turbidity-particle count data are confirmed as a function of frequency through power spectral density analyses, and a strong cross-correlation is observed in the flow-pressure and turbidity-particle count analyses. In addition, physicochemical results show that the intermittent refill of storage tank from large-demand customers induces abnormal flow and pressure fluctuations and results in transient-induced turbid flow mainly composed of fine particles ranging within 2–4 μm and constituting Fe, Si, and Al.

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Internal Jugular and Subclavian Vein Thrombosis in a Case of Ovarian Cancer

Central venous catheter insertion and cancer represent some of the important predisposing factors for deep venous thrombosis (DVT). DVT usually develops in the lower extremities, and venous thrombosis of the upper extremities is uncommon. Early diagnosis and treatment of deep venous thrombosis are of importance, because it is a precursor of complications such as pulmonary embolism and postthrombotic syndrome. A 47-year-old woman visited our department with painful swelling on the left side of her neck. Initial examination revealed swelling of the region extending from the left neck to the shoulder without any redness of the overlying skin. Laboratory tests showed a white blood cell count of 5,800/mm3 and an elevated serum C-reactive protein of 4.51 mg/dL. Computed tomography (CT) of the neck revealed a vascular filling defect in the left internal jugular vein to left subclavian vein region, with the venous lumina completely occluded with dense soft tissue. On the basis of the findings, we made the diagnosis of thrombosis of the left internal jugular and left subclavian veins. The patient was begun on treatment with oral rivaroxaban, but the left shoulder pain worsened. She was then admitted to the hospital and treated by balloon thrombectomy and thrombolytic therapy, which led to improvement of the left subclavian venous occlusion. Histopathologic examination of the removed thrombus revealed adenocarcinoma cells, indicating hematogenous dissemination of malignant cells.

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A New Capacitor-Less Buck DC-DC Converter for LED Applications

In this paper, a new capacitor-less DC-DC converter is proposed to be used as a light emitting diode (LED) driver. The design is based on the utilization of the internal capacitance of the LED to replace the smoothing capacitor. LED lighting systems usually have many LEDs for better illumination that can reach multiple tens of LEDs. Such configuration can be utilized to enlarge the total internal capacitance and hence minimize the output ripple. Also, the switching frequency is selected such that a minimum ripple appears at the output. The functionality of the proposed design is confirmed experimentally and the efficiency of the driver is 85% at full load.

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Co-Infection of Cryptococcal and Multidrug Resistant Tuberculous Meningitis in Immunocompetent Patient

The post Co-Infection of Cryptococcal and Multidrug Resistant Tuberculous Meningitis in Immunocompetent Patient appeared first on Welcome to Avens.



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Woman dies after infection with bacteria resistant to all antibiotics available in US

A woman in the US died of septic shock last year after becoming infected with carbapenem resistant Enterobacteriaceae (CRE) that were resistant to all antimicrobial drugs available in the US.The...
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Eating disorders are more prevalent than expected in women during midlife, study finds

The prevalence of eating disorders in women in midlife is higher than expected, a study published in BMC Medicine has found, as 3.6% of women in their 40s and 50s reported having experienced an...
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Intermediate outcomes of a transcutaneous bone conduction hearing device in a paediatric population

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Publication date: Available online 16 January 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Panagiotis A. Dimitriadis, Suzanne Carrick, Jaydip Ray
ObjectiveThe aim of this study was to review the outcomes of Bone Anchored Hearing Aid (BAHA®) Attract implantation in a cohort of paediatric patients.MethodsProspective data collection and case review were undertaken in apaediatric tertiary referral centre. We have included patients under the age of 16 years with unilateral or bilateral hearing loss that met the criteria for BAHA® Attract implantation. The main outcome measures were surgical complications and Patient Reported Outcomes including the ‘Speech, Spatial and Qualities of Hearing scale’ (SSQ-12) and ‘Qualitative Feedback for BAHA® 5 Hearing Aids’.ResultsTwenty-five paediatric patients were implanted with the BAHA® Attract between June 2014 and July 2016. Nine of them had a conversion from a percutaneous Bone Conduction Hearing Device (BCHD). Four children had minor skin problems that settled with conservative measures. Two children with a previous percutaneous BCHD developed skin dehiscence over the magnet after conversion to the transcutaneous version. The SSQ-12 was completed by 6 children and an improvement of 22% was noted between the unaided and aided condition. The patients and their parents were generally satisfied with the BAHA® Attract.ConclusionsThe BAHA® Attract offers a good solution for hearing rehabilitation in appropriately selected and counseled patients. The complication rate was low for primary surgery but higher in cases of conversion from a percutaneous device. Large, prospective data is needed to evaluate the relative risks and benefits of this BCHD.



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Early childhood otitis media and later school performance – A prospective cohort study of associations

Publication date: Available online 16 January 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Vincent Fougner, Asbjørn Kørvel-Hanquist, Anders Koch, Jesper Dammeyer, Janni Niclasen, Jørgen Lous, Preben Homøe
IntroductionOtitis media (OM) is a common disease in childhood and hearing loss (HL) is the most common complication. Prolonged HL may lead to language delay and cognitive difficulties. However, the consequences of HL due to OM are not fully understood.The aim of this study was to determine the possible association between number of OM episodes in childhood and self-rated school performance controlling for potential confounders.MethodsProspectively gathered systematic interview data on OM episodes in early childhood and school performance at 11 years of age were obtained from The Danish National Birth Cohort, involving >100 000 individual pregnancies and their offspring. We defined four exposure groups (0, 1–3, 4–6 and ≥7 OM episodes) and assessed general school performance, mathematics and literacy. Possible confounders were recognized à priori and associations were determined using proportional odds regression.ResultsOut of 94 745 successful pregnancies, 35,946 children without malformations and their parents completed a questionnaire at age 11 years. No associations were observed between number of OM episodes and school performance, even in children with ≥7 OM episodes.ConclusionThis national birth-cohort study did not support the hypothesis that the number of OM episodes in childhood is associated with reduced self-reported school performance in children at 11 years of age.



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The Temporoparietal Fascia Flap for Coverage of Cochlear Reimplantation Following Extrusion

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Publication date: Available online 16 January 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Kaveh Karimnejad, Asad Shahab Akhter, Scott Gregory Walen, Anthony Alan Mikulec
The management of cochlear implant extrusion (CIE) can be challenging, particularly in the pediatric population in whom reconstructive options are limited. We describe the use of the temporoparietal fascia flap (TPFF) for this purpose due to its ease of use and limited morbidity. We present a case series of two pediatric patients who underwent explantation of their devices, followed by reimplantation with TPFF coverage. Our experience provides evidence that the TPFF can be used to prevent further CIE through a postauricular incision following cochlear reimplantation with successful long-term results.



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The effects of cochlear implantation on vestibular function in 1–4 years old children

Publication date: Available online 16 January 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Mohammad Ajalloueyan, Masoumeh Saeedi, Mohammad Sadeghi, Farzaneh Zamiri
ObjectivesAlthough cochlear implants offer an effective hearing restoration option in children with severe to profound hearing loss, concern continues to exist regarding the possible effects of cochlear implantation on the vestibular system and balance.MethodsIn a prospective cohort study, 27 children with bilateral profound hearing loss (all candidates for cochlear implantation) were evaluated for their vestibular function before and after cochlear implantation. Vestibular evaluations consisted of Vestibular Evoked Myogenic Potentials, caloric testing and the Head-Impulse Test.ResultsMean age at the time of cochlear implantation was 27.19 months. Without considering vestibular evaluation results, one of the ears was selected for surgery. Vestibular tests after surgery were not indicative of any statistically significant change in vestibular system or balance.ConclusionThis limited data shows that cochlear implantation did not impair the vestibular system of these patients. By the results of our study we may conclude that round window implantation does not have any disturbing impact on vestibular function in children. The generalization of this result needs further research.



