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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
This study aimed to evaluate the effect of natural antioxidants in pork liver pâté manufactured with the combination of pork backfat, fish oil and olive oil. Phenolic composition of beer residue extract (BRE), chestnut leaves extract (CLE) and peanut skin extract (PSE) were identified and quantified. Four batches of pork liver pâté were produced: control, BRE, CLE and PSE. Pork liver pâté was evaluated for proximate composition, pH, instrumental colour, free fatty acid content, lipid-derived volatile compounds and lipid oxidation. The major compounds of BRE were benzoic acid and catechin (1.79 and 1.51 mg/L, respectively), in CLE were ellagic and gallic acid (10.26 and 2.70 mg/100 g fresh weight) and in PSE was catechin (20.66 mg/100 g dry weight). Proximate composition was similar for all batches. The pH values were not influenced by any natural antioxidant. Colour parameters were affected by storage time but slight differences were observed among batches. Lipid stability (TBARS and lipid-derived volatile compounds) was not remarkably affected by addition of natural extracts.
The aims of this study were to examine the hypothesis that users of anabolic androgenic steroids (AAS) would have cardiac autonomic disorders and that there is a correlation between sympathetic modulation, high blood pressure (BP) and alterations to cardiac dimensions.
Forty-five male subjects were enrolled in the study. They were categorized into three groups comprising bodybuilders actively using AAS (AAS users; n = 15), bodybuilders who had never used AAS (nonusers; n = 15) and age-paired healthy sedentary controls (n = 15). Hemodynamic parameters, linear and nonlinear analyses of heart rate variability and electrocardiography and echocardiography analyses were performed at rest.
Bodybuilders in the AAS group had a higher mean BP than those in the ASS nonuser group (p < 0.05) and the sedentary controls (p < 0.001). Cardiac sympathetic modulation was higher in AAS users than in AAS nonusers (p < 0.05) and the sedentary controls (p < 0.001), and parasympathetic modulation was lower in AAS users than in nonusers and the sedentary controls (p < 0.05). Shannon entropy was lower in AAS users than in the sedentary (p < 0.05) controls, and the corrected QT interval and QT dispersion were higher in AAS users than in the sedentary controls (p < 0.05). The interventricular septal thickness, left ventricle posterior wall thickness and relative diastolic wall thickness were higher in AAS users than in AAS nonusers and the sedentary controls (p < 0.001). AAS users showed a positive correlation between increased sympathetic modulation and high BP (r = 0.48, p < 0.005), as well as sympathetic modulation and cardiac hypertrophy (r = 0.66, p < 0.001).
There was a marked cardiac autonomic alteration in AAS users, with a shift toward sympathetic modulation predominance and vagal attenuation. The high BP observed in our group of bodybuilders using AAS was associated with increased sympathetic modulation, and this increased sympathetic modulation was associated with structural alterations in the heart. This association may constitute an important mechanism linking AAS abuse to increased cardiovascular risk.
Background/Aims: Rhabdomyosarcoma, the most common pediatric soft tissue sarcoma, may show an intrinsic refractoriness to standard ...
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This study aimed to investigate the possible mechanisms of environmental metal pollutant lead (Pb)-induced apoptosis in chicken. Forty 8-day-old healthy chickens were randomly assigned to two groups (n = 20/group) after raising standard commercial diet and drinking water for 1 week: including control group and Pb group ((CH3COO)2Pb 350 mg/L of drinking water); the chickens were given euthanasia and collected livers at 90 days. A significant increase of apoptosis rate were found in Pb group and Pb induced obvious ultrastructural changes of chicken liver. The mRNA levels of glycometabolism key enzymes were significantly lower in Pb group than those in controls. Higher levels of malondialdehyde (MDA) and nitric oxide (NO) were observed in Pb group; the activities of antioxidant enzymes and ATPases were significantly lower in Pb group than those in controls, while the inducible nitric oxide synthase (iNOS) activity was on the contrary. The mRNA and protein levels of pro-apoptotic genes were all lower in Pb group than those in controls. Altogether, Pb-induced mitochondrial swelling and nuclear chromatin condensation, oxidative stress, energy metabolism disorder, thereby lead to apoptosis via mitochondrial pathway in chicken liver, suggesting that Pb-induced mitochondrial pathway apoptosis plays an important role in the mechanisms of Pb cytotoxicity to chicken liver.
Dr. Myrna Pearce graduated from the University of British Columbia's dentistry program in 1985, but she had by no means completed her education as a general dentist. Just nine months after graduating, she took a practice management course for one and a half years, which cost a month's gross salary.
Twenty four studies were included in this review of caries status in children with cleft lip and palate. The findings suggest that caries experience in higher in children with cleft lip and palate in both primary and permanent dentition
The post Cleft lip and palate patients have higher caries experience appeared first on National Elf Service.
Introduction
Eighty per cent of contraceptive care occurs in the general practice setting. UK Medical Eligibility Criteria provides clear guidelines for the safe provision of appropriate contraception. The Faculty of Sexual and Reproductive Health and the National Institute for Health and Care Excellence offer further recommendations for initiation and continuation of the combined contraceptive pill/oral contraceptives.
Method and analysisUsing the Egton Medical Information Systems database of an inner city, average size general practice we performed a retrospective analysis of combined contraceptive pill/oral contraceptives consultations to identify areas of substandard prescribing. Through three subsequent improvement cycles we demonstrated that the safety of combined contraceptive pill/oral contraceptives prescribing could be enhanced by consistent application of UK Medical Eligibility Criteria. By encouraging general practitioners to promote safe sex and use local long-acting reversible contraception options we were able to enhance the quality of consultations as dictated by national guidelines. Regular education and use of an amended EMIS template (to include UK Medical Eligibility Criteria) enabled us to improve both the safety and quality of community-combined contraceptive pill/oral contraceptives prescribing in a sustainable fashion.