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Androgen-Dependent Repression of ERR{gamma} Reprograms Metabolism in Prostate Cancer

How androgen signaling contributes to the oncometabolic state of prostate cancer remains unclear. Here, we show how the estrogen-related receptor γ (ERRγ) negatively controls mitochondrial respiration in prostate cancer cells. Sustained treatment of prostate cancer cells with androgens increased the activity of several metabolic pathways, including aerobic glycolysis, mitochondrial respiration, and lipid synthesis. An analysis of the intersection of gene expression, binding events, and motif analyses after androgen exposure identified a metabolic gene expression signature associated with the action of ERRγ. This metabolic state paralleled the loss of ERRγ expression. It occurred in both androgen-dependent and castration-resistant prostate cancer and was associated with cell proliferation. Clinically, we observed an inverse relationship between ERRγ expression and disease severity. These results illuminate a mechanism in which androgen-dependent repression of ERRγ reprograms prostate cancer cell metabolism to favor mitochondrial activity and cell proliferation. Furthermore, they rationalize strategies to reactivate ERRγ signaling as a generalized therapeutic approach to manage prostate cancer. Cancer Res; 77(2); 378–89. ©2016 AACR.

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ZIC5 Drives Melanoma Aggressiveness by PDGFD-Mediated Activation of FAK and STAT3

Insights into mechanisms of drug resistance could extend the efficacy of cancer therapy. To probe mechanisms in melanoma, we performed siRNA screening of genes that mediate the development of neural crest cells, from which melanocytes are derived. Here, we report the identification of ZIC5 as a mediator of melanoma drug resistance. ZIC5 is a transcriptional suppressor of E-cadherin expressed highly in human melanoma. ZIC5 enhanced melanoma cell proliferation, survival, drug resistance, in vivo growth and metastasis. Microarray analysis revealed that ZIC5 downstream signaling included PDGFD and FAK activation, which contributes to drug resistance by enhancing STAT3 activation. Silencing of ZIC5 or PDGFD enhanced the apoptotic effects of BRAF inhibition and blocked survival of melanoma cells resistant to BRAF inhibitors. Furthermore, inhibition of FAK or STAT3 suppressed expression of ZIC5, which was positively regulated by PDGFD, FAK, and STAT3 in a positive feedback loop. Taken together, our results identify ZIC5 and PDGFD as candidate therapeutic targets to overcome drug resistance in melanoma. Cancer Res; 77(2); 366–77. ©2016 AACR.

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SPINK6 Promotes Metastasis of Nasopharyngeal Carcinoma via Binding and Activation of Epithelial Growth Factor Receptor

Nasopharyngeal carcinoma has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. The underlying molecular mechanisms of nasopharyngeal carcinoma metastasis are not fully understood. Here, we report the identification of serine protease inhibitor Kazal-type 6 (SPINK6) as a functional regulator of nasopharyngeal carcinoma metastasis via EGFR signaling. SPINK6 mRNA was upregulated in tumor and highly metastatic nasopharyngeal carcinoma cells. Immunohistochemical staining of 534 nasopharyngeal carcinomas revealed elevated SPINK6 expression as an independent unfavorable prognostic factor for overall, disease-free, and distant metastasis–free survival. Ectopic SPINK6 expression promoted in vitro migration and invasion as well as in vivo lymph node metastasis and liver metastasis of nasopharyngeal carcinoma cells, whereas silencing SPINK6 exhibited opposing effects. SPINK6 enhanced epithelial–mesenchymal transition by activating EGFR and the downstream AKT pathway. Inhibition of EGFR with a neutralizing antibody or erlotinib reversed SPINK6-induced nasopharyngeal carcinoma cell migration and invasion. Erlotinib also inhibited SPINK6-induced metastasis in vivo. Notably, SPINK6 bound to the EGFR extracellular domain independent of serine protease–inhibitory activity. Overall, our results identified a novel EGFR-activating mechanism in which SPINK6 has a critical role in promoting nasopharyngeal carcinoma metastasis, with possible implications as a prognostic indicator in nasopharyngeal carcinoma patients. Cancer Res; 77(2); 579–89. ©2016 AACR.

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Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity, and were validated in low-throughput experiments. Principal component analysis revealed that a fraction of all upregulated or downregulated genes of a particular targeted pathway could partly explain cell sensitivity toward agents targeting that pathway. Combination therapies deemed immediately tractable to translation included ABT-263/crizotinib, ABT-263/paclitaxel, paclitaxel/JQ1, ABT-263/XL-184, and paclitaxel/nutlin-3, all of which exhibited synergistic antiproliferative and apoptotic activity in multiple TNBC backgrounds. Mechanistic investigations of the ABT-263/crizotinib combination offering a potentially rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling, and proapoptotic signal induction in basal and mesenchymal stem–like TNBC. Our findings provide preclinical proof of concept for several combination treatments of TNBC, which offer near-term prospects for clinical translation. Cancer Res; 77(2); 566–78. ©2016 AACR.

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A Novel Spectroscopically Determined Pharmacodynamic Biomarker for Skin Toxicity in Cancer Patients Treated with Targeted Agents

Raman spectroscopy is a noninvasive and label-free optical technique that provides detailed information about the molecular composition of a sample. In this study, we evaluated the potential of Raman spectroscopy to predict skin toxicity due to tyrosine kinase inhibitors treatment. We acquired Raman spectra of skin of patients undergoing treatment with MEK, EGFR, or BRAF inhibitors, which are known to induce severe skin toxicity; for this pilot study, three patients were included for each inhibitor. Our algorithm, based on partial least squares-discriminant analysis (PLS-DA) and cross-validation by bootstrapping, discriminated to variable degrees spectra from patient suffering and not suffering cutaneous adverse events. For MEK and EGFR inhibitors, discriminative power was more than 90% in the viable epidermis skin layer; whereas for BRAF inhibitors, discriminative power was 71%. There was a 81.5% correlation between blood drug concentration and Raman signature of skin in the case of EGFR inhibitors and viable epidermis skin layer. Our results demonstrate the power of Raman spectroscopy to detect apparition of skin toxicity in patients treated with tyrosine kinase inhibitors at levels not detectable via dermatological inspection and histological evaluation. Cancer Res; 77(2); 557–65. ©2016 AACR.

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Breast Cancer Resistance to Antiestrogens Is Enhanced by Increased ER Degradation and ERBB2 Expression

Endocrine therapies effectively improve the outcomes of patients with estrogen receptor (ER)-positive breast cancer. However, the emergence of drug-resistant tumors creates a core clinical challenge. In breast cancer cells rendered resistant to the antiestrogen fulvestrant, we defined causative mechanistic roles for the transcription factor YBX1 and the levels of ER and the ERBB2 receptor. Enforced expression of YBX1 in parental cells conferred resistance against tamoxifen and fulvestrant in vitro and in vivo. Furthermore, YBX1 overexpression was associated with decreased and increased levels of ER and ERBB2 expression, respectively. In antiestrogen-resistant cells, increased YBX1 phosphorylation was associated with a 4-fold higher degradation rate of ER. Notably, YBX1 bound the ER, leading to its accelerated proteasomal degradation, and induced the transcriptional activation of ERBB2. In parallel fashion, tamoxifen treatment also augmented YBX1 binding to the ERBB2 promoter to induce increased ERBB2 expression. Together, these findings define a mechanism of drug resistance through which YBX1 contributes to antiestrogen bypass in breast cancer cells. Cancer Res; 77(2); 545–56. ©2016 AACR.

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Circadian Clock Gene Bmal1 Inhibits Tumorigenesis and Increases Paclitaxel Sensitivity in Tongue Squamous Cell Carcinoma

Circadian clock genes regulate cancer development and chemotherapy susceptibility. Accordingly, chronotherapy based on circadian phenotypes might be applied to improve therapeutic efficacy. In this study, we investigated whether the circadian clock gene Bmal1 inhibited tumor development and increased paclitaxel sensitivity in tongue squamous cell carcinoma (TSCC). Bmal1 expression was downregulated and its rhythmic pattern of expression was affected in TSCC samples and cell lines. Ectopic Bmal1 inhibited cell proliferation, migration and invasion in vitro, and tumor growth in mouse xenograft models of TSCC. After exposure to paclitaxel, Bmal1-overexpressing cells displayed a relative increase in apoptosis and were more susceptible to paclitaxel treatment in vivo. Mechanistic investigations suggested a regulatory connection between Bmal1, TERT, and the oncogenic transcriptional repressor EZH2 (enhancer of zeste homolog 2), the recruitment of which to the TERT promoter increased paclitaxel-induced apoptosis and cell growth inhibition. Clinically, paclitaxel efficacy correlated positively with Bmal1 expression levels in TSCC. Overall, our results identified Bmal1 as a novel tumor suppressor gene that elevates the sensitivity of cancer cells to paclitaxel, with potential implications as a chronotherapy timing biomarker in TSCC. Cancer Res; 77(2); 532–44. ©2016 AACR.

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Biphasic Rapamycin Effects in Lymphoma and Carcinoma Treatment

mTOR drives tumor growth but also supports T-cell function, rendering the applications of mTOR inhibitors complex especially in T-cell malignancies. Here, we studied the effects of the mTOR inhibitor rapamycin in mouse EL4 T-cell lymphoma. Typical pharmacologic rapamycin (1–8 mg/kg) significantly reduced tumor burden via direct suppression of tumor cell proliferation and improved survival in EL4 challenge independent of antitumor immunity. Denileukin diftitox (DD)–mediated depletion of regulatory T cells significantly slowed EL4 growth in vivo in a T-cell–dependent fashion. However, typical rapamycin inhibited T-cell activation and tumor infiltration in vivo and failed to boost DD treatment effects. Low-dose (LD) rapamycin (75 μg/kg) increased potentially beneficial CD44hiCD62L+ CD8+ central memory T cells in EL4 challenge, but without clinical benefit. LD rapamycin significantly enhanced DD treatment efficacy, but DD plus LD rapamycin treatment effects were independent of antitumor immunity. Instead, rapamycin upregulated EL4 IL2 receptor in vitro and in vivo, facilitating direct DD tumor cell killing. LD rapamycin augmented DD efficacy against B16 melanoma and a human B-cell lymphoma, but not against human Jurkat T-cell lymphoma or ID8agg ovarian cancer cells. Treatment effects correlated with IL2R expression, but mechanisms in some tumors were not fully defined. Overall, our data define a distinct, biphasic mechanisms of action of mTOR inhibition at doses that are clinically exploitable, including in T-cell lymphomas. Cancer Res; 77(2); 520–31. ©2016 AACR.

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Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra

Pediatric cancers are generally characterized by low mutational burden and few recurrently mutated genes. Recent studies suggest that genomic alterations may help guide treatment decisions and clinical trial selection. Here, we describe genomic profiles from 1,215 pediatric tumors representing sarcomas, extracranial embryonal tumors, brain tumors, hematologic malignancies, carcinomas, and gonadal tumors. Comparable published datasets identified similar frequencies of clinically relevant alterations, validating this dataset as biologically relevant. We identified novel ALK fusions in a neuroblastoma (BEND5–ALK) and an astrocytoma (PPP1CB–ALK), novel BRAF fusions in an astrocytoma (BCAS1–BRAF) and a ganglioglioma (TMEM106B–BRAF), and a novel PAX3–GLI2 fusion in a rhabdomyosarcoma. Previously characterized ALK, NTRK1, and PAX3 fusions were observed in unexpected malignancies, challenging the "disease-specific" alterations paradigm. Finally, we identified recurrent variants of unknown significance in MLL3 and PRSS1 predicted to have functional impact. Data from these 1,215 tumors are publicly available for discovery and validation. Cancer Res; 77(2); 509–19. ©2017 AACR.

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Aurora A and NF-{kappa}B Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA

Aurora A–dependent NF-κB signaling portends poor prognosis in acute myeloid leukemia (AML) and other cancers, but the functional basis underlying this association is unclear. Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. TIFA protein was overexpressed concurrently with Aurora A and NF-κB signaling factors in patients with de novo AML relative to healthy individuals and also correlated with poor prognosis. Silencing TIFA in AML lines and primary patient cells decreased leukemic cell growth and chemoresistance via downregulation of prosurvival factors Bcl-2 and Bcl-XL that support NF-κB–dependent antiapoptotic events. Inhibiting TIFA perturbed leukemic cytokine secretion and reduced the IC50 of chemotherapeutic drug treatments in AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiated the clearance of myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity. Collectively, our results showed that TIFA supports AML progression and that its targeting can enhance the efficacy of AML treatments. Cancer Res; 77(2); 494–508. ©2016 AACR.

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EpCAM Inhibition Sensitizes Chemoresistant Leukemia to Immune Surveillance

The lack of effective tumor-associated antigens restricts the development of targeted therapies against myeloid leukemia. In this study, we compared gene expression patterns of acute myeloid leukemia (AML) and normal bone marrow samples and found that epithelial cell adhesion molecule (EpCAM) is frequently overexpressed in patients with AML, with EpCAM+ leukemic cells exhibiting enhanced chemoresistance and oncogenesis. The chemotherapeutic resistance of EpCAM-positive leukemic cells is a consequence of increased WNT5B signaling. Furthermore, we generated EpCAM antibodies that enabled phagocytosis or cytotoxicity of AML cells by macrophage or natural killer cells, respectively. Finally, EpCAM antibody treatment depleted AML in subcutaneous, disseminated, and intramedullary engrafted mice. In summary, EpCAM exhibits promise as a novel target for the treatment of leukemia. Cancer Res; 77(2); 482–93. ©2016 AACR.

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Transcriptional Selectivity of Epigenetic Therapy in Cancer

A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation, and ChIP-seq analyses the epigenetic response of a set of colon, breast, and leukemia cancer cell lines to small-molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343). We also characterized the effects of DAC as combined with the other compounds. Averaged over the cancer cell models used, we found that DAC affected 8.6% of the transcriptome and that 95.4% of the genes affected were upregulated. DAC preferentially regulated genes that were silenced in cancer and that were methylated at their promoters. In contrast, Depsi affected the expression of 30.4% of the transcriptome but showed little selectivity for gene upregulation or silenced genes. S2101, UNC0638, and GSK343 affected only 2% of the transcriptome, with UNC0638 and GSK343 preferentially targeting genes marked with H3K9me2 or H3K27me3, respectively. When combined with histone methylase inhibitors, the extent of gene upregulation by DAC was extended while still maintaining selectivity for DNA-methylated genes and silenced genes. However, the genes upregulated by combination treatment exhibited limited overlap, indicating the possibility of targeting distinct sets of genes based on different epigenetic therapy combinations. Overall, our results demonstrated that DNA methyltransferase inhibitors preferentially target cancer-relevant genes and can be combined with inhibitors targeting histone methylation for synergistic effects while still maintaining selectivity. Cancer Res; 77(2); 470–81. ©2016 AACR.