Background Cardiac rhythm devices (CRD) require complex management to identify potential device or patient issues. While easy to obtain, report processing is complex and time consuming. In our population, a majority of reports were performed outside of institutional protocols and no method for electrophysiology (EP) notification for unscheduled reports existed. These process breakdowns led to potential issues with safety and associated loss of work efficiency.
Objective Our aim was to decrease the percentage of reports without EP notification from 30% to 10% over a 9-month time period.
Methods We created a detailed process map of in-office and home device reporting. Failure mode and effects analysis (FMEA)/Pareto charts were used to determine the mechanistic underpinnings of notification failures and identify areas for process improvement. Multiple interventions were implemented using the Plan-Do-Study-Act (PDSA) technique. Process run charts and control charts were used to evaluate ongoing changes.
Results Our FMEA identified failures related to (1) lack of physician understanding of the device reporting system, (2) lack of an easy to use method of EP notification and (3) lack of patient understanding of report notification. Pareto charts identified the most frequent failures to be associated with specific cardiology subspecialties as well as reports sent from home. We performed multiple interventions including(1) creation of an easy to use method of EP notification used by patients and medical staff, (2) physician education and (3) patient education. Compared with baseline reporting, there was a decrease from 30% to <10% of device reports obtained without EP notification. This process improvement additionally resulted in a 34% reduction in time required for device processing.
Conclusions Development of a unified EP reporting system and quality improvement methodology resulted in improved CRD report notification and improved efficiency for staff. These process changes resulted in improvement across differing cardiac subspecialty providers and patients.
Objectives
Acute kidney injury (AKI) is common in hospitalised patients, often mandates changes to regular medications and can be unresolved at hospital discharge. General practitioners (GPs) require apposite AKI-related information in electronic discharge letters (EDLs). In 2015 NHS England introduced a care quality standard that all EDLs should include four items of information for patients with AKI. We performed a 12-month quality improvement project (QIP) aimed at achieving above 90% compliance with the quality standard.
MethodsHospital-wide episodes of AKI were detected using the nationally approved electronic AKI alerts system. 25 patient AKI episodes were audited per month for 12 months using the electronic patient record. The target compliance rate was staggered at 35%, 65% and 90% for each subsequent 3-month block. Baseline compliance was 22%. Measures taken to improve compliance included email information, grand rounds, ward-level meetings, computer screensavers, nurse support, clinical governance meetings, and face-to-face rapid education. Annotation of AKI within the computer EDL system was progressively enhanced such that in the final quarter the presence of an AKI-alert mandated the user to complete the AKI annotation before the EDL could be signed off.
ResultsThe completion rate improved to 37% in the second quarter, 51% in the third quarter and 92% in the fourth quarter. This change has been sustained in the 14 months since.
ConclusionsBy the end of the study, omissions relating to AKI information were reduced from 78% to less than 10%, indicating our QIP was highly effective—meeting the quality standard. The single most important factor in improving documentation was to mandate user review of AKI aftercare in patients with electronic AKI alerts. Our study encompassed hospital-wide inpatients, and our results could be replicated at other acute hospitals that have implemented an EDL system connected to an AKI alert system.
Multiple-pulse NMR experiments are a powerful tool for the investigation of molecules with coupled nuclear spins. The product operator formalism provides a way to understand the quantum evolution of an ensemble of weakly coupled spins in such experiments using some of the more intuitive concepts of classical physics and semi-classical vector representations. In this paper I present a new way in which to interpret the quantum evolution of an ensemble of spins. I recast the quantum problem in terms of mixtures of pure states of two spins whose expectation values evolve identically to those of classical moments. Pictorial representations of these classically evolving states provide a way to calculate the time evolution of ensembles of weakly coupled spins without the full machinery of quantum mechanics, offering insight to anyone who understands precession of magnetic moments in magnetic fields.
(Source: International Journal of Oral and Maxillofacial Surgery)
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In this work, an attempt is made to study the effect of mass on convective heat transfer coefficient (CHTC) for open sun drying (OSD) of groundnut (Arachis hypogaea L.). Experiments were conducted during the month of May, 2016 in the climatic condition of Rohtak, India (28°54′0″N 76°34′0″E). Groundnut samples of 130 and 198 g were dried under OSD condition till almost no variation in its mass was recorded. Hourly data of the mass evaporated, groundnut temperature, relative humidity and ambient temperature were recorded. The experimental data obtained were used to determine the constants 'C' and 'n' in the Nusselt number expression using linear regression method. CHTC increased with the increase in mass of groundnuts. The experimental errors in terms of percent uncertainty were found to vary from 44.29 to 48.77%.
The objective of this 3-year split-mouth randomized controlled clinical study was to compare narrow-diameter implants (NDIs) to regular-diameter implants (RDIs) in the posterior region of the jaws (premolars and molars) in regards to (i) the marginal bone level (MBL) and (ii) implant and prosthesis survival and success rates.
A total of 22 patients were included in the study. Each patient received at least one implant of each diameter (Ø3.3 and Ø4.1 mm), placed either in the maxilla or mandible to support single crowns. A total 44 implants (22 NDIs and 22 RDIs) were placed and included in the study. Twenty-one implants were placed in the premolar, whereas 23 were placed in molar areas. Radiographic evaluations to access the MBL were performed immediately after implant placement, 1 and 3 years after implant loading. Peri-implant clinical variables including probing pocket depth (PPD) and bleeding on probing (BoP) were obtained after crown delivery, 1 and 3 years after loading. Furthermore, the survival and success rates of the implants and prosthesis were also evaluated.