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Quantification of Pathway Cross-talk Reveals Novel Synergistic Drug Combinations for Breast Cancer

Combinatorial therapeutic approaches are an imperative to improve cancer treatment, because it is critical to impede compensatory signaling mechanisms that can engender drug resistance to individual targeted drugs. Currently approved drug combinations result largely from empirical clinical experience and cover only a small fraction of a vast therapeutic space. Here we present a computational network biology approach, based on pathway cross-talk inhibition, to discover new synergistic drug combinations for breast cancer treatment. In silico analysis identified 390 novel anticancer drug pairs belonging to 10 drug classes that are likely to diminish pathway cross-talk and display synergistic antitumor effects. Ten novel drug combinations were validated experimentally, and seven of these exhibited synergy in human breast cancer cell lines. In particular, we found that one novel combination, pairing the estrogen response modifier raloxifene with the c-Met/VEGFR2 kinase inhibitor cabozantinib, dramatically potentiated the drugs' individual antitumor effects in a mouse model of breast cancer. When compared with high-throughput combinatorial studies without computational prioritization, our approach offers a significant advance capable of uncovering broad-spectrum utility across many cancer types. Cancer Res; 77(2); 459–69. ©2016 AACR.

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Chemopreventive Effects of ROS Targeting in a Murine Model of BRCA1-Deficient Breast Cancer

There remains great interest in practical strategies to limit the elevated risks of familial breast and ovarian cancers driven by BRCA1 mutation. Here, we report that limiting the production of reactive oxygen species (ROS) is sufficient to reduce DNA lesions and delay tumorigenesis in a murine model of BRCA1-deficient breast cancer. We documented a large amount of endogenous estrogen oxidative metabolites in the mammary gland of the model, which induced DNA adducts and apurinic/apyrimidinic sites associated with DNA double-strand breaks and genomic instability. Repressing estrogen oxidation via antioxidant treatments reduced oxidative DNA lesions and delayed the onset of mammary tumors. Overall our work suggests an answer to the long-standing question of why germline BRCA1 mutations cause tissue-specific tumors, in showing how tissue-specific, ROS-induced DNA lesions create a nongenetic force to promote mammary tumors in BRCA1-deficient mice. Our findings create a rationale for evaluating suitable antioxidant modalities as a chemopreventive strategy for familial breast cancer. Cancer Res; 77(2); 448–58. ©2016 AACR.

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Plk4 Promotes Cancer Invasion and Metastasis through Arp2/3 Complex Regulation of the Actin Cytoskeleton

The polo family serine threonine kinase Plk4 has been proposed as a therapeutic target in advanced cancers based on increased expression in primary human cancers, facilitation of tumor growth in murine xenograft models, and centrosomal amplification induced by its overexpression. However, both the causal link between these phenomena and the feasibility of selective Plk4 inhibition remain unclear. Here we characterize Plk4-dependent cancer cell migration and invasion as well as local invasion and metastasis of cancer xenografts. Plk4 depletion suppressed cancer invasion and induced an epithelial phenotype in poorly differentiated breast cancer cells. In an unbiased BioID screen for Plk4 interactors, we identified members of the Arp2/3 complex and confirmed a physical and functional interaction between Plk4 and Arp2 in mediating Plk4-driven cancer cell movement. This interaction is mediated through the Plk4 Polo-box 1-Polo-box 2 domain and results in phosphorylation of Arp2 at the T237/T238 activation site, which is required for Plk4-driven cell movement. Our results validate Plk4 as a therapeutic target in cancer patients and reveal a new role for Plk4 in regulating Arp2/3-mediated actin cytoskeletal rearrangement. Cancer Res; 77(2); 434–47. ©2016 AACR.

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Polycomb-Mediated Disruption of an Androgen Receptor Feedback Loop Drives Castration-Resistant Prostate Cancer

The lethal phenotype of castration-resistant prostate cancer (CRPC) is generally caused by augmented signaling from the androgen receptor (AR). Here, we report that the AR-repressed gene CCN3/NOV inhibits AR signaling and acts in a negative feedback loop to block AR function. Mechanistically, a cytoplasmic form of CCN3 interacted with the AR N-terminal domain to sequester AR in the cytoplasm of prostate cancer cells, thereby reducing AR transcriptional activity and inhibiting cell growth. However, constitutive repression of CCN3 by the Polycomb group protein EZH2 disrupted this negative feedback loop in both CRPC and enzalutamide-resistant prostate cancer cells. Notably, restoring CCN3 was sufficient to effectively reduce CPRC cell proliferation in vitro and to abolish xenograft tumor growth in vivo. Taken together, our findings establish CCN3 as a pivotal regulator of AR signaling and prostate cancer progression and suggest a functional intersection between Polycomb and AR signaling in CRPC. Cancer Res; 77(2); 412–22. ©2016 AACR.

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Menin and Daxx Interact to Suppress Neuroendocrine Tumors through Epigenetic Control of the Membrane Metallo-Endopeptidase

Neuroendocrine tumors (NET) often harbor loss-of-function mutations in the MEN1 and DAXX tumor suppressor genes. Here, we report that the products of these genes, menin and Daxx, interact directly with each other to suppress the proliferation of NET cells, to a large degree by inhibiting expression of the membrane metallo-endopeptidase (MME). Menin and Daxx were required to enhance histone H3 lysine9 trimethylation (H3K9me3) at the MME promoter, as mediated partly by the histone H3 methyltransferase SUV39H1. Notably, the menin T429K mutation associated with a NET syndrome reduced Daxx binding, MME repression, and proliferation of NET cells. Conversely, inhibition of MME in NET cells repressed proliferation and tumor growth in vivo. Our findings reveal a previously unappreciated cross-talk between two crucial tumor suppressor genes thought to work by independent pathways, focusing on MME as a common target of menin/Daxx to treat NET. Cancer Res; 77(2); 401–11. ©2016 AACR.

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Integrative Comparison of mRNA Expression Patterns in Breast Cancers from Caucasian and Asian Americans with Implications for Precision Medicine

Asian Americans (AS) have significantly lower incidence and mortality rates of breast cancer than Caucasian Americans (CA). Although this racial disparity has been documented, the underlying pathogenetic factors explaining it are obscure. We addressed this issue by an integrative genomics approach to compare mRNA expression between AS and CA cases of breast cancer. RNA-seq data from the Cancer Genome Atlas showed that mRNA expression revealed significant differences at gene and pathway levels. Increased susceptibility and severity in CA patients were likely the result of synergistic environmental and genetic risk factors, with arachidonic acid metabolism and PPAR signaling pathways implicated in linking environmental and genetic factors. An analysis that also added eQTL data from the Genotype-Tissue Expression Project and SNP data from the 1,000 Genomes Project identified several SNPs associated with differentially expressed genes. Overall, the associations we identified may enable a more focused study of genotypic differences that may help explain the disparity in breast cancer incidence and mortality rates in CA and AS populations and inform precision medicine. Cancer Res; 77(2); 423–33. ©2016 AACR.

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Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia

Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. Cancer Res; 77(2); 390–400. ©2016 AACR.