Twenty patients were able to complete the study. There was no statistically significant difference regarding MBL between groups at implant placement (p = .084), 1-year (p = .794) and 3-year (p = .598) time intervals. The mean peri-implant bone loss at 3-year follow-up was −0.58 ± 0.39 mm (95% CI: −0.751 to −0.409) and −0.53 ± 0.46 mm (95% CI: −0.731 to −0.329) for NDIs and RDIs, respectively. BoP was present at 15% and 10% of NDIs and RDIs, respectively, at 3-year follow-up. PPD >5 mm was observed in 5% and 0% of the implants of NDIs and RDIs, respectively, at 3-year follow-up. At the 3-year examination, the implant success rates were in the NDIs and RDIs sites, respectively, 95% and 100%. The corresponding values for prosthesis success rates were 90% for NDIs and 95% for RDIs.
The present study demonstrated that NDIs placed to support single crowns in the posterior region did not differ to RDIs in regards to MBL, implant survival, and success rates.
Eruptive xanthomas are benign skin lesions caused by localised deposition of lipids in the dermis. Xanthomas can present as early manifestations of systemic disorders, which are typically caused by elevated levels of serum triglycerides and uncontrolled diabetes. Early recognition and treatment of the underlying condition decreases morbidity and mortality. After treatment of the underlying metabolic disorders, lesions mostly disappear without leaving scars. We present a case with multiple yellowish, erythematous papules on the extremities suggestive of eruptive xanthomas admitted to our hospital with acute pancreatitis.
Glioblastoma (GBM) is characterized by the presence of hypoxia, stemness and local invasiveness. We have earlier demonstrated that FAT1 promotes invasiveness, inflammation and upregulates HIF-1α expression and its signalling in hypoxic GBM. Here, we have identified the role of FAT1 in regulating EMT (Epithelial-Mesenchymal Transition) and stemness characteristics in GBM. The expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/VEGF/PGK1/CA9) was upregulated in ≥39% of GBM tumors (n=31) with significant positive correlation (p≤0.05) of the expression of FAT1 with LOX/Vimentin/SOX2/HIF-1α/PGK1/VEGF/CA9. Furthermore, positive correlation (p≤0.01) of FAT1 with Vimentin/N-cad/SOX2/REST/HIF-1α has been observed in TCGA GBM-dataset (n=430). Analysis of cells (U87MG/A172) exposed to severe hypoxia (0.2%O2) revealed elevated mRNA expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/PGK1/VEGF/CA9) as compared to their normoxic (20%O2) counterparts. FAT1 knockdown in U87MG/A172 maintained in severe hypoxia and in normoxic primary glioma cultures led to significant reduction of EMT/stemness markers as compared to controls. HIF-1α knockdown in U87MG cells markedly reduced the expression of all the EMT/stemness markers studied except for nestin and SOX2 which were more under the influence of FAT1. This indicates FAT1 has a novel regulatory effect on EMT/stemness markers both via or independent of HIF-1α. The functional relevance of our study was corroborated by significant reduction in the number of soft-agar colonies formed in hypoxic-siFAT1 treated U87MG cells. Hence, this study for the first time reveals FAT1 as a novel regulator of EMT/stemness in hypoxic GBM and suggests FAT1 as a potential therapeutic candidate. This article is protected by copyright. All rights reserved.
Publication date: Available online 10 October 2017
Source:Translational Research
Author(s): Francisco J. Gonzalez-Gonzalez, Navdeep Chandel, Manu Jain, GR Scott Budinger
Pulmonary fibrosis is a relatively rare but devastating disease characterized by the excessive deposition of extracellular matrix. The increased matrix results in reduced lung compliance and increased work of breathing, while the obliteration of alveolar-capillary structures can result in hypoxemia and pulmonary hypertension, which manifests clinically as worsening shortness of breath, respiratory failure and death. Unbiased genome wide association studies combined with animal models suggest that damage to the alveolar epithelium is the initiating factor in pulmonary fibrosis. This epithelial injury leads to the activation and proliferation of myofibroblasts that secrete extracellular matrix proteins characteristic of fibrosis. The best described molecular link between alveolar epithelial dysfunction and myofibroblast activation and proliferation is the profibrotic cytokine transforming growth factor-β (TGF-β). We and others have found that mitochondrial and NADPH oxidase-generated reactive oxygen species (ROS) play a signaling role to enhance TGF-β signaling and promote fibrosis. This purpose of this review is to review ROS signaling downstream of the activation of TGF-β. We suggest that an improved understanding of these pathways might explain the failure of nonselective antioxidants to improve outcomes in patients with pulmonary fibrosis and might identify novel targets for therapy.
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Publication date: Available online 9 October 2017
Source:Journal of Biomechanics
Author(s): Amir Mohammadipour, Alireza Alemi
Computational models are important tools which help researchers understand traumatic brain injury. A mechanistic multi-scale numerical approach is introduced to quantify diffuse axonal injury (DAI), the most important mechanism of TBI, induced by a mechanical insult at micro-scale regions of the white matter or voxels where fiber orientations are the same. Using the mechanical properties of a single axon with a viscoelastic constitutive relation and its functional failure in terms of electrophysiological impairment, a numerical 2D micro-level lattice method is implemented to directly analyze the percentage of injured axons in a voxel containing a bundle of axons all with the same orientation under biaxial stretches. Reference micro-injury maps are then developed with the input parameters based on the principal strain or stretch values and their direction with respect to axons, which provide the percentage of injured axons in the voxel of interest as the output. The methodology is independent of any statistical analyses of the accident data and medical reports to derive probabilistic injury risk curves for DAI. Avoiding a structurally detailed full finite element head model, this study proposes a micro-mechanical approach which considers the anatomical structure of neural axons in the white matter together with their mechanical properties using a numerical lattice method to analyze the brain's diffuse axonal injury. This work has the potential to help develop safer prevention tools and more effective diagnosis methods for DAI.