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Vitamin D3 Prevents Calcium-Induced Progression of Early-Stage Prostate Tumors by Counteracting TRPC6 and Calcium Sensing Receptor Upregulation

Active surveillance has emerged as an alternative to immediate treatment for men with low-risk prostate cancer. Accordingly, identification of environmental factors that facilitate progression to more aggressive stages is critical for disease prevention. Although calcium-enriched diets have been speculated to increase prostate cancer risk, their impact on early-stage tumors remains unexplored. In this study, we addressed this issue with a large interventional animal study. Mouse models of fully penetrant and slowly evolving prostate tumorigenesis showed that a high calcium diet dramatically accelerated the progression of prostate intraepithelial neoplasia, by promoting cell proliferation, micro-invasion, tissue inflammation, and expression of acknowledged prostate cancer markers. Strikingly, dietary vitamin D prevented these calcium-triggered tumorigenic effects. Expression profiling and in vitro mechanistic studies showed that stimulation of PC-3 cells with extracellular Ca2+ resulted in an increase in cell proliferation rate, store-operated calcium entry (SOCE) amplitude, cationic channel TRPC6, and calcium sensing receptor (CaSR) expression. Notably, administration of the active vitamin D metabolite calcitriol reversed all these effects. Silencing CaSR or TRPC6 expression in calcium-stimulated PC3 cells decreased cell proliferation and SOCE. Overall, our results demonstrate the protective effects of vitamin D supplementation in blocking the progression of early-stage prostate lesions induced by a calcium-rich diet. Cancer Res; 77(2); 355–65. ©2016 AACR.

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Central Venous Catheter-Related Bloodstream Infection with Kocuria kristinae in a Patient with Propionic Acidemia

Kocuria kristinae is a catalase-positive, coagulase-negative, Gram-positive coccus found in the environment and in normal skin and mucosa in humans; however, it is rarely isolated from clinical specimens and is considered a nonpathogenic bacterium. We describe a case of catheter-related bacteremia due to K. kristinae in a young adult with propionic acidemia undergoing periodic hemodialysis. The patient had a central venous catheter implanted for total parenteral nutrition approximately 6 months prior to the onset of symptoms because of repeated acute pancreatitis. K. kristinae was isolated from two sets of blood cultures collected from the catheter. Vancomycin followed by cefazolin for 16 days and 5-day ethanol lock therapy successfully eradicated the K. kristinae bacteremia. Although human infections with this organism appear to be rare and are sometimes considered to result from contamination, physicians should not underestimate its significance when it is isolated in clinical specimens.

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A New Solution to an Old Mammoth Mystery

A lack of water, rather than an excess of it, may have killed the Waco mammoths.

-- Read more on ScientificAmerican.com
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16 novel mutations in PNPLA1 in patients with autosomal recessive congenital ichthyosis reveal the importance of an extended patatin domain in PNPLA1 that is essential for proper human skin barrier function

Abstract

Background

Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of keratinocytes. Mutations in nine genes including PNPLA1 are known to cause non-syndromic forms of ARCI. To date, only ten distinct pathogenic mutations in PNPLA1 have been reported.

Objectives

To identify new causative PNPLA1 mutations, we screened genetically unresolved cases including our ARCI collection comprising more than 700 families. Here, we report on 16 novel mutations present in patients from 17 families.

Methods

The screening for mutations was performed either by direct Sanger sequencing or in combination with a multi gene panel, followed by sequence and mutation analysis.

Results

While all previously reported mutations and most of our novel mutations are located within the core patatin domain, here we report on five novel PNPLA1 mutations, which are downstream of this domain. Thus, as recently described for PNPLA2, we hypothesize that a region larger than core domain is required for full enzymatic activity of PNPLA1 in human skin barrier formation.

Conclusions

We estimate the frequency of PNPLA1 mutations amongst ARCI patients to around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotype variation in a small percentage of patients with PNPLA1 mutations.

The variability of the clinical manifestations as well as the lack of typical clinical features are specific for patients with PNPLA1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCIs.

This article is protected by copyright. All rights reserved.



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Mammogram

Mammogram: An X-ray of the breast that is taken with a device that compresses and flattens the breast. A mammogram can help a health professional decide whether a lump in the breast is a gland, a harmless cyst, or a tumor. A mammogram can cause pressure, discomfort, and some soreness that lasts for a little while after the procedure. If the mammogram result raises suspicions about cancer, a biopsy is usually the next step. The American Cancer Society and the American College of Surgeons currently recommend that a woman obtain her first, baseline, mammogram between the ages of 35 and 40. After the age of 40, a mammogram should be done yearly. Women who are at high risk for developing breast cancer may need to obtain mammograms earlier than these recommendations and at more frequent intervals.



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Exploring differences in adverse symptom event grading thresholds between clinicians and patients in the clinical trial setting

Abstract

Purpose

Symptomatic adverse event (AE) monitoring is essential in cancer clinical trials to assess patient safety, as well as inform decisions related to treatment and continued trial participation. As prior research has demonstrated that conventional concordance metrics (e.g., intraclass correlation) may not capture nuanced aspects of the association between clinician and patient-graded AEs, we aimed to characterize differences in AE grading thresholds between doctors (MDs), registered nurses (RNs), and patients using the Bayesian Graded Item Response Model (GRM).

Methods

From the medical charts of 393 patients aged 26–91 (M = 62.39; 43% male) receiving chemotherapy, we retrospectively extracted MD, RN and patient AE ratings. Patients reported using previously developed Common Terminology Criteria for Adverse Events (CTCAE) patient-language adaptations called STAR (Symptom Tracking and Reporting). A GRM was fitted to calculate the latent grading thresholds between MDs, RNs and patients.

Results

Clinicians have overall higher average grading thresholds than patients when assessing diarrhea, dyspnea, nausea and vomiting. However, RNs have lower grading thresholds than patients and MDs when assessing constipation. The GRM shows higher variability in patients’ AE grading thresholds than those obtained from clinicians.

Conclusions

The present study provides evidence to support the notion that patients report some AEs that clinicians might not consider noteworthy until they are more severe. The availability of GRM methodology could serve to enhance clinical understanding of the patient symptomatic experience and facilitate discussion where AE grading discrepancies exist. Future work should focus on capturing explicit AE grading decision criteria from MDs, RNs, and patients.



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The effectiveness of radiotherapy for leukemia cutis

Abstract

Background

Leukemia cutis (LC) is a rare clinical presentation of leukemia that is associated with poor prognosisabs. To date, the value of radiotherapy (RT) for the treatment of LC remains controversial. Therefore, the aim of this study was to analyse the effectiveness of various RT doses for LC.

Methods and materials

Between January 2000 and January 2016, 13 patients underwent RT at our institution after exhibiting progressive disease following other treatment modalities.

Results

A total of 36 radiation courses were administered to 13 patients (8 females, 5 males) with a median age of 41 years (range 2–76). Radiation modalities included 32 focal treatments, while total skin electron beam therapy was applied to four patients. The median RT dose was 27 Gy (range 8–34). A complete response rate (CRR) to RT was achieved for 32/36 (89%) lesions (100% for AML lesions versus 33% for the other leukemias; P < 0.001). The median duration of local control (DOLC) for the entire cohort was 38 months (range 0–98), while the median survival (MS) from the time of LC presentation was 13 months (range 2.5–106). The CRR for the LC lesions treated with high-dose regimens (>26 Gy) versus low-dose regimens (≤26 Gy) was 95 versus 83%, respectively (P = 0.26), and the median DOLC was 44 months versus 10 months, respectively (P = 0.019). AML patients had a better long-term outcome than the other patients according to median DOLC (40 months versus 2 months, respectively; P < 0.001) and MS (24 versus 6 months, P = 0.004). RT was well tolerated without significant adverse events.

Conclusion

A radiation dose ≤26 Gy confer a comparable CRR to high-dose regimens and appears to be an effective treatment for controlling LC progression. However, radiation doses >26 Gy were associated with a longer DOLC. LC patients with underlying AML are associated with better outcome compared with other types of leukemia.



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Depletion of p42.3 gene inhibits proliferation and invasion in melanoma cells

Abstract

Purpose

The p42.3 gene is identified recently, and the upregulated expression has been characterized in a variety of human cancers and embryonic tissues but not yet in malignant melanoma. In this study, we explored the role of p42.3 gene in the development of melanoma.

Methods

The expression of p42.3 was detected by immunohistochemistry staining of 261 cases of patient lesions, including nevi and melanoma, and its correlation with clinical pathological characteristics and prognosis was analyzed. Furthermore, a series of in vitro assays were used to investigate the biological function of p42.3 in melanoma cells.

Results

Immunohistochemistry staining showed an elevated expression level of p42.3 in melanoma compared to nevi (P = 0.001). Statistical analysis indicated that this high level was well correlated with patients’ clinical stage (P = 0.045), but not with gender, age, clinical type, mitotic rate, and overall survival (P > 0.05). Moreover, in vitro assays showed knockdown p42.3 gene expression could inhibit the biological profiling, including proliferation, migration, and invasion of melanoma cells, and also affect PI3K/Akt pathway, MAPK pathway, and β-catenin.

Conclusions

This study suggests that p42.3, acting like an oncogene, is involved in the malignant transformation process of melanoma and may serve as a biomarker for diagnostic and treatment purposes.



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Prognostic value of BRAF V600E mutation and microsatellite instability in Japanese patients with sporadic colorectal cancer

Abstract

Purpose

In colorectal cancer (CRC), the BRAF V600E mutation is an important biomarker for poor prognosis, while high microsatellite instability (MSI-H) indicates good prognosis. Using a commercial BRAF V600E-specific antibody, we investigated the BRAF V600E mutation according to immunohistochemistry (IHC) and the MSI status in Japanese patients with CRC.

Methods

In this retrospective study, tissue samples from 472 Japanese patients with CRC, stratified for MSI, were analyzed to determine the prognostic value of BRAF V600E, as assessed using IHC. Mutations in 254 patients were evaluated using the direct sequencing method to check for concordance.

Results

The frequency of MSI-H was 9.3 % (44/472), and BRAF V600E mutation was detected immunohistochemically in 8.7 % patients (41/472). The sensitivity and specificity for detection of BRAF V600E mutations by IHC were 100 % (17/17) and 98.7 % (234/237), respectively. BRAF V600E mutations were significantly correlated with the anatomical tumor site (P = 0.0035), histological type (P < 0.0001), and MSI status (P < 0.0001). Consistent with other published series, patients with BRAF V600E mutation exhibited a significantly shorter overall survival (hazard ratio = 1.500, P = 0.0432). In particular, the microsatellite stable/BRAF mutation group had inferior prognosis compared with the MSI-H/BRAF wild-type group (hazard ratio = 2.621, P = 0.0004).

Conclusions

IHC using a BRAF V600E-specific antibody was useful for diagnosis and concurred with direct sequencing results. CRC cases could be stratified by combining BRAF V600E mutation and MSI status as a prognostic factor in Japanese patients.



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Proposal of Design Formulae for Equivalent Elasticity of Masonry Structures Made with Bricks of Low Modulus

Bricks of low elastic modulus are occasionally used in some developing countries, such as Indonesia and India. Most of the previous research efforts focused on masonry structures built with bricks of considerably high elastic modulus. The objective of this study is to quantify the equivalent elastic modulus of lower-stiffness masonry structures, when the mortar has a higher modulus of elasticity than the bricks, by employing finite element (FE) simulations and adopting the homogenization technique. The reported numerical simulations adopted the two-dimensional representative volume elements (RVEs) using quadrilateral elements with four nodes. The equivalent elastic moduli of composite elements with various bricks and mortar were quantified. The numerically estimated equivalent elastic moduli from the FE simulations were verified using previously established test data. Hence, a new simplified formula for the calculation of the equivalent modulus of elasticity of such masonry structures is proposed in the present study.

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The Prognostic Role of NEDD9 and P38 Protein Expression Levels in Urinary Bladder Transitional Cell Carcinoma

Background. The most common malignant tumor of the urinary bladder is transitional cell carcinoma (TCC). Neural precursor cell-expressed developmentally downregulated protein 9 (NEDD9) is found to be a cell adhesion mediator. P38 Mitogen-Activated Protein Kinase is a serine/threonine kinases member which can mediate carcinogenesis through intracellular signaling. Methods. To assess their prognostic role; NEDD9 and p38 protein were evaluated in sections from 50 paraffin blocks of TCC. Results. The high expressions of NEDD9 and p38 protein were significantly associated with grade, stage, distant metastasis (), number of tumors, lymph node metastasis, and tumor size (, 0.002; 0.018,

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Optimization of the Extraction and Stability of Antioxidative Peptides from Mackerel (Pneumatophorus japonicus) Protein

This study optimizes the preparation conditions for mackerel protein hydrolysate (MPH) by response surface methodology (RSM) and investigates the stability of the antioxidant activity of MPHs (

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Brazilian Amazon Traditional Medicine and the Treatment of Difficult to Heal Leishmaniasis Wounds with Copaifera

The present study describes the use of the traditional species Copaifera for treating wounds, such as ulcers scarring and antileishmanial wounds. It also relates phytochemical studies, evaluation of the leishmanicidal activity, and toxicity. The species of Copaifera with a higher incidence in the Amazon region are Copaifera officinalis, Copaifera reticulata, Copaifera multijuga Hayne. The copaiba oil is used in the Amazon’s traditional medicine, especially as anti-inflammatory ingredient, in ulcers healing, and in scarring and for leishmaniasis. Chemical studies have shown that these oils contain diterpenes and sesquiterpenes. The copaiba oil and terpenes isolated have antiparasitic activity, more promising in the amastigote form of L. amazonensis. This activity is probably related to changes in the cell membrane and mitochondria. The oil showed low cytotoxicity and genotoxicity. Furthermore, it may interfere with immune response to infection and also has a healing effect. In summary, the copaiba oil is promising as leishmanicidal agent.

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Certain Subclasses of Multivalent Functions Defined by Higher-Order Derivative

In this paper, we define and study some subclasses of multivalent analytic functions of higher order in the unit disc. These classes generalize some classes previously studied. We obtain coefficient inequalities, distortion theorems, extreme points, and integral mean inequalities. We derive some results as special cases.

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Experimental Study on the Utilization of Fine Steel Slag on Stabilizing High Plastic Subgrade Soil

The three major steel manufacturing factories in Jordan dump their byproduct, steel slag, randomly in open areas, which causes many environmental hazardous problems. This study intended to explore the effectiveness of using fine steel slag aggregate (FSSA) in improving the geotechnical properties of high plastic subgrade soil. First soil and fine steel slag mechanical and engineering properties were evaluating. Then 0%, 5%, 10%, 15%, 20%, and 25% dry weight of soil of fine steel slag (FSSA) were added and mixed into the prepared soil samples. The effectiveness of the FSSA was judged by the improvement in consistency limits, compaction, free swell, unconfined compression strength, and California bearing ratio (CBR). From the test results, it is observed that 20% FSSA additives will reduce plasticity index and free swell by 26.3% and 58.3%, respectively. Furthermore, 20% FSSA additives will increase the unconfined compressive strength, maximum dry density, and CBR value by 100%, 6.9%, and 154%. By conclusion FSSA had a positive effect on the geotechnical properties of the soil and it can be used as admixture in proving geotechnical characteristics of subgrade soil, not only solving the waste disposal problem.