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Publication date: Available online 9 October 2017
Source:Journal of Biomechanics
Author(s): S. Sahmani, M.M. Aghdam
The unique geometry with high surface ratio makes lipid micro/nano-tubules as an excellent self-assembled supramolecular structure in various biological applications such as controllable release systems and drug delivery. In the present study, the size-dependent nonlinear vibrations of axially loaded lipid micro/nano tubules associated with the both prebuckling and postbuckling domains are explored comprehensively. To accomplish this purpose, the nonlocal strain gradient theory of elasticity including simultaneously two entirely different features of size dependency is utilized within the framework of the third-order shear deformable beam model. With the aid of Hamilton's principle, the non-classical governing differential equations of motion are established incorporating the nonlinear prebuckling deformations and the large postbuckling deflections. At the end, the Galerkin method in conjunction with an improved perturbation technique is employed to initiate explicit analytical expressions for nonlocal strain gradient nonlinear frequency of pre- and post-buckled lipid micro/nano-tubules. It is seen that by taking the nonlocal size effect into consideration, the influence of geometrical parameters of the lipid micro/nano-tubule on the nonlinear vibration characteristics within the both prebuckling and postbuckling domains decreases and the frequency-deflection curves are more close to each other. However, the strain gradient size dependency has an opposite effect and leads to increase the gap between the frequency-deflection curves of axially compressed lipid micro/nano-tubules with different geometrical parameters.
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This study explores whether sleep duration is associated with sperm chromatin integrity. To do so, we conducted a three-phase panel study of 796 male volunteers from colleges in Chongqing (China) from 2013 to 2015. Sleep duration was measured using a modified Munich Chronotype Questionnaire. Sperm DNA integrity was examined via Sperm Chromatin Structure Assay and Comet assay. Setting 7–7.5 h day−1 of sleep duration as a reference, either longer or shorter sleep duration was associated negatively with high DNA stainability (HDS) (P = 0.009), which reflected the immaturity of sperm chromatin. The volunteers with > 9.0 h day−1 sleep and those with ≤ 6.5 h day−1 sleep had 40.7 and 30.3% lower HDS than did volunteers with 7–7.5 h day−1 sleep. No association was found between sleep duration and DNA fragmentation index or Comet assay parameters. This study suggests that sleep duration is associated with sperm chromatin integrity. Further studies are required to validate these findings and investigate the mechanism underlying this association.
The aims of this study are to examine how frequently near-term and term small-for-gestational-age (SGA) infants were investigated in our clinical practice, whether being born less than the third centile for weight increased the yield of positive investigations, and whether there were additional characteristics in infants with positive investigations. This retrospective cohort study was compiled using a database of a large maternity network, using the search near term and term gestational age (greater than or equal to 35 weeks) over a span of 4 years. SGA babies were further filtered into less than the tenth centile and third centile. Out of a population of 30,461 infants in the study period, 3437 (11.3%) SGA infants were identified. Four hundred fifteen SGA infants (12.1%) underwent screening investigations, of which 49 infants (11.8%) yielded a positive investigation. 27.2% of karyotypes, 12.8% of cranial ultrasounds and 0.4% of urine CMV tests showed positive results in < 10th centile group. Being born less than the third centile for weight did not increase the yield of positive investigations. Most infants with positive investigations had an additional maternal or neonatal characteristic or risk factor present.
Conclusion: SGA babies without additional maternal or neonatal characteristics have a poor yield on neonatal screening investigations. Additional characteristics may be considered while deciding whether a SGA infant needs screening investigation.
What is Known: |
• Small-for-gestational-age (SGA) infants have an increased risk of short- and long-term complications. • Whilst the causes for SGA are multifactorial, there has been a tendency to undertake screening investigations like Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes group of viruses (TORCH) screening and cranial ultrasounds in the neonatal period. |
What is New: |
• Comprehensive study investigating the rates of screening in near-term and term SGA population. • The yield of screening tests for near-term and term SGA infants without additional antenatal and postnatal characteristics is low. |
In this study, we assessed the effect of bacterial and endogenous enzymes on the proteolysis of smoked horse sausage. Commercial starter culture (Staphylococcus xylosus + Lactobacillus sakei) was used in smoked horse sausage. Cathepsin B + L and cathepsin B activities, microbiological growth, pH, and water activity (aw) were measured. Based on PCR-DGGE fingerprint analyses, the starter culture inhibited endogenous bacterial growth. During ripening, the residual activity of cathepsin B + L and cathepsin B was higher in batch C (control) than in batch S (containing starter cultures). The starter and endogenous enzymes promote the degradation of sarcoplasmic and myofibrillar proteins; however, the degradation of these proteins was higher in batch S than in batch C. Therefore, bacterial enzymes played a major role in the degradation of proteins during the ripening of smoked horse sausage.
Publication date: 28 November 2017
Source:Cancer Letters, Volume 409
Author(s): Duale Ahmed, Edana Cassol
Type I interferons (IFN) are increasingly recognized for their role in regulating anti-tumour immune responses. However, chronic activation of these pathways can result in immunosuppression and has been linked to poor responses to genotoxic and radiotoxic therapies. Emerging evidence suggests energy, lipid and amino acid metabolism play an important role in regulating and fine tuning type I IFN responses. Further, dysregulation of these processes has been implicated in the pathogenesis of chronic viral infections and autoimmune disorders. Systematic evaluation of these interrelationships in cancer models and patients may have important implications for the development of targeted IFN based anti-cancer therapeutics with minimal toxicity and limited off target effects.
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Publication date: 1 December 2017
Source:Cancer Letters, Volume 410
Author(s): Mathewos Tessema, Christin M. Yingling, Maria A. Picchi, Guodong Wu, Tyrone Ryba, Yong Lin, Aaron O. Bungum, Eric S. Edell, Avrum Spira, Steven A. Belinsky
The intragenic tumor-suppressor microRNA miR-486-5p is often down-regulated in non-small cell lung cancer (NSCLC) but the mechanism is unclear. This study investigated epigenetic co-regulation of miR-486-5p and its host gene ANK1. MiR-486-5p expression in lung tumors and cell lines was significantly reduced compared to normal lung (p < 0.001) and is strongly correlated with ANK1 expression. In vitro, siRNA-mediated ANK1 knockdown in NSCLC cells also reduced miR-486-5p while the DNA methylation inhibitor 5-aza-2′-deoxycytidine induced expression of both. ANK1 promoter CpG island was unmethylated in normal lung but methylated in 45% (118/262) lung tumors and 55% (17/31) NSCLC cell lines. After adjustment for tumor histology and smoking, methylation was significantly more prevalent in adenocarcinoma (101/200, 51%) compared to squamous cell carcinoma (17/62, 27%), p < 0.001; HR = 3.513 (CI: 1.818–6.788); and in smokers (73/128, 57%) than never-smokers (28/72, 39%), p = 0.014; HR = 2.086 (CI: 1.157–3.759). These results were independently validated using quantitative methylation data for 809 NSCLC cases from The Cancer Genome Atlas project. Together, our data indicate that aberrant ANK1 methylation is highly prevalent in lung cancer, discriminate tumors by histology and patients' smoking history, and contributes to miR-486-5p repression.
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Publication date: 1 December 2017
Source:Cancer Letters, Volume 410
Author(s): Maria Chiara Anania, Elena Cetti, Daniele Lecis, Katia Todoerti, Alessandro Gulino, Giuseppe Mauro, Tiziana Di Marco, Loredana Cleris, Sonia Pagliardini, Giacomo Manenti, Beatrice Belmonte, Claudio Tripodo, Antonino Neri, Angela Greco
Thyroid carcinoma is generally associated with good prognosis, but no effective treatments are currently available for aggressive forms not cured by standard therapy. To find novel therapeutic targets for this tumor type, we had previously performed a siRNA-based functional screening to identify genes essential for sustaining the oncogenic phenotype of thyroid tumor cells, but not required to the same extent for the viability of normal cells (non-oncogene addiction paradigm). Among those, we found the coatomer protein complex ζ1 (COPZ1) gene, which is involved in intracellular traffic, autophagy and lipid homeostasis. In this paper, we investigated the mechanisms through which COPZ1 depletion leads to thyroid tumor cell death. We showed that siRNA-mediated COPZ1 depletion causes abortive autophagy, endoplasmic reticulum stress, unfolded protein response and apoptosis. Interestingly, we observed that mouse tumor xenografts, locally treated with siRNA targeting COPZ1, showed a significant reduction of tumor growth. On the whole, we demonstrated for the first time the crucial role of COPZ1 in the viability of thyroid tumor cells, suggesting that it may be considered an attractive target for novel therapeutic approaches for thyroid cancer.
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Publication date: 28 November 2017
Source:Cancer Letters, Volume 409
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Preclinical studies using genetically engineered mouse models (GEMM) have the potential to expedite the development of effective new therapies; however, they are not routinely integrated into drug development pipelines. GEMMs may be particularly valuable for investigating treatments for less common cancers, which frequently lack alternative faithful models. Here, we describe a multicenter cooperative group that has successfully leveraged the expertise and resources from philanthropic foundations, academia, and industry to advance therapeutic discovery and translation using GEMMs as a preclinical platform. This effort, known as the Neurofibromatosis Preclinical Consortium (NFPC), was established to accelerate new treatments for tumors associated with neurofibromatosis type 1 (NF1). At its inception, there were no effective treatments for NF1 and few promising approaches on the horizon. Since 2008, participating laboratories have conducted 95 preclinical trials of 38 drugs or combinations through collaborations with 18 pharmaceutical companies. Importantly, these studies have identified 13 therapeutic targets, which have inspired 16 clinical trials. This review outlines the opportunities and challenges of building this type of consortium and highlights how it can accelerate clinical translation. We believe that this strategy of foundation–academic–industry partnering is generally applicable to many diseases and has the potential to markedly improve the success of therapeutic development. Cancer Res; 1–6. ©2017 AACR.
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Medical imaging is essential to screening, early diagnosis, and monitoring responses to cancer treatments and, when used with other diagnostics, provides guidance for clinicians in choosing the most effective patient management plan that maximizes survivorship and quality of life. At a gathering of agency officials, patient advocacy organizations, industry/professional stakeholder groups, and clinical/basic science academicians, recommendations were made on why and how one should build a "cancer knowledge network" that includes imaging. Steps to accelerate the translation and clinical adoption of cancer discoveries to meet the goals of the Cancer Moonshot include harnessing computational power and architectures, developing data sharing policies, and standardizing medical imaging and in vitro diagnostics. Cancer Res; 1–4. ©2017 AACR.
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Ligation of PD-1 in the tumor microenvironment is known to inhibit effective adaptive anti-tumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow-derived DC with IL-10 led to increased PD-1 expression. Both groups of DC also responded to PD-1 blockade by increasing production of IL-10. Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody resulted in an increase in IL-10 levels in both serum and ascites. While PD-1 blockade or IL-10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented anti-tumor T and B cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL-10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti-PD-1 (or anti-PD-L1) monotherapies and prompts further studies aimed at identifying such resistance mechanisms.