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Efficiency Evaluation of Strategies for Dynamic Management of Wireless Sensor Networks

This paper presents and evaluates dynamic management strategies to improve efficiency in event-triggered wireless sensor networks. We are considering mobility, where nodes move themselves to maximize the coverage, and load balancing state-of-the-art techniques, by which the number of nodes sensing the same area is reduced. To explore mobility, we present a simple method by which nodes can dynamically reorganize themselves based on the force fields approach of mobile robotics. Firstly, the strategies are evaluated separately through experiments with different network configurations and, afterwards, a joint evaluation has been conducted to observe the impact of mobility on the efficiency of load balancing techniques. We show that mobile nodes significantly contribute to keeping the coverage as nodes die in mesh and powerfully improving it in random deployments. Load balancing techniques achieve important results, increasing lifetime and the number of sensed events. However, in random deployments, these techniques lose efficiency and become unsuitable strategies. Combining these strategies with mobility, we observe that PS-based technique keeps its contribution in mesh and random deployments, as well as improving its performance for not so dense networks. Ant-based technique when combined with mobile nodes loses performance significantly in mesh and keeps its good performance in random deployed and less dense networks.

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Comparative RNA-Sequence Transcriptome Analysis of Phenolic Acid Metabolism in Salvia miltiorrhiza, a Traditional Chinese Medicine Model Plant

Salvia miltiorrhiza Bunge is an important traditional Chinese medicine (TCM). In this study, two S. miltiorrhiza genotypes (BH18 and ZH23) with different phenolic acid concentrations were used for de novo RNA sequencing (RNA-seq). A total of 170,787 transcripts and 56,216 unigenes were obtained. There were 670 differentially expressed genes (DEGs) identified between BH18 and ZH23, 250 of which were upregulated in ZH23, with genes involved in the phenylpropanoid biosynthesis pathway being the most upregulated genes. Nine genes involved in the lignin biosynthesis pathway were upregulated in BH18 and thus result in higher lignin content in BH18. However, expression profiles of most genes involved in the core common upstream phenylpropanoid biosynthesis pathway were higher in ZH23 than that in BH18. These results indicated that genes involved in the core common upstream phenylpropanoid biosynthesis pathway might play an important role in downstream secondary metabolism and demonstrated that lignin biosynthesis was a putative partially competing pathway with phenolic acid biosynthesis. The results of this study expanded our understanding of the regulation of phenolic acid biosynthesis in S. miltiorrhiza.

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Ciprofloxacin Controlled-Solid Lipid Nanoparticles: Characterization, In Vitro Release, and Antibacterial Activity Assessment

The objective of this research was to formulate ciprofloxacin (CIP) in solid lipid nanoparticles (SLNs) in an attempt to develop a controlled drug delivery system. An ultrasonic melt-emulsification method was used for preparing CIP-loaded SLNs. Key findings included that SLNs were successfully produced with average particle sizes ranging from 165 to 320 nm and polydispersity index in the range of 0.18–0.33. High entrapment efficiency values were reported in all formulations. The atomic force scanning microscopic images showed spherical shape with the size range closer to those found by the particle size analyzer. CIP release exhibited controlled-release behavior with various lipids. Ciprofloxacin solid lipid nanoparticles formula containing stearic acid (CIPSTE) displayed the strongest burst effect and the most rapid release rate. The release data revealed a better fit to the Higuchi diffusion model. After storing the CIPSTE formula at room temperature for 120 days, no significant difference in particle size and zeta potential was found. CIP-loaded SLNs exhibited superior antibacterial activity. Incorporation of CIP into SLNs leads to controlled release and a superior antibacterial effect of CIP.

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Morinda citrifolia (Noni) Fruit Juice Reduces Inflammatory Cytokines Expression and Contributes to the Maintenance of Intestinal Mucosal Integrity in DSS Experimental Colitis

Morinda citrifolia L. (noni) has been shown to treat different disorders. However, data concerning its role in the treatment of intestinal inflammation still require clarification. In the current study, we investigated the effects of noni fruit juice (NFJ) in the treatment of C57BL/6 mice, which were continuously exposed to dextran sulfate sodium (DSS) for 9 consecutive days. NFJ consumption had no impact on the reduction of the clinical signs of the disease or on weight loss. Nonetheless, when a dilution of 1 : 10 was used, the intestinal architecture of the mice was preserved, accompanied by a reduction in the inflammatory infiltrate. Regardless of the concentration of NFJ, a decrease in both the activity of myeloperoxidase and the key inflammatory cytokines, TNF-α and IFN-γ, was also observed in the intestine. Furthermore, when NFJ was diluted 1 : 10 and 1 : 100, a reduction in the production of nitric oxide and IL-17 was detected in gut homogenates. Overall, the treatment with NFJ was effective in different aspects associated with disease progression and worsening. These results may point to noni fruit as an important source of anti-inflammatory molecules with a great potential to inhibit the progression of inflammatory diseases, such as inflammatory bowel disease.

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Acute Acalculous Cholecystitis: A Rare Presentation of Primary Epstein-Barr Virus Infection in Adults—Case Report and Review of the Literature

Primary Epstein-Barr virus (EBV) infection is almost always a self-limited disease characterized by sore throat, fever, and lymphadenopathy. Hepatic involvement is usually characterized by mild elevations of aminotransferases and resolves spontaneously. Although isolated gallbladder wall thickness has been reported in these patients, acute acalculous cholecystitis is an atypical presentation of primary EBV infection. We presented a young women admitted with a 10-day history of fever, nausea, malaise who had jaundice and right upper quadrant tenderness on the physical examination. Based on diagnostic laboratory tests and abdominal ultrasonographic findings, cholestasis and acute acalculous cholecystitis were diagnosed. Serology performed for EBV revealed the acute EBV infection. Symptoms and clinical course gradually improved with the conservative therapy, and at the 1-month follow-up laboratory findings were normal. We reviewed 16 adult cases with EBV-associated AAC in the literature. Classic symptoms of EBV infection were not predominant and all cases experienced gastrointestinal symptoms. Only one patient underwent surgery and all other patients recovered with conservative therapy. The development of AAC should be kept in mind in patients with cholestatic hepatitis due to EBV infection to avoid unnecessary surgical therapy and overuse of antibiotics.

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Assessment of School Readiness in Chronic Cholestatic Liver Disease: A Pilot Study Examining Children with and without Liver Transplantation

Background. Assessment of school readiness evaluates physical, social-emotional, and neuropsychological domains essential for educational success. Cognitive testing of preschool aged children with chronic liver disease may guide more timely interventions and focused efforts by health care providers. Patients and Methods. Children with chronic cholestatic liver disease diagnosed as an infant and still with their native liver (NL) and children who received a liver transplant (LT) before age of 2 years underwent testing with a battery of well-validated pediatric psychometric measures. Results. Eighteen (13 LT, 5 NL) patients (median age of 4.45 and 4.05 years, resp.) were tested. Median Full-Scale IQ was 98 (range 102–116) for LT and 116 [(range 90–106), , NS] for NL subjects. LT recipients had significantly greater visual based difficulties, poorer caregiver rated daily living skills (), and higher levels of executive function based difficulties (e.g., inattention, inhibition). Conclusion. This pilot study highlights the risk of neuropsychological difficulties in early school age children who were under 2 years of age at time of LT. Comprehensive early school age assessment should integrate psychometric measures to identify children at greatest risk, thus allowing for proactive educational intervention.