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The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity, reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV. Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease.
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Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis, and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis-associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance.
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Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and how its growth inhibitory effects are mitigated and uncertain. Here we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3' untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced auto-activating process and a distinct intracellular routing that prevented its extracellular secretion. Together these events led to a dramatic increase in processing of the pro-growth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this pro-enzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer.
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To study the incidence and magnitude of bacteremia after dental extraction and supragingival scaling.
Blood samples were taken before and 5 and 30 minutes after dental extraction and supragingival scaling from individuals at high (n=42) or negligible risk (n=53) for infective endocarditis. The former received prophylactic antibiotic therapy. Samples were subjected to aerobic and anaerobic culture and quantitative real-time polymerase chain reaction to determine the incidence of bacteremia and total bacterial levels.
Patients who did not receive prophylactic antibiotic therapy had a higher incidence of positive blood cultures (26% 5 min after extraction) than patients who received prophylactic antibiotic therapy (0% 5 min after extraction; P=.01). Molecular analysis did not reveal significant differences in the incidence or magnitude of bacteremia between the two patient groups either 5 or 30 minutes after each of the procedures evaluated. Extraction was associated with higher incidence of bacteremia than supragengival scaling by molecular analysis (P=.05).
Molecular methods revealed that dental extraction and supragingival scaling were associated with similar incidence of bacteremia in groups receiving or not prophylactic antibiotic therapy. However, blood culture revealed that antibiotic therapy reduced viable cultivable bacteria in the bloodstream in the extraction group.
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A 35-year-old woman with severe cystic fibrosis was admitted for sudden loss of strength in both legs, revealing a myelitis. The medullar lesion biopsy revealed phaeohyphomycosis caused by Cladophialophora species. Myelitis caused by Cladophialophora bantiana is a rare disease associated with high mortality.
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Cladophialophora bantiana brain abscesses are rare, but are frequently and quickly lethal in transplanted patients. We report the case of a 63-year-old man who had undergone lung transplantation for chronic obstructive pulmonary disease and presented with headaches and a neurological deficit. Magnetic resonance imaging revealed multiple brain abscesses. C. bantiana was identified by DNA sequencing performed directly on cerebral tissue obtained by surgical biopsy. After 6 months of antifungal treatment, the brain abscesses were replaced by ischemic sequelae. The patient died suddenly 2 months later from a pulmonary bacterial infection. This is the second reported case of C. bantiana brain abscesses in a lung transplant recipient, to our knowledge, who experienced a long survival period with medical antifungal treatment alone. We review the literature and discuss our treatment.
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The middle temporal artery flap is a vascularized periosteal flap that is highly useful for otologic reconstruction including the middle cranial fossa, mastoidectomy defect, and external auditory canal. The course of the artery is close to the external auditory canal and is easily injured during preliminary exposure and elevation of flaps.
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The purpose of this study was to describe the role of explorative tympanotomy in patients with Profound Sudden Sensorineural Hearing Loss (SSNHL) without clinical evidence of perilymphatic or labyrinthine fistula and to compare intraoperative findings with the postoperative hearing outcome.
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Nasal Polyposis is a benign tumor in nasal or paranasal mucosa, which confronts difficulties in management of healing after treatments with surgery. The aim of this study was to evaluate the effects of Spray Cryotherapy (SCT) on management of healing in patients with nasal polyposis who undergone functional endoscopic sinus surgery.
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Compare the outcomes of primary exclusive endoscopic ear surgery with those of the microscopic ear surgery in a group of patients affected by attic cholesteatoma.
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The objective of this study was to characterize the delivery of allergy care in North Carolina using a large payer charge database and visualization techniques.
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The middle temporal artery flap is a vascularized periosteal flap that is highly useful for otologic reconstruction including the middle cranial fossa, mastoidectomy defect, and external auditory canal. The course of the artery is close to the external auditory canal and is easily injured during preliminary exposure and elevation of flaps.
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The purpose of this study was to describe the role of explorative tympanotomy in patients with Profound Sudden Sensorineural Hearing Loss (SSNHL) without clinical evidence of perilymphatic or labyrinthine fistula and to compare intraoperative findings with the postoperative hearing outcome.
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Nasal Polyposis is a benign tumor in nasal or paranasal mucosa, which confronts difficulties in management of healing after treatments with surgery. The aim of this study was to evaluate the effects of Spray Cryotherapy (SCT) on management of healing in patients with nasal polyposis who undergone functional endoscopic sinus surgery.
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Compare the outcomes of primary exclusive endoscopic ear surgery with those of the microscopic ear surgery in a group of patients affected by attic cholesteatoma.
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The objective of this study was to characterize the delivery of allergy care in North Carolina using a large payer charge database and visualization techniques.
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Weight discrimination is the unjust treatment of individuals because of their weight. There have been very few interventions to address weight discrimination, due in part to the lack of consensus on key messages and strategies. The objective of the third Canadian Weight Bias Summit was to review current evidence and move towards consensus on key weight bias and obesity discrimination reduction messages and strategies. Using a modified brokered dialogue approach, participants, including researchers, health professionals, policy makers and people living with obesity, reviewed the evidence and moved towards consensus on key messages and strategies for future interventions. Participants agreed to these key messages: (1) Weight bias and obesity discrimination should not be tolerated in education, health care and public policy sectors; (2) obesity should be recognized and treated as a chronic disease in health care and policy sectors; and (3) in the education sector, weight and health need to be decoupled. Consensus on future strategies included (1) creating resources to support policy makers, (2) using personal narratives from people living with obesity to engage audiences and communicate anti-discrimination messages and (3) developing a better clinical definition for obesity. Messages and strategies should be implemented and evaluated using consistent theoretical frameworks and methodologies.
Settled agriculture didn't spawn the first states. Two new books help expose the real drivers, the pressures on marginalised people – and what they can teach us
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Seedlings of durum wheat [Triticum turgidum subsp. durum (Desf.) Husn] were exposed to zinc nutrition and to ozone (O3) in a factorial combination: adequate (+Zn treatment) or no Zn (−Zn) in the nutrient solution, followed by exposure to either ozone-free air (filtered air, FA) or to 150 nL L−1 ozone (O3) for 4 h. Although omitting Zn from the nutrient solution failed to impose a genuine Zn deficiency, −Zn*FA durum wheat seedlings showed a typical deficiency behaviour, i.e. Zn mobilisation from root to shoot. Such inter-organ Zn redistribution, however, did not occur in −Zn*O3 plants. Exposure to each stress singly decreased the activity and the protein amount of foliar plasma membrane H+-ATPase, but not stress combination, which even increased the H+-ATPase expression with respect to control. In the −Zn*O3 plants, moreover, the foliar activities of the plasma membrane-bound NAD(P)H-dependent superoxide synthase and of Cu,Zn-superoxide dismutase, and the transcripts abundance of the luminal binding protein and of the protein disulphide isomerase, were also stimulated. It is proposed that, even in the absence of actual Zn starvation, the perception of deficiency conditions could trigger changes in redox homoeostasis at the plasma membrane level, helpful in compensating an O3-dependent oxidative damage.
Introduction
Tranexamic acid (TXA) administration within the recommended time of 3 hours has been demonstrated to improve outcomes following trauma. The aim of this study was to identify potential knowledge gaps in the administration of TXA in order to target further educational training in those doctors responsible for the management of acute trauma.
Methods104 military and 852 civilian doctors were invited to complete a four-item web-based questionnaire pertaining to the indications, dose, side effects and evidence base for TXA administration in trauma. Doctors of all grades and surgical specialties including emergency trainees and anaesthetics were surveyed.
Results65 military and 460 civilian doctors responded with a response rate of 62% and 54%, respectively. Responses were required for every question to allow progression and submission. 93% of military doctors knew the initial dose of TXA compared with 34% of civilian doctors. The Clinical randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH) 2 trial was known to 91% of military doctors compared with 24% of civilian doctors. The optimal time for delivery of TXA in under 3 hours was correctly identified by 91% of military doctors compared with 10% by civilian doctors.
DiscussionMilitary doctors are more familiar with TXA and its side effect profile. Given the potential impact of TXA on patient outcome and the findings of this study, further education of all doctors is recommended including dose, timing and potential side effects.
Introduction
When a service person has been wounded, injured or sick (WIS), family members may provide care during their recovery in an unpaid capacity. This may occur in diverse environments including hospitals, inpatient rehabilitation centres, in the community and at home.
MethodThirty-seven family members of WIS personnel were interviewed regarding their support needs, family relationships and use of UK support services. Semistructured, in-depth telephone interviews were used, with data analysis undertaken using a thematic approach.
Results'Family member involvement' was the main theme under which four subthemes were situated: 'continuity of support', 'proactive signposting and initiating contact', 'psychoeducation and counselling' and 'higher risk groups'. Family members felt they might benefit from direct, consistent and continuous care regardless of the WIS person's injury or engagement type, and whether the WIS person was being treated in a hospital, rehabilitative centre or at home.
ConclusionThe findings of this study suggest that family members of WIS personnel value proactive, direct and sustained communication from support service providers. We suggest that families of UK service personnel may benefit from family care coordinators, who could provide continuous and consistent care to family members of WIS personnel.
Anti-angiogenesis effect of a prodrug of green tea polyphenol (–)-epigallocatechin-3-gallate (Pro-EGCG) in malignant tumors is not well studied. Here, we investigated how the treatment with Pro-EGCG inhibited tumor angiogenesis in endometrial cancer. Tumor xenografts of human endometrial cancer were established and subjected to microarray analysis after Pro-EGCG treatment. First, we showed Pro-EGCG inhibited tumor angiogenesis in xenograft models through down-regulation of vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF1α) in tumor cells and chemokine (C-X-C motif) ligand 12 (CXCL12) in host stroma by immunohistochemical staining.
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Inhibition of autophagy is a promising strategy for non-small cell lung cancer (NSCLC) treatment, which is in the clinical trials. However, only chloroquine is used in clinic as an autophagic inhibitor and the inhibitory effect of chloroquine on autophagy is finite. Therefore, the development of an alternative autophagic inhibitor for NSCLC therapy becomes necessary. In the present study, cepharanthine (CEP), an alkaloid extracted from Stephania cepharantha Hayata, was identified as a novel autophagic inhibitor in NSCLC cells.
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Here the underlying role of CNOT2, a subunit of CCR4-NOT complex, was elucidated in cancer progression. CNOT2 was overexpressed in HIT-T15, ASPC-1, BXPC-3, PC-3, LNCaP, MCF-7 and MDA-MB-231 cell lines, which was confirmed by Tissue array in various human tumor tissues. Also, CNOT2 depletion suppressed proliferation and colony formation of MDA-MB-231 cells. Of note, microarray revealed decreased expression of CNOT2, VEGF-A, HIF2 alpha (<0.5 fold) and increased expression of UMOD1, LOC727847, MMP4, hCG and other genes (>2.0 fold) in CNOT2 depleted MDA-MB-231 cells compared to untreated control.