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Intelligibility Evaluation of Pathological Speech through Multigranularity Feature Extraction and Optimization

Pathological speech usually refers to speech distortion resulting from illness or other biological insults. The assessment of pathological speech plays an important role in assisting the experts, while automatic evaluation of speech intelligibility is difficult because it is usually nonstationary and mutational. In this paper, we carry out an independent innovation of feature extraction and reduction, and we describe a multigranularity combined feature scheme which is optimized by the hierarchical visual method. A novel method of generating feature set based on -transform and chaotic analysis is proposed. There are BAFS (430, basic acoustics feature), local spectral characteristics MSCC (84, Mel -transform cepstrum coefficients), and chaotic features (). Finally, radar chart and -score are proposed to optimize the features by the hierarchical visual fusion. The feature set could be optimized from 526 to 96 dimensions based on NKI-CCRT corpus and 104 dimensions based on SVD corpus. The experimental results denote that new features by support vector machine (SVM) have the best performance, with a recognition rate of 84.4% on NKI-CCRT corpus and 78.7% on SVD corpus. The proposed method is thus approved to be effective and reliable for pathological speech intelligibility evaluation.

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Role of Helicobacter pylori Eradication Therapy on Platelet Recovery in Chronic Immune Thrombocytopenic Purpura

Background. Idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder in which the immune system destroys native platelets. In this condition an autoantibody is generated against a platelet antigen. ITP affects women more often than men and is more common in children than adults. Objective. To assess the effect of Helicobacter pylori eradication therapy (HPET) on platelet count in Helicobacter pylori associated chronic immune thrombocytopenic purpura (chronic ITP) in adult. Materials and Methods. It is an interventional prospective study conducted at Liaquat University of Medical and Health Sciences, Jamshoro, from 2014 to 2015. A set of 85 patients diagnosed with chronic ITP were included in the study via convenient sampling. Patients with platelets count 3 months were selected. They were posed to first-line investigations which comprised complete blood count (CBC) and peripheral blood smear examination followed by second-line tests including bone marrow examination and Helicobacter pylori stool specific antigen (HpSA-EIA). Standard H. pylori eradication therapy was offered and the patients were assessed at regular intervals for 6 months. Results. Of the 85 study patients, 32 (37.6%) were male and 53 (62.3%) were female. Mean ages of H. pylori positive and negative subjects were 43.89 ± 7.06 and 44.75 ± 7.91 years, respectively. Bone marrow examination confirmed the diagnosis and excluded other related BM disorders. H. pylori stool antigen (HpSA) was detected in 34 (40%) patients and hence regarded as H. pylori positive; the rest were negative. Treatment with eradication therapy significantly improved the mean platelet counts from × 109/l to × 109/l. Conclusion. We concluded that the anti-H. pylori eradication therapy improves blood platelet counts in chronic immune thrombocytopenia.

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Does MMP-9 Gene Polymorphism Play a Role in Pituitary Adenoma Development?

Purpose. To determine if the MMP-9 genotype has an influence on development of pituitary adenoma (PA). Methodology. The study enrolled patients with PA and healthy controls (reference group). The genotyping of MMP-9 was carried out using the real-time polymerase chain reaction method. Results. Our data demonstrated that the MMP-9 (–1562) C/C genotype was more frequent in PA group than in healthy controls (81.4% versus 64.6%, ); C/C genotype was more frequently present in PA females compared to healthy control females, 81.5% versus 64.6%, , as well. MMP-9 (–1562) C/C genotype was frequently observed for all subgroups: noninvasive and invasive, nonrecurrence, and inactive PA compared to healthy controls: 81.8% versus 64.6%, ; 81.0% versus 64.6%, ; 81.8% versus 64.6%, ; 100.0% versus 64.6%, , respectively. MMP-9 (–1562) C/C genotype was more frequent in inactive PA compared to active PA: 100.0% versus 71.4%; . Conclusion. MMP-9 (–1562) C/C genotype plays a role in nonrecurrence, inactive, and invasive as well as in nonivasive PA development.

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Statistical Downscaling and Projection of Future Air Temperature Changes in Yunnan Province, China

The SDSM was employed for downscaling of daily mean temperature of 32 meteorological stations (1954–2014) and future scenarios were generated up to 2100. The data were daily NCEP/NCAR reanalysis data and the daily mean climate model outputs for the RCP2.6, RCP4.5, and RCP8.5 scenarios from the MRI of Japan. Periodic features were obtained by wavelet analysis. The results showed the following. () The pattern of change and the numerical values of the air temperature could be reasonably simulated, with the average between observed and generated data being 0.963 for calibration and 0.964 for validation. () All scenarios projected increases of different degrees of temperature in all seasons, except for spring in the 2020s. Annually, the most remarkable changes in the 2020s, 2050s, and 2080s were 0.27, 1.00, and 1.84°C, respectively. Seven dominant periods appeared under RCP4.5 and RCP8.5 from 1954 to 2100; however, an additional period appeared under RCP2.6. () In future periods, especially the 2020s, decreases in temperature were significantly located in the center of Yunnan under all three scenarios, whereas there were distinct increases in northwest and southeast Yunnan in most future periods. Besides, the RCP8.5 scenario showed the greatest increase in the 2080s.

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The Hyperlipidemia Caused by Overuse of Glucocorticoid after Liver Transplantation and the Immune Adjustment Strategy

The overuse of glucocorticoid may cause the metabolic disorders affecting the long term outcome of liver transplantation. This study aims to investigate the immune adjustment strategy by decreasing use of glucocorticoid after liver transplantation. The follow-up study was carried out on liver function and lipid metabolism. This study included adult recipients of liver transplantation. There were 3 groups according to their use of glucocorticoid: long term (>3 months, ), short term (

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Acute Feasibility of Neuromuscular Electrical Stimulation in Severely Obese Patients with Obstructive Sleep Apnea Syndrome: A Pilot Study

Objective. Obesity and obstructive sleep apnea (OSA) are closely interconnected conditions both leading to high cardiovascular risk. Inactivity is frequent and physical activity programs remain difficult in these patients. We investigated the acute feasibility of two neuromuscular electrical stimulation (NMES) modalities in extremely inactive obese patients with OSA. Design. A randomized cross-over study, with two experimental sessions (one per condition: multipath NMES versus conventional NMES). Setting. Outpatient research hospital. Subjects. Twelve patients with obesity, already treated for OSA. Interventions. No intervention. Measures. Feasibility outcomes included NMES current intensity, knee extension force evoked by NMES, and self-reported discomfort. Results. We found higher current intensity, a trend to significantly higher evoked force and lower discomfort during multipath NMES versus conventional NMES, suggesting better tolerance to the former NMES modality. However, patients were rapidly limited in the potential of increasing current intensity of multipath NMES. Conclusion. Both NMES modalities were feasible and relatively well tolerated by obese patients with OSA, even if multipath NMES showed a better muscle response/discomfort ratio than conventional NMES. There is an urgent need for a proof-of-concept study and interventional randomized controlled trials comparing NMES therapy versus current care to justify its utilization in obese and apneic patients with low physical activity levels.

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Transient Free Convective MHD Flow Past an Exponentially Accelerated Vertical Porous Plate with Variable Temperature through a Porous Medium

This paper is concerned with analytical solution of one-dimensional unsteady laminar boundary layer MHD flow of a viscous incompressible fluid past an exponentially accelerated infinite vertical plate in presence of transverse magnetic field. The vertical plate and the medium of flow are considered to be porous. The fluid is assumed to be optically thin and the magnetic Reynolds number is considered small enough to neglect the induced hydromagnetic effects. The governing boundary layer equations are first converted to dimensionless form and then solved by Laplace transform technique. Numerical values of transient velocity, temperature, skin friction, and Nusselt number are illustrated and are presented in graphs for various sets of physical parametric values, namely, Grashof number, accelerating parameter, suction parameter, permeability parameter, radiation parameter, magnetic parameter, and time. It is found that the velocity decreases with increases of the suction parameter for both cases of cooling and heating of the porous plate whereas skin friction increases with increase of suction parameter.

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