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Melanoma antigen A6 (MAGEA6)/TRIM28 complex is a cancer-specific ubiquitin ligase, which degradates tumor suppressor protein AMP-activated protein kinase (AMPK). We show that MAGEA6 is uniquely expressed in human glioma tissues and cells, which is correlated with AMPKα1 downregulation. It is yet absent in normal brain tissues and human astrocytes/neuronal cells. MAGEA6 knockdown by targeted-shRNA in glioma cells restored AMPKα1 expression, causing mTORC1 in-activation and cell death/apoptosis. Reversely, AMPKα1 knockdown or mutation ameliorated glioma cell death by MAGEA6 shRNA.
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Maintaining reductive-oxidative (redox) balance is an essential feature in breast cancer cell survival, with cellular metabolism playing an integral role in maintaining redox balance through its supply of reduced NADPH. In the present studies, the effect of 1,25-dihydroxyvitamin D (1,25(OH)2D) on redox balance was investigated in early stages of breast cancer. Treatment with 1,25(OH)2D promoted oxidative stress in MCF10A-ras and MCF10A-ErbB2 breast epithelial cells, as measured by the decreased ratios of NADPH/NADP+ and reduced to oxidized glutathione (GSH/GSSG).
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There are currently no clinically validated therapeutic targets for biliary tract cancer (BTC). Despite promising results in other cancers, compounds targeting the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, alone or in combination with Ras/Raf/MEK pathway inhibitors, have not been evaluated in BTC. Here, we examined the effects of a pan-PI3K inhibitor (BKM120) with or without a MEK inhibitor (MEK162), on eight human BTC cell lines carrying mutations in K-Ras and/or the PI3K catalytic subunit, PI3KCA.
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Mirroring has been used as a diagnostic tool in orbital wall fractures for many years, but limited research is available proving the assumed symmetry of orbits. The purpose of this study was to evaluate volume and contour differences between orbital cavities in healthy humans.
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The aim of this study was to compare ChronOS™ (beta-tricalcium phosphate), BioOss®, and their addition to autogenous bone graft in a 1:1 ratio in human maxillary sinuses bone augmentation.
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The purpose of the study was to clarify the reasons for, the types and degree of involvement of the orbital wall, and the severity of orbital fractures in geriatric patients and to compare the differences between geriatric and younger adult patients.
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Posterior dislocation of the mandibular condyle is a rare disorder caused by trauma to the chin, accompanied by damage to the external auditory canal. Treatment of posterior condylar dislocation (PCD) is directed at repositioning the condyle into the glenoid fossa, preventing recurrent dislocations, and maintaining patency of the ear canal. With early intervention, closed reduction with manual manipulation is successful but in chronic protracted PCD, this may be ineffective. This case report describes an elderly patient with a chronic protracted PCD resulting from a blow to the chin, and in which manual reduction was unsuccessful.
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Reconstruction remains one of the challenges faced by the reconstructive surgeon. The mandible and the maxilla are multifunctional structures with complex architecture and mechanics, responsible for basic oral functions such as normal mastication, speech, phonation and swallowing, and they cosmetically define the facial thirds. Loss of mandibular or maxillary continuity compromises oral function and aesthetic appearance impacting quality of life. Currently, the free fibula flap is the first choice when it comes to osteocutaneous free flaps used for oromandibular reconstruction both in our center and the literature.
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Head and neck (H&N) cancer is the sixth most common malignancy worldwide, with a reported incidence of 500,000 cases annually (Jemal et al., 2011). Surgical resection with subsequent reconstruction is the cornerstone of H&N cancer treatment. The spectrum of composite tissue defects following oncological resection creates challenging reconstructions. Microvascular free tissue transfer (MFTT) is the gold standard in reconstruction of H&N defects (Urken et al., 1994), and yet not all patients with H&N cancer are suitable candidates.
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Establishment of a consistent bedtime routine is often recommended to families with young children with sleep difficulties. However, there are limited studies assessing specific bedtime routines in the treatment of infant and toddler sleep disturbances. Thus, the purpose of this study was to examine the impact of a massage-based bedtime routine on infant sleep, maternal sleep, and maternal mood. 123 mothers and their 3- to 18-month-old infant were randomly assigned to a routine (1-week baseline of usual bedtime routine, 2-weeks intervention) or control group (3-weeks of their usual bedtime routine).
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/Background: Cataplexy is the pathognomonic symptom of narcolepsy type 1 (NT1). Since it is considered difficult to be directly observed or documented by clinicians, its diagnosis relies mainly on history taking. Our study aimed at testing the feasibility of a standardized video recording procedure under emotional stimulation to document cataplexy in the diagnostic work-up of suspected hypersomnia of central origin.
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Up to 50% of overweight/obese children have obstructive sleep apnea (OSA) compared to up to 6% of normal weight children. We compared cardiovascular variables between normal weight and overweight/obese children with and without OSA, and controls.
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Sleep-related hypermotor epilepsy (SHE) is a rare form of focal epilepsy characterized by repeated episodes of vigorous hyperkinetic limb movements commonly confined to sleep. Seizures are highly stereotyped within patients and usually last less than two minutes.1 Wrist-actigraphy is commonly used to estimate the sleep-waking rhythm.2 Limb accelerometer sensors have been occasionally used for the detection of epileptic events during sleep,3-6 but routine wrist-actigraphy has not been described in SHE.
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Periodic limb movements during sleep (PLMS) are prevalent in the general population, but their impact on sleep and association with cardiometabolic disorders are a matter of debate.
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Insomnia symptoms are highly prevalent among patients with psychiatric disorders and this mandates the need to identify the best self-administered sleep measure to screen for insomnia disorder among them.
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